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Annexins as potential targets in ocular diseases

This review highlights the main findings on the distribution and function of annexins under normal and pathological conditions in the eye. Their potential to act upon inflammatory responses makes them attractive therapeutic candidates for human ocular disease treatment.

Ocular application of Electrospun Materials

onventional ocular drug delivery approaches are prone to low bioavailability, poor penetration and degradation of therapeutics, including cell-based therapies, leading to the need for frequent topical applications or intraocular injections. However, owing to their exceptional structural properties, nanofibrous and microfibrous electrospun materials have gained significant interest in ocular drug delivery and biomaterial applications

Brain-derived neurotrophic factor (BDNF) in perinatal depression: side show or pivotal factor?

Perinatal depression is the most common psychiatric complication of pregnancy. This study reviews the role of BDNF in reproductive biology and its pregnancy-related changes as a surrogate endpoint for translational and clinical studies of depression.

Translating Precision Medicine for Autism Spectrum Disorder: A Pressing Need

High genetic and clinical heterogeneity has rendered existing drug discovery efforts inefficient for patients with neurodevelopmental disorders, highlighting the need for omics- and endophenotyping-based approaches in patient diagnosis and treatment.

Inflammation, stress and depression: an exploration of ketamine’s therapeutic profile

This review investigates the role of inflammation in chronic stress and depression, as well as how the rapid-acting antidepressant ketamine can exert some of its therapeutic effects via anti-inflammatory mechanisms.

Emerging trends in pulmonary delivery of biopharmaceuticals

Pulmonary delivery of biopharmaceuticals is a niche area of the current pharmaceutical market holding immense scope for drug discovery and development. To combat the limitation-driven conventional treatments, pulmonary administration of biopharmaceuticals has navigated remarkable change in targeted drug delivery

Engineering nanoparticle therapeutics for impaired wound healing in diabetes

We focus on emerging nanotherapeutics capable of addressing the pathophysiology of chronic wounds in diabetes to better manage the impaired healing that current clinical treatments fail to address.

Stimuli sensitive drug delivery systems for site specific antibiotic release

This review provides key insights into current challenges and future directions of exogenous and endogenous stimuli-sensitive targeted and on-demand release of therapeutic doses of antibiotics both cost-effectively and safely.

Medicinal Chemistry Strategies for the Discovery of Antivirals Targeting to Influenza Virus PB2 Cap-binding Domain

This review covers the strategies and challenges in the discovery and development of small-molecule inhibitors for the influenza A PB2 cap-binding domain.

Machine Learning to Design Antimicrobial Combinations Promises and Pitfalls

We discuss strategies for applying machine learning methods to identify synergistic drug combinations from millions of candidates using information on the compound, pathogen and disease environment.

Targeting Clostridioides difficile New uses for old drugs

Here, we summarize the recent progress of ‘repurposable’ drugs against Clostridioides difficile and make recommendations for further development of new uses for old drugs for the treatment of C. difficile.

De novo Molecular Design and Generative Models

De novo molecular design methodologies can propose sensible and novel chemical structures. These technologies have a rich history and machine learning now offers the potential to enhance objective molecular design and augment current medicinal chemistry practices

Developing inhaled drugs for respiratory diseases a medicinal chemistry perspective

Inhaled drug delivery is crucial, but challenging, for many respiratory diseases. Medicinal chemists should follow guidelines aiding inhaled drug design to optimise their chances of downstream success

Designing Small Molecules for Therapeutic Success A Contemporary Perspective

How can drug design strategies evolve to improve the productivity of pharmaceutical R&D when most failures are currently related to late-stage target-based attrition in the clinic?

Pharmaceutical strategies in the emerging era of antibody-based biotherapeutics for the treatment of cancers overexpressing MET receptor tyrosine kinase

Cancerous MET overexpression is a common pathological feature manifested by genetic, molecular, and cellular abnormalities. Conventional therapeutic antibodies targeting MET, under clinical trials for almost 10 years, have made little progress with various setbacks. Novel biotherapeutics, such as bispecific antibodies, antibody-drug conjugates, and their combination, are under anti-MET clinical trials. Amivantamab, a MET/EGFR bispecific antibody, has been granted the Breakthrough Therapy Designation status for treatment of advanced NSCLC. An emerging era of antibody-based biotherapeutics for treatment of cancer overexpressing MET is in the horizon.

The political economics of cancer drug discovery and pricing

In highly politicised and heavily regulated markets for new anticancer drugs, the long-term value of extending life and reducing illness-related distress and disability is at risk of being underestimated: the fundamental goal of pharmaceutical price regulation should be to help assure universal access to continuously improving treatment

From patent to patient: analysing access to innovative cancer drugs

Analysis of EMA-licensed cancer drugs finds that authorisations are increasing, but with low numbers in cancers with poorest outcomes, increased time to license new drugs, and evidence that highly innovative treatments are not sufficiently prioritised

Drug Discovery for Epigenetics Targets

Epigenetic changes modify genetic information without altering the DNA sequence. Epigenetics related proteins are classified into readers, writers and erasers Dysregulation of the epigenome is associated with a number of diseases. Screening and rational design have been successfully applied to epigenetic targets

Epigenetics and therapeutic targets in gastrointestinal malignancies

Discusses the epigenetics in gastrointestinal (GI) cancers Explore the metastatic role(s) of epigenetics in GI cancers. Present epigenetics as biomarkers for the diagnosis and monitoring of GI cancers. Epigenetics as therapeutic solutions for GI cancers

Epigenetic regulation in macrophage migration inhibitory factor (MIF) mediated signaling in cancer and inflammation

Macrophage migration inhibitory factor (MIF) plays a crucial role in cancer and inflammatory diseases. Epigenetic mechanisms are involved in MIF-mediated signaling. Histone deacetylase inhibitors (HDACi) and non-coding RNAs are important regulators of MIF gene expression. Epigenetic mechanisms in MIF- and D-dopachrome tautomerase (D-DT)-mediated signaling are underexplored.

Optimising proteolysis-targeting chimeras (PROTACs) for oral drug delivery: a drug metabolism and pharmacokinetics perspective

PROTACs have become an established modality with examples reaching the clinic. PROTACs often breach “rule-of-5” limits, but oral bioavailability is achievable. The wide range of physicochemical properties can challenge ADME assays. The complex metabolism of PROTACs can potentially impact pharmacodynamics. Lessons learned supporting PROTAC oral drug discovery will be highlighted.

Degraders early developability assessment: face-to-face with molecular properties

Degraders could revolutionize future drug discovery. Degraders are large and flexible compounds that do not comply with Lipinski’s Ro5. Property-based drug design of degraders cannot be performed with common tools used for Ro5-compliant compounds. Ionization, lipophilicity, polarity and chameleonicity of degraders are experimentally accessible. For a small dataset of degraders permeability is governed by polarity expressed as ?log kWIAM

Could PROTACs Protect Us From COVID-19

In this article, we analyze specific requirements that define potent PROteolysis TArgeting Chimeras (PROTACs), and discuss their potential therapeutic power to target SARS-CoV-2 for both the treatment and prevention of COVID-19.

Advances in the development of entry inhibitors for sialic-acid-targeting viruses

Entry inhibitors might overcome the limitation of viral mutation. Antiviral research benefits from a broad-spectrum approach. Sialic acids can serve as a platform to create broad-spectrum antiviral drugs. Sialic-acid-targeting drugs such as DAS-181 are promising antiviral strategies. Multivalency is crucial when designing sialic-acid-based receptor analogues.

Exosomes as therapeutic solutions for pancreatic cancer

Exosomes promote progression and metastasis in pancreatic cancer (PC). Exosomes promote chemoresistance in PC. Exosomes carry signals between PC cells and its surrounding microenvironment cells. Exosomes can be used as biomarkers or targets for PC management.

Therapeutic agents for targeting desmoplasia: current status and emerging trends

Desmoplasia comprises of cellular and acellular components causing hindrance to chemotherapy. Decreased elasticity and increased interstitial fluid pressure deters drug delivery. Small molecule drugs, genes and peptide therapeutics have potential to target desmoplasia. Ongoing clinical trials on these molecules signify their potential in chemotherapy.

Current and future approaches to nonclinical cardiovascular safety assessment

Developing newer modalities requires bespoke cardiovascular safety assessment. • Monitorable approaches to structural cardiotoxicity ensured clinical progression. • Link from in vitro inhibition to clinical response guided chemical design. • Disease models offer assessment of patient-relevant therapeutic index. • Focus developments in humanised models, mechanism and patient predictions.

Human-based evidence for the therapeutic potential of arginase inhibitors in cardiovascular diseases

Arginase is a ubiquitous enzyme involved in nitric oxide- and polyamine-dependent vascular homeostasis. • In vitro and ex vivo human data demonstrated that overactive arginase is a key event of endothelial dysfunction, a hallmark of cardiovascular diseases. • Preliminary clinical studies confirmed that arginase inhibition is a promising therapeutic option for the treatment of cardiovascular diseases. • Only a few available arginase inhibitors are suitable for clinical use, and more research is needed.

Cardiovascular diseases: a therapeutic perspective around the clock

Cardiovascular disease therapy still faces major challenges, e.g. high interpatient variability. • Circadian fluctuations regulate the cardiovascular system, e.g. blood pressure. • Circadian timing system disruption has been associated with cardiovascular disease. • New therapeutic strategies such as chronotherapy could improve patient care.

Organotypic cancer tissue models for drug screening: 3D constructs, bioprinting and microfluidic chips

Development of biomimetic in vitro organotypic tissue models has witnessed momentous progress and technological innovations to achieve predictable drug screening.

Advancing computer-aided drug discovery (CADD) by big data and data-driven machine learning modeling

Recent progress of machine learning to deep learning and the development of new algorithms answers the big data challenges.

Artificial intelligence in drug discovery: what is realistic, what are illusions? Part 1: Ways to make an impact, and why we are not there yet

Data generation and analysis needs to move on from what can be done, to what should be done to arrive at safe and efficacious drugs faster and at lower cost.

Artificial Intelligence in Drug Discovery and Development

Artificial intelligence- integrated drug discovery and development has accelerated the growth of the pharmaceutical sector, leading to a revolutionary change in the pharma industry. Here, we discuss areas of integration, tools, and techniques utilized in enforcing AI, ongoing challenges, and ways to overcome them.

Guide for Authors March 2021

This is the Guide for Authors intending to submit an article to Drug Discovery Today

Nanovehicles for co-delivery of anticancer agents

Using nanovehicles for co-delivery of two or more anticancer agents shows benefits including: synergistic effects, promoting apoptosis pathways, reduction of toxicity and side effects, and overcoming multidrug resistance

Evolving nanoformulation strategies for diagnosis and clinical interventions for Parkinson’s disease

Early diagnosis and treatment of Parkinson’s disease achieved through innovative nanoformulation strategies can improve safety as well as the efficacy of diagnostic and therapeutic agents.

Clinical applications of nanomedicine in cancer therapy

One step forward to treat advanced and metastatic cancers: how cancer nanomedicine improves patient survival and clinical outcome while reducing systemic adverse effects of conventional treatments.

Fragment-based drug discovery using cryo-EM

Cryo-EM maps can be used for structure-based drug design. • Cryo-EM can provide the throughput necessary to support fragment-based screening. • They present the first cryo-EM structure of the oncology target PKM2. • We discuss future developments that will enhance fragment-based drug discovery.

Voltage-Gated Sodium Channels:Structures, Functions and Molecular Modeling

The structures and functions of VGSCs are briefly outlined. • The major binding sites and isoform-selective modulators of VGSCs are summarized. • The studies on the molecular modeling and CADD for VGSCs are reviewed.

Human ether-à-go-go-related potassium channel: exploring SAR to improve drug design

hERG primary anti-target responsible for serious side-effects. • hERG structure–activity relationships, data and models. • hERG channels structure and pathophysiology. • Testing screening methods and CIPA guidelines. • hERG target with a role in cancer.

Sprinkling the pixie dust: reflections on innovation and innovators in medicinal chemistry and drug discovery

Practical suggestions for enhancing innovation by managers and bench scientists in medicinal chemistry and drug discovery are discussed: ‘sprinkling pixie dust’

Pharmaceutical applications of cyclotides

Cyclotides are cyclic peptides, present in several plant families, that show diverse biological properties. Structurally, cyclotides share a distinctive head-to-tail circular knotted topology of three disulfide bonds. This framework provides cyclotides with extraordinary resistance to thermal and chemical denaturation. There is increasing interest in the therapeutic potential of cyclotides, which combine several promising pharmaceutical properties, including binding affinity, target selectivity, and low toxicity towards healthy mammalian cells. Recently, cyclotides have been reported to be orally bioavailable and have proved to be amenable to modifications. Here, we provide an overview of the structure, properties, and pharmaceutical applications of cyclotides.

Reaching for the bright StARs (Structure-Activity Relationships) in Chemical Space

StAR/SmARt is at the interface of chemical space, and activity landscape modeling. • Data visualization and its interpretation depends on molecular representation. • Methods for SAR are accessible in stand-alone software and web-based applications. • Approaches for SAR visualization can be used to analyze virtual screening results.

3D in vitro models of tumors expressing EGFR family receptors: a potent tool for studying receptor biology and targeted drug development

This review highlights currently used 3D in vitro models of tumors expressing EGFR family receptors with special focus on factors affecting tumor cell biology and resistance to antitumor agents

Organ-On-A-Chip Technology – Turning its Potential for Clinical Benefit into Reality

Establishing connected and interacting cell models using organ-on-a-chip (OOAC) technology has the potential to recapitulate patient physiology ‘on chip’, leading to more successful drug discovery.

Mini-gut: a promising model for drug development

The importance of mini-guts for drug development to combat cystic fibrosis, cancer and infectious disease, in addition to their use in drug screening, personalized medicine and developing new medical tools for drug development are highlighted.

From patent to patient: analysing access to innovative cancer drugs

Cancers of high unmet need are missing out on new drugs seen for other tumours

New generation drugs for treatment of multiple myeloma

This review will examine the efficacy and pro-thrombotic effects of MM therapies.

Clinical Applications of Nanomedicine in Cancer Therapy

By describing the state-of-the-art of nanomedicines and discussing their clinical advantages and challenges, we provide a perspective on the development of more effective therapeutic regimens to improve the clinical outcomes of cancer treatments.

Solid nanoparticles for oral delivery of antimicrobials: A review

Solid nanoparticles can be used as carriers for antimicrobial drugs.

Improving the Therapeutic Efficiency of Non-Coding RNAs In Cancers Using Targeted Drug Delivery Systems

• The role of non-coding RNA in treating various cancers is emphasized. • Recent advances in drug delivery systems to enhance ncRNA stability and efficiency are reviewed. • Clinical applications of miRNA and its potential use is discussed.

Current potential and challenges in the advances of liquid crystalline nanoparticles as drug delivery systems

In this review, we highlight recent advances and challenges in the development and application of LCN, providing examples of their topical, oral, and intravenous drug delivery applications, and discussing translational obstacles to LCN as a NP technology.

Drug-induced Rhabdomyolysis Atlas (DIRA) for Idiosyncratic Adverse Drug Reaction Management

A drug-induced rhabdomyolysis (DIR) classification scheme was developed based on drug labeling information.

Drug Induced Liver Injury severity and toxicity (DILIst) Binary classification of 1303 drugs by human hepatotoxicity

This drug list provides access to the largest number of drugs classified for human hepatotoxicity.

Adverse drug reactions on sexual functioning: a systematic overview

More than 300 drugs are registered that have sexual adverse drug reactions.

Deep Learning in Drug Discovery Opportunities, Challenges and Future Prospects

We review deep learning methods/tools relevant to drug discovery research.

Artificial Intelligence in Drug Development: The present status and Future prospects

The pharma industry is collaborating with AI industries to overcome challenges.

Machine Learning on adverse drug reactions for Pharmacovigilance

The application of machine learning in pharmacovigilance

Advance of promising targets and agents against 2019-nCoV in China

Considering the seriousness and suddenness of the COVID-19 outbreak, ~200 clinical trials on COVID-19 have commenced in China, and it is promising to report that certain targets and their agents have displayed strong antiviral potential, of which some have been permitted to be used in an attempt to combat the disease in clinical trials.

Allosteric inhibition of HIF-2a as a novel therapy for clear cell renal cell carcinoma

A brief discussion of the role of HIF-2a in ccRCC and provide insight into recent advances in the discovery, development, and mode of action of HIF-2a allosteric inhibitors.

Emergence of allosteric drug-resistance mutations: New challenges for allosteric drug discovery

Here, we review the emergence of allosteric drug-resistance mutations with an emphasis on examples covering clinically important therapeutic targets, including Breakpoint cluster region-Abelson tyrosine kinase (Bcr-Abl), Akt kinase [also called Protein Kinase B (PKB)], isocitrate dehydrogenase (IDH), MAPK/ERK kinase (MEK), and SRC homology 2 domain-containing phosphatase 2 (SHP2).

Quantifying the allosteric interactions within a G protein-coupled receptor heterodimer

Here, a mathematicalmodel is presented that quantifies the allosteric interactions within a receptor heterodimer.

Without a bug’s life: Germ-free rodents to interrogate microbiota-gut-neuroimmune interactions

This review describes the utility and limitations of the germ-free rodent model approach to assess microbiota-gut-brain axis.

Model systems for the study of how symbiotic associations between animals and extracellular bacterial partners are established and maintained

As with the use of models in other fields of biology where complexity is daunting (e.g., developmental biology or brain circuitry), each model has its strengths and weaknesses, i.e., no one model system will provide easy access to all the questions defining what is conserved in cell–cell interactions in symbiosis and what creates diversity within such partnerships.

Protein degradation for drug discovery

The authors present a collection of reviews that aim to highlight how targeted protein degradation has impacted drug discovery to date, the tools available, and the challenges and opportunities that lie ahead. All of the authors are leaders in their field, have themselves contributed critically to what we know today, and as active practitioners continue to shape the future of protein degradation drug discovery.

CRISPR/Cas9: A powerful tool for identification of new targets and cancer treatment

• CRISPR/Cas9 has been widely used for the identification of potential therapeutic targets in cancer. • Several potential targets such as CD38, CXCR2, MASTL and RBX2 have been identified using CRISPR/Cas9. • CRISPR/Cas9 is able to specifically target mutant alleles of oncogenes such as EGFR and KRAS. • CRISPR/Cas9 delivery methods need to be improved before entering into clinic.

Current Outlook on Drug Resistance in Chronic Myeloid Leukemia (CML) and Potential Therapeutic Options

• Bcr-Abl oncogene is the hallmark of chronic myeloid leukemia. • Leukemic cells can readily resist against tyrosine kinase inhibitor drugs. • Understanding molecular basis of adaptation will help to overcome drug-resistance. • Personalized approach is needed to identify the ideal drug therapy.

A new generation of antidepressants: an update of the pharmaceutical pipeline for novel and rapid-acting therapeutics in mood disorders based on glutamate/GABA neurotransmitter systems

• Monoamine deficiency hypothesis cannot explain the neurobiology of mood disorders. • Amino acid neurotransmitters are central to the pathophysiology of mood disorders. • Novel glutamatergic/GABAergic compounds show promise and are in development. • These compounds may be available as approved clinical treatments in the near future. • The improved antidepressant pipeline should engender cautious optimism.

Fungal Immunomodulatory Proteins: Characteristic, Potential Anti-Tumor Activities and Their Molecular Mechanisms

We comment on the source and diversity of FIPs. • We provide a comparative analysis of structural and physicochemical properties of these proteins. • Antitumor effects of FIPs are discussed. • Molecular mechanisms involved in the antitumor activity of FIPs were analyzed. • FIPs offer enormous growth potential as future immunotherapeutics.

Cannabinoid receptors as therapeutic targets for autoimmune diseases – where do we stand?

CB1 and CB2 receptors are essential for innate and adaptive immune responses. • The ECS and associated receptors are involved in autoimmune diseases. • CB2R agonists have emerged as new strategies for autoimmunity diseases. • ?9-THC and CBD showed immunosuppressive activity.

Optimizing Intracellular Signaling Domains for CAR NK Cells in HIV Immunotherapy: a Comprehensive Review

• NK cells are key effectors of antiviral responses that become dysregulated during HIV infection. • CAR strategies can redirect T cell and NK cell functions towards HIV-infected cells. • CAR T cell strategies applied in NK cells are sub-optimal due to differences in signal transduction. • Understanding these differences in NK and T cell signaling may enhance NK-specific CAR design. • NK and T cell signal transduction are summarized and novel NK-specific CAR strategies are discussed.

Synthetic biology – reimagine drug discovery

Synthetic biology is a term used to describe an approach by which novel artificial biological pathways, organisms or devices are designed and constructed. Bringing together skills from biology, chemistry, bioinformatics and engineering, it applies engineering-like techniques, at scale, to solve biological problems through a rational process of ‘biodesign’.

Therapy for Glioblastoma – is it working?

As of July 2018, there were 759 ongoing or projected clinical trials for glioblastoma. • Drug therapies appear compromised by the need to combat tumour heterogeneity. • Immunotherapy approaches targeting multiple tumour antigens are showing promise in the clinic. • Improved understanding of glioblastoma tumour biology is paving the way for better drugs and integrated treatment strategies.

Walking a tightrope: drug discovery in visceral leishmaniasis

Global collaborative efforts are filling the pipeline of new antileishmanial drugs. • Target and phenotypic assays are complementary in providing new first-in-class drugs. • Ex vivo splenic explants are proposed as disease-relevant assays in drug screening. • Real-time in vivo imaging allows the appraisal of the disease and treatment outcomes. • These techniques will accelerate the selection candidates entering Phase I trials.

Small molecule inhibitors of macrophage migration inhibitory factor (MIF) as emerging class of therapeutics for immune disorders

• MIF plays a key part in inflammatory diseases and cancer. • Many structural scaffolds are available for MIF inhibition. • Not all studies provide proper assessment of MIF inhibitory potency. • MIF tautomerase activity does not obey standard Michelis–Menten enzyme kinetics.

Design principles of ocular drug delivery systems: importance of size, material surface, drug payload and release

Ocular drug delivery is a field in which regular ADME tools are not useful. Pharmacokinetics based dosing aid for ocular drug delivery is presented. User-friendly dosing aid guides early stage design of delivery systems. Guidance for the delivery route, dosing and formulation design is presented.

Hydrogels for sustained delivery of biologics to the back of the eye

Hydrogels provide a flexible platform for design of ocular delivery systems. Intraocular injection of hydrogels can be accomplished via several strategies. Achieving long-term release of biologics remains a major hurdle. Ocular tolerability and CMC challenges must be addressed for clinical success.

Drug delivery to retinal photoreceptors

Routes of administration to retinal photoreceptors. The blood–retinal barrier as a challenge for photoreceptor drug delivery. Review of nanoparticle drug delivery systems used for intraocular applications. Perspectives for topical drug delivery to the retina.

Bicyclic peptides: types, synthesis and applications

Bicyclic peptides categorized into two groups: natural and synthetic. • Bicyclic peptides form one of the promising platforms for drug development owing to their biocompatibility, similarity and chemical diversity to proteins. • Bicyclic peptides can be employed as effective alternatives to complex molecules, such as antibodies, or small chemical molecules. Bicyclic peptides can be used as antimicrobial agents, drug targeting, imaging and diagnosis agents and therapeutics tools.

Host-defense peptides and their potential use as biomarkers in human diseases

• Host-defence peptides (HDPs) play a crucial role in innate and adaptive immunity. • Mutations in HDPs are worldwide spread and are population-specific. • HDPs may be correlated to various diseases making potential biomarker.

Peptide-based therapeutics: quality specifications, regulatory considerations, and prospects

• Harmonized pharmacopoeial peptide monograph will reduce manufacturer’s burden. • Quality assessment of peptides is crucial to ensure optimal safety to patients. • Purity characterization of peptides is critical for development of peptide therapeutics. • Global peptides therapeutic market is predicted to flourish in near future.

Solid nanoparticles for oral delivery of antimicrobials: A review

Solid nanoparticles can be used as carriers for antimicrobial drugs. • Provide better solutions for challenges related to oral antimicrobial drug delivery. • Improve the efficacy of antimicrobials to achieve the desired effect.

Design strategies for chemical stimuli-responsive programmable nanotherapeutics

Various chemical stimuli existing in the biological systems are discussed. • Strategies for designing chemical stimuli-responsive nanocarriers are summarized. • Biomedical applications of chemical stimuli-responsive nanocarriers are reviewed. • Limitations and future perspectives of current nanotherapeutics are addressed.

Ultrasmall iron oxide nanoparticles: synthesis, surface modification, assembly and biomedical applications

Various synthetic strategies used to synthesize USIO NPs are summarized. • Diverse surface modification and assembly methods of USIO NPs are detailed. • Different biomedical applications of USIO NP-based nanohybrids are reviewed. • Outlooks of USIO-based NPs for biomedical applications are discussed.

Acceleration of Rare Disease Therapeutic Development: A Case Study of AGIL-AADC

Here, the authors highlight the factors that enabled this remarkable pace of successful drug development for an ultra-rare disease.

Adaptive pathway development for Fabry disease: a clinical approach

The article examines how the search for therapies for Fabry disease by the adoption of adaptive pathways

The A-Z of Zika drug discovery

A comprehensive A–Z review of the recent advances in ZIKV drug discovery efforts is presented, highlighting drug repositioning and computationally guided compounds, including discovered viral and host cell inhibitors.

The rise of deep learning in drug discovery

The first wave of applications of deep learning in pharmaceutical research has emerged in recent years, and its utility has gone beyond bioactivity predictions and has shown promise in addressing diverse problems in drug discovery

Machine learning in chemoinformatics and drug discovery

Machine learning is currently one of the most important and rapidly evolving topics in computer-aided drug discovery

Computational prediction of chemical reactions current status and outlook

To be able to predict chemical reactions is of the utmost importance for the pharmaceutical industry. Recent trends and developments are reviewed for reaction mining, computer-assisted synthesis planning, and QM methods, with an emphasis on collaborative opportunities.

When more isnt merrier pharmaceutical alliance networks and breakthrough innovation

The authors show the importance of adopting a portfolio perspective of strategic alliances

Renal precompetitive consortium (RPC2) discovering therapeutic targets together

The authors describe how they formed an academic–industry consortium to share molecular target identification efforts and expertise across academia and the pharmaceutical industry.

Increased Building Block Access Through Collaboration

the authors discuss the benefits of collaboration in the access of building blocks at the precompetitive stage

The emerging role of copper 64 radiopharmaceuticals as cancer theranostics

Copper radioisotopes are emerging as potent tools for developing unprecedented clinical approaches for cancer treatment by exploiting the intrinsic biological properties of ionic copper and the richness of copper chemistry.

Role of IncRNAs in overaran cancer defining new biomarkers for therapeutic purposes

Therapeutic intervention based on silencing or functional inhibition of target lncRNAs will be beneficial for ovarian cancer patients.

Deubiquitinating enzymes in cancer stem cells functions and targeted inhibition for cancer therapy

In this review, the authors discuss the roles of various DUBs involved in the regulation of core stem cell transcription factors and CSC-related proteins that are implicated in the modulation of cellular processes and carcinogenesis.

Streamlining nonclinical drug development using the US FDA 505(b)(2) New Drug Application regulatory pathway

New drug applications (NDAs) using the FDA 505(b)(2) regulatory pathway can streamline and reduce nonclinical drug development requirements while potentially maintaining marketing exclusivity

“Bioexit”: Navigating the Policy and Regulatory Pathways for the Biotechnology Industry in a Post-Brexit Landscape

here we examine four post-Brexit political options and highlight the need to explore alternative approaches, with a focus on ensuring continued investment in biomedical research and development, while also safeguarding patients’ access to medicines

Marketing authorisation applications submitted to the European Medicines Agency by Small and Medium sized enterprises: an analysis of major objections and their impact on outcome

This report analyses the profile of major objections in applications for medicines for human use submitted by SMEs to the EMA with a positive or negative outcome (negative opinion or withdrawal) between 2011 and 2015, and their impact on the outcome.

Drug targeting of one or more aminoacyl-tRNA synthetases in the malaria parasite P. falciparum

Conducting comprehensive target safety reviews early in the drug discovery process enables project teams to make the right decisions about which drug targets to take forward.

Retinal pigment epithelial cells as therapeutic targets linked to the neurons survival in retina degenerative diseases

The authors suggest tools for cell engineering to discover new ways for activating the endogenous regeneration of barrier functions and/or of the retinal precursors in RPE cells.

Drug targeting of one or more aminoacyl-tRNA synthetases in the malaria parasite P. falciparum

This review establishes a platform for systematic experimental dissection of malarial parasite aaRSs as a new focus for sustained drug development efforts against malaria

Understanding drug targets - there's no such thing as bad news

Conducting comprehensive target safety reviews early in the drug discovery process enables project teams to make the right decisions aboutwhich drug targets to take forward.

NTM drug discovery status gaps and the way forward

From crisis to cures – a review on status, knowledge gaps and major obstacles in NTM drug discovery and development, and how to move forward

Approved CAR T cell therapies ice bucket challenges on glaring safety risks and long term impacts

Here, we focus on addressing the crucial challenges in relation to the gaps.

The rise of deep learning in drug discovery

Examples will be discussed covering bioactivity prediction, de novo molecular design, synthesis prediction and biological image analysis.

A bibliometric review of drug repurposing

there have been striking, and perhaps instructive, successful attempts of drug repurposing for unexpected, novel therapeutic areas

Machine learning in chemoinformatics and drug discovery

Here, we present basic principles and recent case studies to demonstrate the utility of machine learning techniques in chemoinformatics analyses; and we discuss limitations and future directions to guide further development in this evolving field.

Protein peptide docking opportunities and challenges

Key challenges are briefly discussed, such as modeling of large-scale conformational changes upon binding, scoring of predicted models, and optimal inclusion of varied types of experimental data and theoretical predictions into an integrative modeling process.

Design strategies for physical stimuli responsive programmable nanotherapeutics

Here, we present a systematic approach to design different programmable physicalstimuli-responsive nanotherapeutics intended for controlled and targeted delivery of various therapeutic agents.

Facilitating the translation of nanomedicines to a clinical product challenges and opportunites

Understanding of fundamental, characterization, clinical and regulatory aspects of nanomedicines is vital to enhance their translational potential. Hence, challenges and opportunities related to the commercialization of nanomedicines are discussed.

Pharmaceutical nanocrystals production by wet milling and applications

This review outlines the advantages, stabilization, and production of drug nanocrystals with an emphasis on wet milling. Covering their pharmaceutical applications, it reveals why nanocrystals are an industrially feasible formulation strategy.

Carbon dots emerging theranostic nanoarchitectures

Carbon dots show significant potential as theranostics for the improved management and treatment of cancer.

Microarray patches potentially useful delivery systems for long acting nanosuspensions

This article discusses the utility of dissolving microneedles in delivering nanoparticles into skin

Strategies for the enhanced intracellular delivery of nanomaterials

This review provides an update of recent advances in intracellular delivery and reports mechanisms that could help drugs reach their target efficiently, resulting in smarter drugs that reach their target still with the original bioavailability.

Use of CRISPR Cas9 gene editing tools for developing models in drug discovery

This review provides insights into in vitro and in vivo use of CRISPR/Cas9 system for drug target identification and validation.

Human cell derived organoids as a new ex vivo model for drug assays in oncology

We describe the development of this new in vitro model, its use for anticancer agent assays and the advantages compared with the currently used 2D models.

Mouse models of nonalcoholic steatohepatitis in preclinical drug development

Available mouse models of NASH address different aspects of the disease, have varying clinical translatability, and, therefore, also show different utility in drug discovery

Molecular epigenetic targets for liver diseases: current challenges and future prospects

This paper is a demonstration of the potential of epigenetic approaches that will inevitably begin to move into more clinical trials for use in patients with liver diseases including hepatocellular carcinoma

Molecular targets and pathways for the treatment of visceral leishmaniasis

The authors outline novel targets that might be of value in the treatment of Leishmaniasis

Progranulin as a biomarker and potential therapeutic agent

n this review, the authors summarise the most recent research advances concerning the potential role of progranulin as a therapeutic target and biomarker in cancer, neurodegenerative and inflammatory diseases.

Interfering peptides targeting protein protein interactions the next generation of drugs

Today, by improving administration, stability and intracellular delivery, the interest in peptides as potential drugs is resurgent, especially for targeting the thousands of intracellular protein–protein interactions implicated in cellular homeostasis and pathological conditions

Revisiting asthma therapeutics: focus on WNT signal transduction

WNT signalling is a relevant, yet underappreciated pathway in asthma. Recent insights into the pathology of asthma have highlighted this pathway as a potential novel therapeutic point of intervention. With this in mind, we attempt to answer the question: is WNT signalling a valid target for asthma therapy?

Haspin: a promising target for the design of inhibitors as potent anticancer drugs

inhibition of Haspin might have fewer adverse effects compared with other anticancer agents. Here, we highlight the chemical structures and actions of currently known Haspin inhibitors.

Discovery of hidden allosteric sites as novel targets for allosteric drug design

The identification of hidden allosteric sites is a significant challenge. Several computational and experimental approaches have been developed to identify such sites in proteins. Here, we outline these approaches, with a focus on examples of the successful use of such techniques.

Designed covalent allosteric modulators an emerging paradigm in drug discovery

The authors discuss the challenges and future directions in the development of covalent allosteric modulators.

Quantifying the allosteric interactions within a G protein coupled receptor heterodimer

Here, a mathematical model is presented that quantifies the allosteric interactions within a receptor heterodimer. The model is based on the operational model of allosterism including constitutive receptor activity, which provides the pharmacological analysis of heteromerization with well-established and widely used modeling and fitting procedures.

Microfluidic technologies for anticancer drug studies

Microfluidic technology offers an excellent alternative for current in vitro models. This review examines the impact of microfluidic systems on chemotherapeutic studies as a basis for diminishing the gap between in vivo and in vitro models.

Human cell derived organoids as a new ex vivo model for drug assays in oncology

In this review, we focus on human-derived organoid use for anticancer drug screening.

Exosomes a new horizon in lung cancer

An overview of the biology and function of exosomes and exosome miRNAs as indicators of diagnosis and treatment response in lung cancer is presented

The positive impacts of real world data on the challenges facing the evolution of biopharma

The biopharmaceutical industry must access, manage, and analyze Real-World Data (RWD) to generate Real-World Evidence (RWE), but does each company need to build their own in-house capability? Precompetitive collaboration should lead to better, morecost- effective solutions.

Interfering peptides targeting protein protein interactions the next generation of drugs

Today, by improving administration, stability and intracellular delivery, the interest in peptides as potential drugs is resurgent, especially for targeting the thousands of intracellular protein–protein interactions implicated in cellular homeostasis and pathological conditions.

The next generation of antimicrobial peptides as molecular therapeutic tools for the treatment of diseases with social and economic impacts

This review provides an integrated scenario of the most relevant aspects in the development of useful drugs provided by natural sources and recent advances in the biosynthesis and structural design of antimicrobial peptides.

Stapled peptide design principles and roles of computation

Computational techniques have an increasingly important role in the design of stapled peptides to target protein–protein interactions.

Transparency in drug regulation public assessment reports in Europe and Australia

The authors describe the experiences of two established medicines regulators in publishing public assessment reports, and reflect on their future role in communicating medicines information.

Is the European regulatory framework sufficient to assure the safety of citizens using health products containing nanomaterials

The review examines the stratified regulatory framework concerning the use of nanomaterials in healthcare products intended to be marketed in the European Economic Area, and highlights the current criticisms associated with the framework.

FDA drug labeling rich resources to facilitate precision medicine drug safety and regulatory science

The authors illustrate the utility of FDALabel using case scenarios in pharmacogenomics biomarkers and ADR studies.

Pipeline Progressing: the UK’s global bioscience cluster in 2017

This article outlines the health of the biological therapy pipeline of the UK

Drug discovery tomorrow: how to Catapult ourselves into the future

Chris Molloy discusses how the Catapult enterprise may facilitate the development of drugs in the future

Drug discovery tomorrow: how to Catapult ourselves into the future

The Medicines Discovery Catapult has been created to support the drug discovery community on its journey to the development of novel pharmaceuticals. Its facility at Alderley Park, Cheshire, provides a fragmented sector with a place to work together, access to scarce assets and to de-risk their new prototypes and services.

Industrial medicinal chemistry insights neuroscience hit generation at Janssen

Modern medicinal chemistry impacts drug discovery in many ways beyond just optimization of clinical candidates. Here we describe the formation and work of a small team dedicated to hit and lead generation with novel methods inside Janssen.

Binding thermodynamics discriminates fragments from druglike compounds a thermodynamic description of fragment based drug discovery

A large thermodynamic dataset from Astex, AstraZeneca, Pfizer and academic labs that includes fragment–protein interactions demonstrates that, when compared with many traditional druglike compounds, fragments bind more enthalpically to their protein targets.

Mechanistic applications of click chemistry for pharmaceutical drug discovery and drug delivery

Click chemistry is set to develop new potential molecules and biomaterials for treatment of various diseases, drug delivery and diagnostics, respectively.

Pharmaceutical and biomaterial engineering via electrohydrodynamic atomization technologies

This short review focuses on key selected recent and established advances in the field of pharmaceutical and biomaterial applications.

Molecular dynamics-driven drug discovery: leaping forward with confidence

Molecular dynamics (MD) is an important tool that can offer significant benefits to structure-based drug design. This review addresses the theoretical background and various applications of MD that can transform the current drug discovery efforts

miRNA nanotherapeutics for cancer

The article focuses on the development of miRNA nanoformulations to achieve enhanced cellular uptake, bioavailability, and accumulation at the tumor site.

Self emulsifying drug delivery systems an approach to enhance oral bioavailability

This article presents an exhaustive account of various literature reports on diverse types of self-emulsifying formulations with emphasis on their formulation, characterization and in vitro analysis, with examples of currently marketed preparations

DDT Guide for Authors amended Nov 2017

Amended Guide for Authors

The use of nanoscaffolds and dendrimers in tissue engineering

Advances in the manufacturing of dendritic nanoparticles and scaffold architectures Successful have resulted in the successful incorporation of dendritic scaffolds in tissue engineering has become true due to the advancement of science in the manufacturing of dendritic nanoparticles and the scaffold architecture.

Intracellular transport of nanocarriers across the intestinal epithelium

Understanding the complex intracellular processes of nanocarrier trafficking is particularly essential for the rational design of oral drug delivery systems

In vivo fate of lipid based nanoparticles

Elucidation of the in vivo fate of LBNs helps weigh the balance between lipolysis and biorecognition, and is emerging as a new field of research.

A new golden age for the antitubercular target InhA

This review provides insight into the most advanced InhA inhibitors, which show clear evidence of successful target engagement and represent excellent pointers for further drug optimization

Learning from the past for TB drug discovery in the future

We describe the shift from a target-based approach to one that uses phenotypic high-throughput screens providing examples of success and failure from recent largescale FP7 collaborations for tuberculosis drug discovery.

Targeting tuberculosis using structure guided fragment based drug design

Fragment-based drug discovery has produced a number of potent inhibitors against multiple tuberculosis targets. Here, we review the successes, opportunities and challenges of this approach in tuberculosis drug discovery.

Stapled peptide design principles and roles of computation

Computational techniques have an increasingly important role in the design of stapled peptides to target protein–protein interactions.

Recent developments in the pharmacology of prenylated xanthones

The authors survey data published over the past decade relating to the properties of prenylated xanthones

Current progress in a second generation claudin binder anti claudin antibody for clinical applications

Here, the authors overview recent advances in the creation of anti-CLDN antibodies and discuss CLDNs as drug development targets.

Guide for Authors August 2017

This contains the instructions for how to prepare an article for submission to Drug Discovery Today

Towards a 21st-century roadmap for biomedical research and drug discovery: consensus report and recommendations

To discover and develop new therapies, we need 21st-century roadmaps for biomedical research based on multiscale human disease pathways, and supported by policy and funding strategies that prioritise human relevance.

Reorienting the immune system in the treatment of cancer by using anti PD 1 and anti PD L1 antibodies

Promising clinical results have been obtained by PD-1 pathway blockade in a range of cancers while still maintaining a manageable toxicity profile, and two anti-PD-1 antibodies are now approved by the US Food and Drug Administration (FDA) for the treatment of metastatic melanoma.

Molecular similarity considerations in the licensing of orphan drugs

Here, the authors discuss the similarity of medicines in the context of orphan drug legislation.

The many roles of molecular complexity in drug discovery

Molecular complexity has been associated with target selectivity and success in progressing into clinical development; therefore, quantification of molecular complexity has a major impact on drug discovery.

Computational functional group mapping for drug discovery

Rapidly creating novel, synthetically- accessible ligands is greatly facilitated by using recent advances in computational functional group mapping that provide 3D maps for intuitive, interactive design by medicinal chemists.

Nanoporous metal organic frameworks as hybrid polymer metal composites for drug delivery and biomedical applications

Metal organic frameworks as hybrid nanocomposites in drug delivery and biomedical applications

Self assembly drug conjugates for anticancer treatment

Here, we have reviewed the scope of nanotechnology-based self-assembly drug delivery approaches focusing on prodrugs able to form NPs by self-assembly

Mucoadhesive polymers in the treatment of dry X syndrome

Mucoadhesive polymers are able to provide protection or even mucus substitution for leaky mucus barriers associated with a dry eye, dry mouth, and dry vagina, collectively named ‘dry X syndrome’.

Marine pharmacology therapeutic targeting of matrix metalloproteinases in neuroinflammation

Marine pharmacology therapeutic targeting of matrix metalloproteinases in neuroinflammation

Molecular dynamics driven drug discovery leaping forward with confidence

Molecular dynamics (MD) is an important tool that can offer significant benefits to structure-based drug design. This review addresses the theoretical background and various applications of MD that can transform the current drug discovery efforts.

Split protein biosensor assays in molecular pharmacological studies

Genetically encoded split biosensors based on protein fragment complementation are a sensitive and robust tool for monitoring dynamic protein–protein interactions and activities of druggable targets in cell-based assays.

Defining Drug Response for Stratified Medicine

Understanding the patterns of variation in drug response, in terms of both therapeutic efficacy and safety, can help identify individuals or groups of patients requiring different treatments for similar symptoms and improve their care.

Design of efficient computational workflows for in silico drug repurposing

This review provides a comprehensive description of the conceptual foundation and computational developments in the field of in silico repurposing. Furthermore, a generic modular description for repurposing workflows is described.

Drug combination therapy increases successful drug repositioning

Drug combination therapy facilitates drug repositioning by a synergistic effect of two drugs with different mechanisms of action.

Drug repositioning approaches to parasitic diseases a medicinal chemistry perspective

Drug repurposing is an evolving strategy to deliver timely and cost-effective solutions in tropical disease drug discovery.

miRNA nanotherapeutics for cancer

This article focuses on the development of miRNA nanoformulations to achieve enhanced cellular uptake, bioavailability, and accumulation at the tumor site.

Proteomics and drug discovery in cancer

This article presents a perspective on how proteomics could be applied in the future to determine prognostic biomarkers and direct strategies for effective cancer treatment.

The MEK ERK5 signalling pathway in cancer a promising novel therapeutic target

The article explores the major known contributions of MEK5/ERK5 signalling to the onset and progression of several types of cancer, and highlight the potential clinical relevance of targeting MEK5/ERK5 pathways.

An improved model for fragment based lead generation at AstraZeneca

This description of the fragment library and approach of AstraZeneca to fragment-based lead generation shows that 2D and 3D fragments provide complementary hits to explore binding pockets, and that both can deliver 3D lead series.

Open for collaboration an academic platform for drug discovery and development at SciLifeLab

SciLifeLab DDD is the national powerhouse for academic drug discovery in Sweden. The platform offers industry-standard infrastructure and expertise for developing small molecule and biological therapeutics.

The changing model of big pharma impact of key trends

The pharmaceutical industry is facing significant barriers in the form of pricing and reimbursement, continued patent expirations and challenging market dynamics. In this article, we have analyzed data from the 1995–2015 period, on key aspects

Transparency in drug regulation public assessment reports in Europe and Australia

Two of the world’s leading medicines regulators reflect on their experiences with transparency through the publication of information about their regulatory decisions over the past 20 years.

Nanobodies as therapeutics big opportunities for small antibodies

This review provides an extensive overview of the current state of all the possible therapeutic and diagnostic uses of nanobodies.

Critical considerations for developing nucleic acid macromolecule based drug products

This review provides a synopsis of challenges in the formulation and stability of DNA/m-RNA based medicines and probable mitigation strategies including a brief summary of delivery options to the target cells.

Immunocytokines as novel class of products for the treatment of chronic inflammation and autoimmune conditions

This review analyzes basic principles in the design of immunocytokines and describes the most advanced products in preclinical and clinical development.

A look into the future of ALS research

A review of the current models, including animal models, used in ALS research and new models to accelerate drug discovery.

An analysis of FDA-approved drugs for neurological disorders

The majority of drugs for neurology target ion channels or G-protein-coupled receptors (GPCRs) but the mechanistic basis for many NMEs remains unclear or controversial.

Neuroprotective agents for neonatal hypoxic ischemic brain injury

To minimize the neurological consequences of HIE, new and more-effective neuroprotective strategies are urgently required.

Neuroprotective agents target molecular mechanisms of disease in ALS

Riluzole, the only FDA-approved treatment, prolongs patient life by only three months. Thus, curative therapies are urgently needed

Integrating biophysics with HTS driven drug discovery projects

Although biophysical protein–ligand studies are established HTS hit triaging tools, this review will show how further impact can be made by deploying biophysics during HTS assay development itself.

A New Paradigm for Addressing Compound Property Related Drug Attrition

The traditional physical-property-based argument for drug attrition is developed and extended to one that incorporates drug–transporter interactions. A new algorithm is proposed that facilitates the evaluation of this hybrid property space.

Covalent Inhibitors in Drug Discovery: From Accidental Discoveries to Avoided Liabilities and Designed Therapies

Covalent inhibition has a rich history in drug discovery and continues to be a highly successful strategy for addressing diverse targets and disease areas.

Peptide therapeutics: current status and future directions

Here, the authors discuss the current status, the strengths and weaknesses of peptides as medicines and the emerging new opportunities in peptide drug design and development.

Cyclodextrins in pharmaceutical formulations I: structure and physicochemical properties, formation of complexes, and types of complex

The authors describe the physicochemical properties of various cyclodextrins and the effects of substituents on these properties. Additionally, the authors discuss how cyclodextrins offer an additional tool to pharmaceutical scientists to overcome drug delivery challenges for problematic drugs

Cyclodextrins in pharmaceutical formulations II: solubilization, binding constant, and complexation efficiency

In this short review, we discuss the determination of binding constants and complexation efficiency, and factors that influence the latter. We also describe the use of the complexation efficiency value to assess the stabilizing effects of various cyclodextrins

Multidrug co-crystals: towards the development of effective therapeutic hybrids

This review emphasizes those multidrug co-crystals that could find potential applications in the treatment of various diseases and in the development of cost-effective hybrid therapeutics.

COX-2 inhibitors: a novel strategy in the management of breast cancer

Cyclooxygenase-2 plays an important role in breast cancer pathogenesis, which stimulates the necessity for extensive research and development of new COX-2 inhibitors by the use of in silico, in vitro and in vivo techniques.

Expanding roles of superoxide dismutases in cell regulation and cancer

Superoxide dismutases are not only key antioxidant enzymes but they also have important roles in cell signaling, metabolism and transcription. They are involved in cancer initiation, progression and metastasis, and are potential anticancer drug targets.

Proteomics and drug discovery in cancer

The field of proteomics has developed quickly over the past decade and its application to cancer research has considerable potential in the area of precision medicine.

Where will we get the next generation of medicinal chemists?

This Editorial deals with the issue of how industry can interest and attract the very best of new synthetic organic chemists to take up a career in medicinal chemistry in the Pharma Industry

DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans

This paper provides the largest, revised drug reference list annotated and ranked by the risk for developing hepatotoxicity in humans (DILIrank). We created the new DILIrank list by complementing the previously used druglabeling information together with existing evidence of clinical causality assessments.

The ELF Honest Data Broker: informatics enabling public–private collaboration in a precompetitive arena

The European Lead Factory’s Honest Data Broker underpins a pan-European industry– academia hit discovery consortium and provides the HTS triage tools and IP safeguards necessary for sustainable collaboration.

Compound Passport Service: supporting corporate collection owners in open innovation

The increased trend towards open innovation provides organisations with new 17 challenges in managing their compound collections.

Expansion of chemical space for collaborative lead generation and drug discovery: the European Lead Factory Perspective

Herein we discuss a European, intersectoral crowdsourcing approach to innovative, high-quality compound libraries design and synthesis for high-throughput biological screening and drug discovery.

Passing on the medicinal chemistry baton: training undergraduates to be industry-ready through research projects between the University of Nottingham and GlaxoSmithKline

Drug discovery research is a stimulating, viable and worthwhile endeavour for the undergraduate preparing for a career in industry.

A practical drug discovery project at the undergraduate level

‘You make the compounds you design’: this article describes a new way for chemistry undergraduates to learn about drug discovery.

Identifying compound efficacy targets in phenotypic drug discovery

Available approaches to target deconvolution can be grouped based on underlying principles and should be used in combination to exploit their complementarity in efforts toward understanding compound mechanism of action.

Phenotypic screening the future of antibody discovery

Drug screening based on phenotype, rather than target, is currently an undervalued approach for antibody discovery. In this review, we find significant opportunities in accessing novel target space through phenotypic antibody discovery

Phenotypic screens as a renewed approach for drug discovery

Phenotypic screening is gaining new momentum in drug discovery with the hope that this approach may revitalize drug discovery and improve the success rate of drug approval through the discovery of viable lead compounds and identification of novel drug targets

Peptide therapeutics: current status and future directions

This article concentrates on the current developments and uses of peptide therapeutics

Bispecific antibodies

Bispecific antibodies (bsAbs) combine the functionality of two antibodies in one molecule. Two bsAb-drugs are currently on the market (one recently approved) and more are in clinical development. Driven by large pharma, bsAbs are emerging as next-generation biologics.

Challenges and opportunities for non-antibody scaffold drugs

The first candidates from the promising class of small non-antibody protein scaffolds are now moving into clinical development and practice. Challenges remain, and scaffolds will need to be further tailored toward applications where they provide real advantages over established therapeutics to succeed in a rapidly evolving drug development landscape.

Expansion of chemical space for collaborative lead generation and drug discovery: the European Lead Factory Perspective

High-quality compound collections are a main determinant of drug discovery success. • Generation of relevant collections is a significant challenge for any organization. • The European Lead Factory employs a consortium approach to address this challenge. • This has produced novel, diverse and complex compounds with reduced lipophilicity.

Rethinking ‘academic’ drug discovery: the Manchester Institute perspective

Academic and charitable drug discovery enterprises face common challenges, such as hit finding and target identification. Here, we describe our own creative solutions to these issues.

Crowdsourcing in pharma: a strategic framework

The authors present a comprehensive overview of the use of crowdsourcing approaches in the pharmaceutical industry arranged within a strategic framework.

Racing to define pharmaceutical R&D external innovation models

Pharmaceutical R&D is rapidly being redefined with a race at foot to identify the external innovation models which will promote breakthrough innovation and the most transformational new medicines for patients.

Epigenetic mechanisms in heart development and disease

Spatio-temporal epigenetic gene regulation is essential for the proper development of the heart, and aberrant epigenetic mechanisms contribute to susceptibility to cardiovascular disease

Epigenetic modifications as potential therapeutic targets in age-related macular degeneration and diabetic retinopathy

The authors describe how epigenetic aberration could represent future targets for the treatment of some eye diseases

Epigenetic code and potential epigenetic-based therapies against chronic diseases in developmental origins

Epigenetic changes in response to prenatal stimuli may be responsible for the origin of various chronic diseases,

Databases and collaboration require standards for human stem cell research

If stem cell research is to achieve its expected potential the field needs an increase in collaboration and transparency. This may be facilitated by the creation of standards and databases that adhere to them.

Engineering physical microenvironment for stem cell based regenerative medicine

Recent advances in the technologies for the construction of physical microenvironment and their implications in controlling stem cell fate are highlighted.

Systems mapping of genes controlling chemotherapeutic drug efficiency for cancer stem cells

The authors describe a statistical framework for mapping genes that control tumor responses to chemotherapeutic drugs as well as the efficacy of treatments in arresting tumor growth.

Securing reliability and validity in biomedical research: an essential task

This article discusses the impact of ‘old’ and contemporary data on hypothesis generation in relation to human physiology and in the effort to optimally implement translational sciences.

Active learning strategies in computer assisted drug discovery

This article provides a comprehensive overview of the various computational active-learning approaches and outlinetheir potential for drug discovery.

Machine-learning approaches in drug discovery: methods and applications

This paper focuses on machine learning approaches in the context of ligand-based virtual screening for addressing complex compound classification problems and predicting new active molecules.

Is there a link between selectivity and binding thermodynamics profiles

Exploring binding thermodynamics-selectivity relationship to aid drug design.

University of Surrey presentation 21st May 2015

The powerpoint slides from a talk on Drug Discovery at the University of Surrey

Current status and future directions for antibody-drug conjugates

Recent advances in the discovery and development of antibody–drug conjugates have led to FDA approvals and a rich clinical pipeline of promising new cancer therapies.

Peptide therapeutics - Current status and future directions

The authors examine a chain of thoughts leading to the conclusion that peptides offer tremendous untapped potential as future medicines.

HCV/E2 core structures and mAbs: something is still missing

Recently described HCV E2 core crystallographic structures greatly improve the knowledge about this elusive protein. However, they partially disagree with immunological and functional data. This paper highlights these discrepancies and proposes an alternative structural arrangement.

Small molecule inhibitors of Ebola virus infection

A comprehensive summary of small molecules inhibitors of ebola virus infection, their identification and available biological evidence

Therapeutic applications of the cell-penetrating HIV-1 Tat peptide

Finding an efficient way to deliver drugs to specific target is crucial for clinical translation; here drugs conjugation with cell penetrating peptides, in particular with HIV-derived Tat peptide is discussed.

Development of Anticancer Agents: Wizardry with Osmium

The drawbacks of currently used cancer chemotherapeutics have led to the development of novel anticancer agents with alternative modes of action. Compounds featuring an osmium center are a promising class of new therapeutics with widely tunable activity.

Targeting of mitochondrial dysfunction as in aging and glaucoma

This article examines methods of addressing age related reduction in mitochondrial activity

mitoNEET as novel drug target for mitochondrial dysfunction

This article reviews how the mitochondrial protein mitoNEET, the target of thiazolidone diones, may be a useful target for other diseases, including neurodegeneration, breast cancer, diabetes and inflammation.

Increased Mitochondrial Fission and Neuronal Dysfunction in Huntington's Disease: Implications for Molecular Inhibitors of Excessive Mitochondrial Fission

This article discusses how restoring an appropriate level of mitochondrial fission might help in disease, in particular Huntington's Disease

Designing novel building blocks is an overlooked strategy to improve compound quality

Here, we outline general principles that should be applied to ensure that a building block collection has the greatest impact on drug discovery projects, by discussing design principles for novel reagents and what types of reagents are popular with medicinal chemists in general

Evolutions in fragment-based drug design: the deconstruction– reconstruction approach

In this critical review, we focus on the construction of fragment libraries and the advantages and disadvantages of various fragment-based screening (FBS) for constructing such libraries

Activity cliffs in drug discovery: Dr Jekyll or Mr Hyde?

In this review, the duality of activity cliffs in medicinal chemistry and computational approaches is addressed, with emphasis on the rationale and potential solutions for handling the ‘ugly face’ of activity cliffs.

Activity Cliffs in Drug Discovery

Point of view of the current state of the activity cliff phenomenon focusing on the rationale, effects and potential solutions to handle the influence of activity cliffs in drug discovery

Are there meaningful biomarkers of treatment response for depression

Proposing an integrative use of biomarkers for antidepressant treatment outcome bridging the gap from blockbuster medicine to personalized treatment.

Data driven medicinal chemistry in the era of big data

All scientific disciplines, including medicinal chemistry, are the subject of a revolution as data are generated at unprecedented rates and their analysis and exploitation become increasingly fundamental to innovation

Translational research the changing landscape of drug discovery

In this article the author discusses how the increasing adoption of translational research is leading to novel integrated discovery nexuses that may change the landscape of drug discovery.

Translational medicines research

This article discusses fundamental processes of translational research: Understanding the biological basis of human disorders; Lead generation and optimisation; Clinical testing

Translational CNS medicines research

Translating neuroscience research into new medicines is challenging, largely because of the complexity of the human brain. The critical factors involved in this process are considered, along with the future prospects.

Computational advances in the identification of allosteric sites in proteins

The authors discuss the challenges in predicting allosteric sites reliably in proteins

Allosteric modulation of the M1 muscarinic acetylcholine receptor: improving cognition and a potential treatment for schizophrenia and Alzheimer’s disease

The authors discuss targeting allosteric glutamatergic receptors for the possible treatment of cns diseases, in particular schizophrenia

aC helix displacement as a general approach for allosteric modulation of protein kinases

The authors discuss the benefits of adopting an allosteric approach to perturb protein kinases, a class of molecule that is difficult to selectively modulate by other, more traditional approaches.

Biophysical microenvironment and 3D culture physiological relevance

The authors review the implication of microenvironment on the development of 3D cell cultures for high throughput screening.

Microtissue size and hypoxia in HTS with 3D cultures

The authors discuss those microenvironmental factors that characterize 3D cell cultures

Three-dimensional cell culture: the missing link in drug discovery

The authors discuss the benefits of using 3D cell cultures in the drug discovery pathway, rather than the conventional 2D approach.

A Practical Drug Discovery Project at the Undergraduate Level

You make the compounds you design’: this article describes a new way for chemistry undergraduates to learn about drug discovery.

Expanding Medicinal Chemistry Space

Many of the new, highly attractive targets being identified fit in relatively unexplored bioactive space which traditional lead generation approaches and existing compound libraries are not well placed to exploit

The conformational musings of a medicinal chemist

A personal perspective on the use of molecule conformation in drug design

Guide for Authors June 2014

This is the current guide for authors

Future directions for peptide therapeutics development

The unprecedented number of marketing approvals in 2012 for peptide therapeutics may be a harbinger for the innovative peptide-based drugs in the clinical pipeline.

Immunosuppressive peptides and their therapeutic applications

The immune system is responsible for detecting and eliminating foreign pathogens and tumor cells, but avoiding self-recognition. Therefore, tolerance mechanisms are continuously under surveillance to retain this homeostasis.

Phage Display as a Technology Delivering on the Promise of Peptide Drug Discovery

Available for near three decades, has the full potential of phage display been realized in peptide drug discovery?

Text mining for systems biology

A substantial proportion of information relevant to the modelling and simulation of physiological and pathophysiological processes is not available from databases but is instead present in unstructured scientific documents, such as journal articles, reviews and monographs.

Emergence of zebrafish models in oncology for validating novel anticancer drug targets and nanomaterials

The zebrafish (Danio rerio) as an in vivo model organism offers great promise to investigate the molecular mechanisms of diverse human diseases, including cancers, because it constitutes a simple and cost effective animal model for performing some genetic alterations and large-scale experiments with high reproducibility

Phenotypic screens as a renewed approach for drug discovery

Well before molecular target-based drug discovery became popular, phenotypic-based screening strategies were the foundation of pharmaceutical drug discovery (Fig. 1). In the past 25 years, molecular target-based drug screening has become the main drug discovery paradigm used in both the pharmaceutical industry and in academic translational research centers. Recently, however, there appears to be renewed interest in reinventing phenotypic screens for lead discovery

Shifting from the single to the multitarget paradigm in drug discovery

It is currently evident that the concept that one drug acts on a single receptor is not as effective as expected from the reductionism view of the lock and key model. The growing evidence for polypharmacology (i.e. that clinical effects are often because of the interaction of single or multiple drugs with multiple targets) is encouraging the shift to experimental and computational multitarget approaches

High-content multiplexed tissue imaging and quantification for cancer drug discovery

This method to quantify tumor model phenotypes can be useful for cancer drug discovery by increasing the understanding of: (i) tumor models used in efficacy studies, (ii) changes occurring during the growth of the tumor, and (iii) novel mechanisms of actions of cancer therapeutics.

Low-dose metronomic chemotherapy: from past experience to new paradigms in the treatment of cancer

This article summarizes preclinical and clinicalexperience with LDM chemotherapy, emphasizing the potential contribution of this new treatmentmodality to future paradigms in the systemic treatment of patients with cancer.

The development and application of small molecule modulators of SF3b as therapeutic agents for cancer

The identification of potent spliceosome modulators that demonstrate antitumor activity indicates that this complex may be a target for drug development

Cell-specific delivery of biologicals

We have entered the era of biologicals. Although new chemical entities are still produced and successfully reach the market, many new biological products like antibodies and their derivatives, siRNA, cytokines, enzymes and other therapeutic peptides are now being developed. Already a third of all new therapeutic products in 2011 were biologicals rather than chemical derivatives. In this review the authors aim to summarize the possibilities to deliver anti-fibrotic agents to the fibrotic liver. They specifically focus on the use of biological products

Current challenges and opportunities in nonclinical safety testing of biologics

Industry experts gathered on 3–4 December 2012 in Basel for the 2nd Annual BioSafe European General Membership Meeting, where they shared experiences and insights into the nonclinical safety assessment of new biotherapeutic entities.

Structural mass spectrometry in biologics discovery: advances and future trends

Biologics produced by recombinant DNA technologies are generally complex, heterogeneous, and subject to a variety of modifications. The biological efficacy, clearance, safety and immunogenicity of biologics are highly dependent on their structures. Therefore, there is a growing need for protein structural characterization, particularly during the drug discovery phase when a large number of candidates are being investigated.

Understanding the Publishing Process

How best to write and publish a scientific paper

Sclerostin: how human mutations have helped reveal a new target for the treatment of osteoporosis

This article describes how the study of a rare monogenic high bone mass disorder called sclerosteosis has provided a new insight into the regulation of bone formation.

Is autologous chondrocyte implantation (ACI) an adequate treatment option for repair of cartilage defects in paediatric patients?

Articular cartilage injury is a common orthopaedic problem affecting many people including children and adolescents. The main cause for cartilage defects in the knee includes acute traumatic injuries.

Treating osteoporosis by targeting parathyroid hormone to bone

Over 300,000 hip fractures per year can be attributed to osteoporosis, resulting in direct patient care costs of over 18 billion dollars in 2005. As the population ages, this cost is anticipated to rise to approxi- mately 25.3 billion dollars by 2025

Shifting from the single to the multitarget paradigm in drug discovery

Increasing evidence that several drug compounds exert their effects through interactions with multiple targets is boosting the development of research fields that challenge the data reductionism approach. In this article, we review and discuss the concepts of drug repurposing, polypharmacology, chemogenomics, phenotypic screening and high-throughput in vivo testing of mixture-based libraries in an integrated manner. These research fields offer alternatives to the current paradigm of drug discovery, from a one target–one drug model to a multiple-target approach. Furthermore, the goals of lead identification are being expanded accordingly to identify not only ‘key’ compounds that fit with a single-target ‘lock’, but also ‘master key’ compounds that favorably interact with multiple targets (i.e. operate a set of desired locks to gain access to the expected clinical effects).

Three-dimensional cell culture: the missing link in drug discovery

Here, in the context of anticancer drug screening, we review 2D and 3D culture approaches, consider the strengths and relevance of each method.

Molecular determinants of drug–receptor binding kinetics

We review some of the key factors thought to control drug–receptor binding kinetics at the molecular level and discuss several possible approaches for the rational design of drugs with desired binding kinetics.

Financing drug discovery for orphan diseases

An orphan-disease ‘megafund’ less than a billion dollars can provide sufficient risk reduction to be financed by long-term bonds and still generate attractive investment returns with only 10–20 projects in the portfolio.

Predictive in vivo animal models and translation to clinical trials

In this article the authors consider the different types of animals models used to test novel therapeutics and chemotherapies, and discuss the strengths and weaknesses of each in this regard.

Animal models of Alzheimer’s disease and drug development

The objective, therefore, of this brief review is to discuss the potential role of the current animal disease models for AD in drug development.

Emergence of zebrafish models in oncology for validating novel anticancer drug targets and nanomaterials

This article reviews recent advances on the potential applications of transparent zebrafish embryo and adult zebrafish models in molecular oncology to investigate the specific functions of gene products and molecular pathways altered in cancer cells during the disease progression in addition to a xenotransplantation system to validate novel anticarcinogenic drugs.

Expanding medicinal chemistry space

New technologies and approaches are beginning to emerge that could provide novel lead generation capabilities that enable access to new drug target classes

Subtleties in GPCR drug discovery: a medicinal chemistry perspective

This article discusses the subtle aspects of GPCR drug discovery from the medicinal chemistry perspective

Gold-catalyzed formation of heterocycles – an enabling new technology for medicinal chemistry

Emergent applications of gold catalysis have played a key role in the synthesis of biologically active molecules including a drug candidate

Bartfai and Lees: The Future of Drug Discovery

What medicines you will need & why you might not ever have them

Multi-objective optimization methods in drug design

This paper reviews the latest multi-objective methods and applications reported in the literature, specifically in quantitative structure– activity modeling, docking, de novo design and library design. Further, the paper reports on related develop- ments in drug discovery research and advances in the multi-objective optimization field.

The graphical representation of ADME-related molecule properties for medicinal chemists

This article reviews various approaches that have been used to represent molecule properties graphically in the context of oral ‘drug likeness’, with the goal of improving the decision making of medicinal chemists during the drug discovery process.

• Target–drug interactions: first principles and their application to drug discovery

In this review, we begin by introducing the basic principles of kinetics and thermodynamics of target–drug binding within the context of drug discovery. In addition, we present a meta-analysis of the recent literature describing the kinetic and thermodynamic resolution of successful clinical candidates with diverse mechanisms of action. We finish by discussing the best practices in the triage and chemical optimization towards clinical candidates with maximal in vivo efficacy devoid of adverse events.

• The growing impact of click chemistry on drug discovery

Click chemistry is a modular approach that uses only the most practical and reliable chemical transformations. Its applications are increasingly found in all aspects of drug discovery, ranging from lead finding through combinatorial chemistry and target-templated in situ chemistry, to proteomics and DNA research, using bioconjugation reactions. The copper-(I)-catalyzed 1,2,3-triazole formation from azides and terminal acetylenes is a particularly powerful linking reaction, due to its high degree of dependability, complete specificity, and the bio-compatibility of the reactants. The triazole products are more than just passive linkers; they readily associate with biological targets, through hydrogen bonding and dipole interactions.

• Follow-on drugs: How far should chemists look?

This paper highlights the fact that even simple atomic variations can cause drastic changes in molecular properties responsible for therapeutic advantages.

• Follow-on drugs: How far should chemists look?

This paper highlights the fact that even simple atomic variations can cause drastic changes in molecular properties responsible for therapeutic advantages

• Translational research: the changing landscape of drug discovery

This article discusses how the increasing adoption of translational research is leading to novel integrated discovery nexuses that may change the landscape of drug discovery.

Literature analysis for systematic drug repurposing: a case study from Biovista

This review focuses on primary literature as one of the data sources and on Literature-Based Discovery (LBD) strategies for DR, presenting a relevant case study for the treatment of Multiple Sclerosis (MS).

• Drug discovery in pharmaceutical industry: productivity challenges and trends

This article reflects on the current status of the pharmaceutical industry and reasons for continued low productivity.

The road ahead for large pharma: long-term science and innovation

The authors of this editorial take a more optimistic view: namely that those with a long-term vision to exploit the intellectual assets internally and externally, who focus in disease areas of genuine unmet need

Multifaceted roles of ultra-rare and rare disease patients/parents in drug discovery

Individual parents and patients are increasingly doing more to fund, discover and develop treatments for rare and ultra-rare diseases that afflict their children, themselves or their friends. They are performing roles in business development that would be classed as entrepreneurial; and their organizational roles in driving the science in some cases are equivalent to those of principal investigators.

Decision support methods for the detection of adverse events

Spontaneous reporting is a crucial component of post-marketing drug safety surveillance despite its significant limitations. The size and complexity of some spontaneous reporting system databases represent a challenge for drug safety professionals who traditionally have relied heavily on the scientific and clinical acumen of the prepared mind. Computer algorithms that calculate statistical measures of reporting frequency for huge numbers of drug-event combinations are increasingly used to support pharamcovigilance analysts screening large spontaneous reporting system databases.

Combining imaging and pathway profiling: an alternative approach to cancer drug discovery

Conventional drug discovery strategies are typically ‘target centric’ based on the selection of lead compounds with optimised ‘on-target’ potency and selectivity profiles. However, high-attrition rates are often the result of compensatory or redundant cancer mechanisms and the fact that tumours do not find it difficult to escape inhibition of a single pathway.

Collaborative approaches to anticancer drug discovery and development: a Cancer Research UK perspective

The pharmaceutical industry is under huge pressure to overhaul what is currently viewed as a highly inefficient operating model. Unacceptable levels of late-stage failure in clinical development remain a fundamental problem for the sector. Lack of efficacy is a major reason for candidate failure and a lack of understanding of disease biology is considered to be a key issue underpinning this problem. There has been a recent upsurge in interest from pharmaceutical and biotechnology companies to collaborate with academic institutions, with the latter viewed as being home to research teams with in-depth biological knowledge and translational research expertise.

Targeting cancer-initiating cell drug-resistance: a roadmap to a new-generation of cancer therapies?

The occurrence of drug resistance in oncology accounts for treatment failure and relapse of diverse tumor types. Cancers contain cells at various stages of differentiation together with a limited number of ‘cancer-initiating cells’ able to self-renew and divide asymmetrically, driving tumorigenesis. Cancer initiating cells display a range of self-defense systems that include almost all mechanisms of drug resistance. Different molecular pathways and markers, identified in this malignant sub-population, are becoming targets for novel compounds and for monoclonal antibodies, which may be combined with conventional drugs. These interventions might eliminate drug-resistant cancer-initiating cells and lead to remission or cure of cancer patients.

Modeling colorectal cancer as a 3-dimensional disease in a dish: case for drug screening using organoids, zebrafish, and fruit flies

In this review Michele Markstein discusses recent shifts in the understanding of colorectal cancer as a stem cell based disease, based on findings that tie patient prognosis to the presence of cancer stem cells in colorectal tumors.

Getting the most out of your IP – patent management along its life cycle

Effectively managing and optimizing the value of the patent portfolio is a major challenge for many firms, especially those in knowledge intensive industries, such as the pharmaceutical, biotechnological and chemical industry. However, insights on effective patent portfolio strategies are rare. Therefore, in this article we investigate in detail how firms successfully manage and optimize their patent portfolios to increase their overall competitiveness. We discover that successful patent portfolio management is rooted in managing the patents along their life cycles. Based on the findings of ten case studies, we develop a holistic patent life cycle management model reflecting five distinctive phases of patent management: explore, generate, protect, optimize and decline. We conclude with how our findings can be used in practice.

Future strategies in epigenetic drug discovery

Most current research aimed at the discovery of epigenetic therapies adheres to the paradigm of target based drug discovery, focusing on the modulation of single enzymes involved in DNA methylation and histone modifications. The recent discovery of promising small molecule inhibitors for a class of nonenzymatic chromatin regulators, the BET bromodomains, suggests that future drug discovery for epigenetic therapy will involve the modulation of protein–protein interactions and multi-protein complexes.

Everybody’s welcome: the big tent approach to epigenetic drug discovery

The rapid expansion of epigenetics research is fueled by the increasing understanding that epigenetic processes are critical to regulating cellular development and dysfunction of epigenetic programs is responsible for a diverse set of human pathologies, including cancer, autoimmune, and neurodegenerative diseases. The expansive set of components contributing to epigenetic disease mechanisms and the often reversible nature of epigenetic lesions provide prime opportunities for the development of novel therapeutic strategies.

Epigenetic drugs that do not target enzyme activity

While the installation and removal of epigenetic post- translational modifications or ‘marks’ on both DNA and histone proteins are the tangible outcome of enzymatically catalyzed processes, the role of the epigenetic reader proteins looks, at first, less obvious. As they do not catalyze a chemical transformation or process as such, their role is not enzymatic. However, this does not preclude them from being potential targets for drug discovery as their function is clearly correlated to transcriptional activity and as a class of proteins, they appear to have binding sites of sufficient definition and size to be inhibited by small molecules. This suggests that this third class of epigenetic proteins that are involved in the interpretation of post-transla- tional marks (as opposed to the creation or deletion of marks) may represent attractive targets for drug discovery efforts.

Recent progress in structure-based anti-influenza drug design

In this review, Juan Du, Timothy A. Cross and Huan-Xiang Zhou present an overview of recent progress in structure-based anti-influenza drug design, paying close attention to the increasing role of computation and strategies for overcoming drug resistance.

Structure-based methods for predicting target mutation-induced drug resistance and rational drug design to overcome the problem

Drug resistance has become one of the biggest challenges in drug discovery and/or development and has attracted great research interests worldwide. During the past decade, computational strategies have been developed to predict target mutation-induced drug resistance. Meanwhile, various molecular design strategies, including targeting protein backbone, targeting highly conserved residues and dual/multiple targeting, have been used to design novel inhibitors for combating the drug resistance.

Multi-objective optimization methods in drug design

Drug discovery is a challenging multi-objective problem where numerous pharmaceutically important objectives need to be adequately satisfied for a solution to be found. The problem is characterized by vast, complex solution spaces further perplexed by the presence of conflicting objectives. Multi-objective optimization methods, designed specifically to address such problems, have been introduced to the drug discovery field over a decade ago and have steadily gained in acceptance ever since.

A chemistry wiki to facilitate and enhance compound design in drug discovery

At AstraZeneca a focus on hypothesis-driven design and the formation of drug design teams has placed a greater emphasis on collaboration in the drug discovery process. Graeme R. Robb and his team have created a novel software tool based on the principles of wikis and social networks to facilitate collaborative working, visual planning and incorporation of predictive science to improve design capability.

Light-activated antibodies in the fight against primary and metastatic cancer

The very cytotoxic potency of therapeutic antibodies used in the fight against cancer makes their specific tumour targeting of crucial importance. Unfortunately, in practice, this is often not achieved and can lead to dangerous side-effects. A way of greatly reducing such side-effects is to make the antibodies region-specific to the areas bearing tumour. This can now be achieved by rendering them light dependent so they are only active where illuminated.

Platforms for high-throughput screening of Wnt/Frizzled antagonists

Signaling cascades initiated by Wnt lipoglycoproteins and their receptors of the Frizzled family regulate many aspects of animal development and physiology. Improper activation of this signaling promotes carcinogenic transformation and metastasis. Development of agents blocking the Wnt-Frizzled signaling is of prime interest for drug discovery. Despite certain progress no such agents are as yet brought to the market or even to clinical trials. One reason for these delays might be the use of suboptimal readout assays.

Shifting from the single to the multitarget paradigm in drug discovery

Increasing evidence that several drug compounds exert their effects through interactions with multiple targets is boosting the development of research fields that challenge the data reductionism approach.

The holistic integration of virtual screening in drug discovery

During the past decade, virtual screening has come of age. In this article, Yusuf Tanrikulu, Bjorn Kruger and Ewgenij Proschak document the evolution and maturation of virtual screening from a rather exotic, stand-alone method toward a versatile hit and lead identification technology. Virtual screening campaigns have become fully integrated into drug discovery campaigns, evenly matched and complementary to high-throughput screening (HTS) methods.

Characterization of epitopes recognized by monoclonal antibodies: experimental approaches supported by freely accessible bioinformatic tools

Monoclonal antibodies (mAbs) have been used successfully both in research and for clinical purposes. The possible use of protective mAbs directed against different microbial pathogens is currently being considered. The fine definition of the epitope recognized by a protective mAb is an important aspect to be considered for possible development in epitope-based vaccinology. The most accurate approach to this is the X-ray resolution of mAb/antigen crystal complex. Unfortunately, this approach is not always feasible. Under this perspective, several surrogate epitope mapping strategies based on the use of bioinformatics have been developed.

Targeting chemokines and chemokine receptors with antibodies

Chemokines and their receptors are highly interesting therapeutic targets for pharmaceutical and biotechnology companies. In particular, industrial development pipelines are filled with new chemokine-targeting drugs to treat inflammatory diseases and malignancies.

Monoclonal antibodies for chronic refractory asthma and pipeline developments

Patients with severe asthma suffer persistent symptoms and/or frequent exacerbations despite high-intensity treatment. Their severe unrelenting symptoms have a huge impact on healthcare resources owing to frequent hospital admissions and requirement for intensive treatments. Consequently, there is an undeniable need for more effective and safer medications. Expanding knowledge of innate and adaptive immune responses is leading to the development of novel therapies for severe asthma.

Foundation review: the future of antibodies as cancer drugs

Targeted therapeutics such as monoclonal antibodies (mAbs) have proven successful as cancer drugs. To profile products that could be marketed in the future, Janice M. Reichert and Eugen Dhimolea examined the current commercial clinical pipeline of mAb candidates for cancer.

In silico repositioning of approved drugs for rare and neglected diseases

One approach to speed up drug discovery is to examine new uses for existing approved drugs, so-called ‘drug repositioning’ or ‘drug repurposing’, which has become increasingly popular in recent years. Analysis of the literature reveals many examples of US Food and Drug Administration-approved drugs that are active against multiple targets (also termed promiscuity) that can also be used to therapeutic advantage for repositioning for other neglected and rare diseases.

In silico drug repositioning – what we need to know

In this article, Zhichao Liu et al. propose the key bioinformatics steps essential for discovering valuable repositioning methods.

Drug repurposing in pediatrics and pediatric hematology oncology

In this review, Julie Blatt and Seth J. Corey explore the scope of drug repurposing in pediatric hematology oncology and in pediatrics in general.

Orphan/rare drug discovery through drug repositioning

In this article Ramaiah Muthyala discusses new approaches to developing therapeutic options for orphan diseases.

Towards the use of hydrogels in the treatment of limbal stem cell deficiency

In this focussed review Bernice Wright, Shengli Mi and Che J. Connon highlight hydrogels as biomaterial substrates which may replace and/or complement amniotic membrane in the treatment of limbal stem cell deficiency.

The promise of stem cells for age-related macular degeneration and other retinal degenerative diseases

In this article Marco Zarbin reviews the development of hESC/iPSC-based therapies for treating age-related macular degeneration and other retinal degenerative diseases associated with abnormalities in the retinal pigment epithelium (RPE) and/or photoreceptors.

Stem cell technology for drug discovery and development

In this article Lilian A. Hook discusses how stem cells have already been used in the drug discovery process and how novel technologies, particularly in relation to stem cell differentiation, can be applied to attain widespread adoption of stem cell technology by the pharmaceutical industry.

Human pluripotent stem cell-derived cardiovascular progenitors for heart regeneration

In this article Lui et al. discuss the innate capacity for cardiac regeneration in zebrafish, the types of progenitors driving development in the mammalian heart and how to empower cardiac progenitor cells or myocytes derived from human pluripotent stem cells to survive, engraft and improve function in the hostile microenvironment of the post-ischemic heart.

Strategic alliances and market risk

In this article Matthias Havenaar and Peter Hiscocks make the case that strategic alliances can fail because of how they are negotiated. Alliance contracts are often inflexible and do not allow for changes in market conditions.

Early chemical development at Legacy Wyeth Research

In this article Michael K. O’Brien et al. describe an approach to early process development in the context of the productivity model in legacy Wyeth (i.e. to deliver two New Drug Applications per year for New Molecular Entities).

Alternative business models for drug discovery

Sean Ekins and Barry Bunin discuss alternative business models that allow researchers simultaneously to ‘cooperate and compete’ and academics to continue to have a much bigger role in discovery research than they have in the past.

Biopharma business models in Canada

This article provides new insights into the different strategy paths or business models currently being implemented by Canadian biopharma companies.

The graphical representation of ADME-related molecule properties for medicinal chemists

The importance of striving for and maintaining drug-like physicochemical properties during the hit and lead optimization process is now well documented, and many published studies have suggested optimal ranges and/or limits for key molecule descriptors such as size, lipophilicity, H-bonding characteristics, rotatable bond and aromatic ring counts, particularly with regard to the design of orally administered drugs.

Toward in silico structure-based ADMET prediction in drug discovery

Quantitative structure–activity relationship (QSAR) methods and related approaches have been used to investigate the molecular features that influence the absorption, distribution, metabolism, excretion and toxicity (ADMET) of drugs. As the three-dimensional structures of several major ADMET proteins become available, structure-based (docking-scoring) computations can be carried out to complement or to go beyond QSAR studies. Applying docking-scoring methods to ADMET proteins is a challenging process because they usually have a large and flexible binding cavity; however, promising results relating to metabolizing enzymes have been reported.

Utility of protein structures in overcoming ADMET-related issues of drug-like compounds

The number of solved X-ray structures of proteins relevant for ADMET processes of drug molecules has increased remarkably over recent years. In principle, this development offers the possibility to complement the quantitative structure–property relationship (QSPR)-dominated repertoire of in silico ADMET methods with protein-structure-based approaches. However, the complex nature and the weak nonspecific ligand-binding properties of ADMET proteins take structural biology methods and current docking programs to the limit.

The growing impact of click chemistry on drug discovery

Click chemistry is a modular approach that uses only the most practical and reliable chemical transformations. Its applications are increasingly found in all aspects of drug discovery, ranging from lead finding through combinatorial chemistry and target-templated in situ chemistry, to proteomics and DNA research, using bioconjugation reactions.

Drug discovery in pharmaceutical industry: productivity challenges and trends

Low productivity, rising R&D costs, dissipating proprietary products and dwindling pipelines are driving the pharmaceutical industry to unprecedented challenges and scrutiny. In this article Ish Khanna reflects on the current status of the pharmaceutical industry and reasons for continued low productivity.

Target–drug interactions: first principles and their application to drug discovery

In this review, Sara Nunez, Jennifer Venhorst and Chris G. Kruse begin by introducing the basic principles of kinetics and thermodynamics of target–drug binding within the context of drug discovery.

Liposomal drug formulations in cancer therapy: 15 years along the road

Liposomes as pharmaceutical drug carriers were developed to increase antitumour efficacy and decrease drug toxicity. Doxorubicin HCl liposomal injection was the first liposomal encapsulated anticancer drug to receive clinical approval. To date, virtually all traditional anticancer drugs have been encapsulated in liposomes.

The formulation of polyhedral boranes for the boron neutron capture therapy of cancer

The early promise of boron neutron capture therapy as a method for the treatment of cancer has been inhibited by the inherent toxicity associated with therapeutically useful doses of 10B-containing pharmacophores, the need for target-tissue specificity and the challenges imposed by biological barriers.

Formulation technology to repurpose drugs for inhalation delivery

Inhalation of drugs for both medicinal and recreational purposes has occurred for centuries. Over the past two decades, a variety of new formulation technologies and inhaler devices have been developed to repurpose drugs given by other routes of administration as superior inhalation products with improvements in safety, efficacy and convenience for patients.

Lipid-based formulations for oral delivery of lipophilic drugs

In the past decade there has been a growing interest in lipid-based formulations to deliver challenging compounds such as lipophilic drugs.

Foundation review: MRI as a tool for evaluation of oral controlled release dosage forms

In this article Przemyslaw P. Dorozynski, Piotr Kulinowski, Anna Mlynarczyk and Greg J. Stanisz review milestones, research directions and the evolution of approaches to the application of MRI to the analysis of CR systems.

Preclinical optical imaging and MRI for drug development in Alzheimer’s disease

In this review Maarten Rotman, Thomas J.A. Snoeks and Louise van der Weerd demonstrate the preclinical use of the two imaging techniques in Alzheimer’s disease, including examples from recent applications and discuss what is needed to improve their applicability for drug discovery.

A procedural framework for good imaging practice in pharmacological fMRI studies applied to drug development #1: processes and requirements

There is increasing interest in the application of quantitative magnetic resonance imaging (MRI) methods to drug development, but as yet there is little standardization or best practice guidelines for its use in this context. Pharmaceutical trials are subject to regulatory constraints and sponsor company processes, including site qualification and expectations around study oversight, blinding, quality assurance and quality control (QA/QC), analysis and reporting of results. In this article, Adam J. Schwarz et al. review the processes on the sponsor side and also the procedures involved in data acquisition at the imaging site.

High field MRI in clinical practice

One of the most important unmet needs in the development of new drugs as well as the delivery and monitoring of new medicinal entities is the development of new biomarkers that can be used as (surrogate) endpoints to assess the therapeutic effect. Imaging, combining high-resolution spatial information with specific functional and molecular information, is making important inroads in producing such new biomarkers.

3D cell culture opens new dimensions in cell-based assays

3D cell culture technologies have revolutionized our understanding of cellular behavior, both in culture and in vivo, but adoption by cell-based screening groups has been slow owing to problems of consistency, scale and cost. The evolving field of high content screening technologies will, however, require a rethinking of 3D cell culture adoption to ensure the next generation of cells provide relevant in vivo-like data.

Label-free whole-cell assays: expanding the scope of GPCR screening

A new class of instruments offers an unprecedented combination of label-free detection with exquisite sensitivity to live-cell responses. These instruments can quantify G-protein-coupled receptor (GPCR) signaling through Gs, Gi and Gq pathways and in some cases distinguish G-protein coupling, with sensitivity high enough to detect endogenous receptors.

Microtissue size and hypoxia in HTS with 3D cultures

The three microenvironmental factors that characterize 3D cultures include: first, chemical and/or biochemical composition, second, spatial and temporal dimensions, and third, force and/or substrate physical properties. Although these factors have been studied individually, their interdependence and synergistic interactions have not been well appreciated.

Biomarkers for simplifying HTS 3D cell culture platforms for drug discovery: the case for cytokines

In this review, the authors discuss the microenvironmental cues that modulate the status of cells to yield physiologically more relevant three-dimensional (3D) cell-based high throughput drug screening (HTS) platforms for drug discovery. Evidence is provided to support the view that simplifying 3D cell culture platforms for HTS applications calls for identifying and validating ubiquitous three-dimensionality biomarkers. Published results from avascular tumorigenesis and early stages of inflammatory wound healing, where cells transition from a two-dimensional (2D) to 3D microenvironment, conclusively report regulation by cytokines, providing the physiological basis for focusing on cytokines as potential three-dimensionality biomarkers.

Stem cells and cell lines from the human auditory organ: applications, hurdles and bottlenecks in the development of regenerative therapies for deafness

The development of any stem-cell-based therapy (and a potential one for deafness is no exception) relies on the generation of the necessary tools: ‘cell drugs’ that can be safely manufactured for their clinical application.

Orphan drug development: an economically viable strategy for biopharma R&D

Orphan drug incentives have stimulated research into diseases with significant unmet medical need.

Optical biosensors: where next and how soon?

Matthew A. Cooper outlines the progress of optical label-free in the drug discovery technology markets.

Label-free receptor assays

Ye Fang outlines how label-free biosensors provide a new dimension for elucidating receptor biology and for facilitating drug discovery.

Label-free whole-cell assays: expanding the scope of GPCR screening

Clay W Scott and Matthew F. Peters review emerging data evaluating impedance- and optical-based label-free instruments for GPCR drug discovery.

Launch excellence for diabetes medicines

Sarah Rickwood and Carolyn Gauntlett from the European Thought Leadership Group IMS Health discuss the market for non-insulin diabetes treatments.

Non-optical screening platforms: the next wave in label-free screening?

In this article Matthew A. Cooper highlights key advances in commercial label-free analysis platforms, which complement more traditional optical systems and which also enable novel assay formats for the analysis of previously intractable targets.

Drug discovery and p53

In this article David Lane and Ted Hupp discuss the p53 gene. The p53 gene is one of many tumour suppressors and appears to be relatively unique in its function at a nodal point as a mediator of the cellular response to changes in the microenvironment. In this article the authors outline the p53 transcriptional pathway, mutant p53 as an anti-cancer drug target and refolding of the structural class of mutant p53.

The role of fragment-based and computational methods in polypharmacology

In this article Giovanni Bottegoni et al. report on fragment-based and computational methods that might accelerate and optimize the discovery of multitarget drugs. In particular, they illustrate that fragment-based approaches can be particularly suited for polypharmacology, owing to the inherent promiscuous nature of fragments.

Fragment screening to predict druggability (ligandability) and lead discovery success

In this article Fredrik N.B. Edfeldt et al. discuss using an initial fragment screen to determine the ligandability of new targets. An insightful analysis of the ligandability score, the success of HTS and entry into hit-to-lead is presented for 36 targets.

Ligand efficiency as a guide in fragment hit selection and optimization

Fragment-based screening (FBS) has become an established approach for hit identification. Starting points identified by FBS, are small fragments that require substantial modification to become leads. As fragments are different from classical hits a process tailored for fragment evolution is required. Scores for ligand efficiency have been proposed as guides for this process. In this article the Sabine Schultes et al. review how these have been applied to guide the selection and optimization of fragment hits.

Fragments: past, present and future

In this article Mark Whittaker et al. review the origin of the fragment-based drug discovery approach, discuss how it is being applied and the prospects for future development. Futhermore, they illustrate this with examples from their own projects where they have found that information from fragments can inform the optimisation of hits identified by other means (e.g. HTS and/or virtual screening) and vice versa.

Getting physical in drug discovery II: the impact of chromatographic hydrophobicity measurements and aromaticity

Here, we review the performance of chromatographic hydrophobicity measurements in a data set of 100 000 GlaxoSmithKline compounds, demonstrating the advantages of the method over octanol–water partitioning and highlighting new insights for drug discovery. The value of chromatographic measurements, versus other hydrophobicity estimates, was supported by improved relationships with solubility, permeation, cytochrome P450s, intrinsic clearance, hERG binding and promiscuity. We also observed marked differentiation of the relative influence of intrinsic and effective hydrophobicity. The summing of hydrophobicity values plus aromatic ring count [log DpH7.4 (or log P) + #Ar], indicated a wide relevance for simplistic ‘property forecast indices’ in developability assays, clearly enhanced by chromatographic values; therefore establishing new foundations for enriching property-based drug design.

Characterization of protein therapeutics by mass spectrometry: recent developments and future directions

This review article by Guodong Chen, Bethanne M. Warrack, Angela K. Goodenough, Hui Wei, David B. Wang-Iverson and Adrienne A. Tymiak describes recent developments and future trends in the characterization of protein therapeutics using mass spectrometry.

Capillary electrophoresis and small molecule drug discovery: a perfect match?

In this article Alfonso Espada and Manuel Molina-Martin review capillary electrophoresis fundamentals, well-established capillary electrophoresis methodologies in drug discovery of small molecules and discuss trends that, in their opinion, might emerge in the coming years.

How to conduct and interpret ITC experiments accurately for cyclodextrin–guest interactions

In this review Kawthar Bouchemal and Silvia Mazzaferro explain how to conduct ITC experiments correctly for CD–guest interactions, how to choose an accurate fitting model for the titration curve and how to interpret carefully the ITC results. Also, the use of ITC for the characterization of CD-containing nanoparticles is discussed.

Targeting the mTOR kinase domain: the second generation of mTOR inhibitors

Yan-Jie Zhang, Yanwen Duan and X.F. Steven Zheng discuss the potential therapeutic value and issues of novel antineoplastic agents, with emphasis placed on those that have already entered clinical trials.

Cytoplasmic ATM protein kinase: an emerging therapeutic target for diabetes, cancer and neuronal degeneration

In this article Da-Qing Yang, Marie-Jo Halaby, Yan Li, Jody C. Hibma and Paul Burn discuss recent advances in elucidating the cytoplasmic localization and function of ATM. Particular attention is given to the role of ATM in insulin signaling and Akt activation. The potential for cytoplasmic ATM protein kinase to be an emerging therapeutic target for treating diabetes, cancer and neuronal degeneration is discussed.

Aurora-A kinase inhibitor scaffolds and binding modes

Aixia Yan, Liyu Wang, Shuyu Xu and Jun Xu summarize the common binding modes of Aurora-A kinase inhibitors, the hot spot residues in the binding sites and the privileged inhibitor structures. Their review of the reported chemical scaffolds of Aurora-A kinase inhibitors and their binding modes could provide a useful framework from which new design strategies for inhibitors might be assessed or developed.

HIV-1 proteins join the family of LIM kinase partners. New roads open up for HIV-1 treatment

In this article Fabrizio Manetti discusses the area of LIM kinases and how the development of inhibitors of these enzymes might be a successful approach to the treatment of AIDS.

Should medicinal chemists do molecular modelling?

In this article Timothy J. Ritchie and Iain M. McLay discuss the pros and cons of medicinal chemists undertaking three-dimensional (3D) computer-aided Q2 drug design (CADD) activities for themselves, from the viewpoint of both medicinal chemists and computational chemists.

Conformations and 3D pharmacophore searching

Christof H. Schwab gives some insights into the general challenges and problems in the area of 3D structure and conformation generation and focuses on some available and recent software technologies and approaches applicable for this task.

3D pharmacophores as tools for activity profiling

In this article Daniela Schuster highlights the concept, recent applications and caveats of pharmacophore-based activity profiling.

The value of in silico chemistry in the safety assessment of chemicals in the consumer goods and pharmaceutical industries

In this article Sandeep Modi, Michael Hughes, Andrew Garrow and Andrew White discuss limitations and strengths of in silico tools. Additionally, they look at different parameters that are necessary to make the best use of these tools, and also how to gain acceptance outside the modelling community and into the regulatory arena.

In silico repositioning of approved drugs for rare and neglected diseases

Sean Ekins, Antony J. Williams, Matthew D. Krasowski and Joel S. Freundlich discuss how drug repurposing will emerge for neglected or rare and/or orphan diseases. Using proof-of-principle examples, they suggest that with current in silico technologies and databases of the structures and biological activities of chemical compounds (drugs) and related data, as well as close integration with in vitro screening data, improved opportunities for drug repurposing will emerge for neglected or rare/orphan diseases.

Toward in silico structure-based ADMET prediction in drug discovery

In this article Gautier Moroy, Virginie Y. Martiny, Philippe Vayer, Bruno O. Villoutreix and Maria A. Miteva discuss recently reported in silico studies aiming at predicting small molecules binding to ADMET-related proteins based on the knowledge of the 3D structures of these macromolecules with a special emphasis on metabolizing enzymes.

Computational models for predicting substrates or inhibitors of P-glycoprotein

Lei Chen, Youyong Li, Huidong Yu, Liling Zhang and Tingjun Hou review in silico approaches and computational models for identifying substrates or inhibitors of P-gp. The advances in the datasets for model building and available computational models are summarized and the advantages and drawbacks of these models are outlined.

The graphical representation of ADME-related molecule properties for medicinal chemists

Timothy J. Ritchie, Peter Ertl and Richard Lewis review various approaches that have been used to represent molecule properties graphically in the context of oral ‘drug likeness’, with the goal of improving the decision making of medicinal chemists during the drug discovery process.

ROCK: the Roche medicinal chemistry knowledge application – design, use and impact

Alexander Maywe et al. discuss ROCK (Roche medicinal chemistry knowledge), an internal user-friendly and peer-reviewed Wiki-like application to capture, browse and search tacit knowledge, key discoveries and property effects related to chemical structure, which is used as a primary source for addressing challenges faced in drug design.

The future of discovery chemistry: quo vadis? Academic to industrial – the maturation of medicinal chemistry to chemical biology

In this article, Torsten Hoffmann and Cheryl Bishop outline a chain of thoughts that concludes that chemistry has a wider part to play in innovative drug discovery than it is currently permitted by industry to have.

How well do medicinal chemists learn from experience?

David R. Cheshire provides evidence that suggests that modern medicinal chemists are overproductive in that they synthesise many more compounds than are required to achieve the objectives of the project.

Drug repurposing from an academic perspective

Drug repurposing from an academic perspective; featured article from Drug Discovery Today: Therapeutic Strategies, Winter 2011

Orphan/rare drug discovery through drug repositioning

Highlight from Drug Discovery Today: Therapeutic Strategies, Winter 2011

Orphan/rare drug discovery through drug repositioning

Highlight from the Winter 2011 issue of Drug Discovery Today: Therapeutic Strategies

Cheminformatic/bioinformatic analysis of large corporate databases: Application to drug repurposing

Highlight from the Winter 2011 issue of Drug Discovery Today: Therapeutic Strategies

Repositioned drugs: integrating intellectual property and regulatory strategies

This is a highlight of the Winter 2011 issue of Drug Discovery Today: Therapeutic Strategies

Drug repurposing through nonhypothesis driven phenotypic screening

A highlight of the Winter 2011 issue of Drug Discovery Today: Therapeutic Strategies

Abiraterone acetate: redefining hormone treatment for advanced prostate cancer

In this article Carmel J. Pezaro, Deborah Mukherji and Johann S. De Bono review the preclinical discovery and clinical development of abiraterone acetate and outline the strategy of parallel translational research.

Targeting cancer metabolism – aiming at a tumour’s sweet-spot

Neil Jones and Almut Schultz discuss how targeting cancer cell metabolism has emerged as a new area for anticancer drug discovery.

New regulatory framework for cancer drug development

Recent changes to non-clinical cancer guidelines offer a golden opportunity to expedite the translation of new anticancer drugs into the clinic. In this article Paul S. Jones and David Jones look at how these guidelines can be implemented and how they can be integrated with non-clinical and clinical study design to produce robust and safe clinical trials.

HSP90 inhibition: two-pronged exploitation of cancer dependencies

In this article Jon Travers, Swee Sharp and Paul Workman evaluate the key role of HSP 90 in enabling the functional and structural stabilisation of a host of client oncoproteins.

A quality alert and call for improved curation of public chemistry databases

The quality of much of the chemical structure-based data introduced to the public domain is poor. The authors of this editorial describe some of the errors found in the recently released NIH Chemical Genomics Center ‘NPC browser’ database as an example.

Clinical and biological data integration for biomarker discovery

In this review the authors have integrated parameters across clinical trials and associated genetic, gene expression and protein data. They provide examples to illustrate the utility of data integration to explore disease heterogeneity and develop predictive biomarkers.

A structural informatics approach to mine kinase knowledge bases

In this article, the authors describe a combination of structural informatics approaches developed to mine data extracted from existing structure knowledge bases (Protein Data Bank and the GVK database) with a focus on kinase ATP-binding site data.

Current trends in antimicrobial agent research: chemo- and bioinformatics approaches

This article reviews progress in the development of computational methods, tools and databases used for organizing and extracting biological meaning from antimicrobial research.

Recent progress toward biomarker identification in osteoarthritis

In this review, De Ceuninck et al. highlight the difficulties associated with osteoarthritis diagnosis and discuss the most recent research efforts and successes for the identification of reliable osteoarthritis biomarkers.

A generic operational strategy to qualify translational safety biomarkers

The importance of using translational safety biomarkers that can predict, detect and monitor drug-induced toxicity during human trials is becoming increasingly recognized. In this article Matheis et al. discuss a generic qualification strategy, established by the IMI SAFE-T consortium, for new translational safety biomarkers that will allow early identification, assessment and management of drug-induced injuries throughout R&D.

Clinical and biological data integration for biomarker discovery

Sorani et al. describe a data integration strategy that implements a clinical and biological database and a wiki interface. They integrated parameters across clinical trials and associated genetic, gene expression and protein data. They also provide examples to illustrate the utility of data integration to explore disease heterogeneity and develop predictive biomarkers.

The biomarker is not the end

In this article Michael Nohaile discusses several areas of expertise that need to be considered for drug discovery and translational scientists to use stratification with biomarkers to improve the chances of getting medicines to patients.

Diabetic cardiomyopathy: mechanisms and therapeutic targets

Pavan K Battiprolu et al. discuss insights into mechanisms and molecular events involved in the pathogenesis of diabetic cardiomyopathy.

New strategies to improve the intranasal absorption of insulin

Xiaopin Duan and Shirui Mao describe the main barriers preventing nasal insulin absorption, and special attention is given to new approaches to improve the intranasal absorption of insulin, including the application of new safe absorption enhancers and the use of appropriate delivery systems.

The potential of incretin-based therapies in type 1 diabetes

Chen S. Suen and Paul Burn discuss the preclinical and clinical data that have been accumulated to date on incretin-based therapies in type 1 diabetes and type 2 diabetes settings.

Pharmacogenomic strategies in drug safety

This review highlights some successes in discovery and translation of pharmacogenomic biomarkers for adverse drug events and outlines future strategies to optimize the development and clinical application of pharmacogenomic information.

Mitochondrial pharmacogenomics: barcode for antibiotic therapy

This article explores the exciting potential of mitochrondrial pharmacogenetics. Ribosomal RNA (rRNA)-targeting drugs inhibit protein synthesis and represent effective antibiotics for the treatment of infectious diseases.

Progress towards personalized medicine

Stewart Bates explores how the advent of improved genomic tools has greatly hastened our understanding of the molecular pathology of diseases and how this could enable us to redefine diseases at the molecular level. Together with improved diagnostic criteria, Bates discusses the question: ‘how close is personalized medicine to delivering on its promise?’

European attitudes to gene therapy and pharmacogenetics

Hudson and Orviska discuss the views of pharmacogenetics and gene therapy across European countries.

Instructions for Authors

These are the instructions to authors for submission of articles to Drug Discovery Today

A quality alert and call for improved curation of public chemistry databases

In the last ten years, public online databases have rapidly become trusted valuable resources upon which researchers rely for their chemical structures and data for use in cheminformatics, bioinformatics, systems biology, translational medicine and now drug repositioning or repurposing efforts. Their utility depends on the quality of the underlying molecular structures used. Unfortunately, the quality of much of the chemical structure-based data introduced to the public domain is poor. As an example we describe some of the errors found in the recently released NIH Chemical Genomics Center ‘NPC browser’ database as an example. There is an urgent need for government funded data curation to improve the quality of internet chemistry and to limit the proliferation of errors and wasted efforts.

Dendrimer-based drug and imaging conjugates: design considerations for nanomedical applications

This review focuses on several crucial issues related to those dendrimer features, namely the role of dendrimers as nanoscaffolding and nanocontainers, crucial principles that might be invoked for improving dendrimer cytotoxicity properties, understanding dendrimer cellular transport mechanisms and the exciting role of dendrimers as high-contrast MRI imaging agents.

Cancer nanotechnology: application of nanotechnology in cancer therapy

This review focuses on the approaches of cancer nanotechnology in the advancement of cancer therapy.

On the edge of new technologies (advanced therapies, nanomedicines)

Nanotechnology-based and advanced therapy medicinal products are at the cutting edge of innovation in translational drug development, potentially offering new treatment approaches for diseases with limited or no therapeutic alternatives.

Functionalized carbon nanotubes for potential medicinal applications

This review focuses on the progress of the functionalizations of CNTs, which are the preconditions for CNT applications in medicine, the potential applications of CNTs in the treatment of intractable issues in medicine and the associated potential risks of CNT applications in nanomedicine.

Animal models of asthma: value, limitations and opportunities for alternative approaches

Current in vivo asthma models are poorly predictive of human disease. In vitro and human model approaches may fill remaining knowledge gaps and pharmaceutical company asthma drug pipelines, whilst reducing reliance on animal models.

Cytoplasmic ATM protein kinase: an emerging therapeutic target for diabetes, cancer and neuronal degeneration

Recent advances in elucidating the cytoplasmic localization and function of ATM are reviewed. Particular attention is given to the role of ATM in insulin signaling and Akt activation. The potential for cytoplasmic ATM protein kinase to be an emerging therapeutic target for treating diabetes, cancer and neuronal degeneration is discussed.

Interference with islet-specific homing of autoreactive T cells: an emerging therapeutic strategy for type 1 diabetes

In this review molecular mechanisms governing transendothelial migration of the diabetogenic effector cells are discussed and resulting pharmacological strategies are considered.

Drug discovery in the next decade: innovation needed ASAP

In this article the author introduces a new concept, termed ‘innovation ASAP’ (iASAP; asking powerful questions, seeking the outliers, accepting defeat and populating astutely) and provides support for it using examples of several successful drugs.

Outsourcing lead optimization: the eye of the storm

This article is the third in a series examining the evolution of the market for outsourced lead optimization services and covers developments from late 2006 to the present.

Creativity, innovation and lean sigma: a controversial combination?

In this article the authors consider the conditions required for improved organizational creativity and innovation. They also explore whether lean sigma deployment has characteristics that make it inherently anti-innovative or a supportive pro-innovative force.

A biological stabilization technology for peptide drugs: enzymatic introduction of thioether-bridges

This review describes the biological technology of using Lactococcus lactis containing the nisin-modifying enzymes for producing thioether-stabilized therapeutic peptides.

Building on bortezomib: second generation proteasome inhibitors as anti-cancer therapy

Inhibition of the proteasome is an effective anti-cancer therapeutic approach, as demonstrated by the first-in-class agent bortezomib. Various new proteasome inhibitors are now in development, including peptide boronic acid analogs MLN9708 and CEP-18770, peptide epoxyketones carfilzomib and PR-047, and NPI-0052, a beta-lactone compound. In this review the authors review the second-generation proteasome inhibitors and assess the potential pharmacologic impact of their different chemical properties.

Synthetic therapeutic peptides: science and market

This review reports on the unexpected and considerable number of peptides that are currently available as drugs and the chemical strategies that were used to bring them into the market. As demonstrated in this review, peptide-based drug discovery could be a serious option for addressing new therapeutic challenges.

HIV-derived peptide mimics

Peptides capable of mimicking functionally important regions of HIV proteins are excellent tools to explore structure and function of HIV proteins. Recent advances in the design and generation of HIV mimetic peptides are summarized in this article.

Evolving molecules using multi-objective optimization: applying to ADME/Tox

Human nature focuses the scientist on one parameter at a time, yet drug discovery is multidimensional, so to improve our decision making we need tools that can aid in optimizing all key parameters simultaneously.

Biotransformation pathway maps in WikiPathways enable direct visualization of drug metabolism related expression changes.

Recent advances in pharmacogenetics, pharmacogenomics and toxicogenomics have 20 increased our knowledge on the genetics and functional genomics of drug metabolizing 21 enzymes. In addition, a wealth of data on drug-related transcriptomics, proteomics and 22 metabolomics has become available. Despite the availability of large amounts of 23 biological information on xenobiotic biotransformation from literature and online 24 resources, the number of available biotransformation pathway maps that can easily be 25 used for visualization of multiple “omics” data, is limited.

Computational toxicology–a tool for early safety evaluation

This review focuses on recent developments in computational toxicology. Direct modeling of toxic endpoints has been deceiving and hampered the wide acceptance of computer predictions. The current trend is to make simpler predictions, closer to the mechanism of action, and to follow them up with in vitro or in vivo assays as appropriate. predictions, closer to the mechanism of action, and to follow them up with in vitro or in vivo assays as appropriate.

The graphical representation of ADME-related molecule properties for medicinal chemists

This article reviews the various approaches that have been used to represent ADME related molecule properties graphically in the context of oral drug-likeness.

Utility of protein structures in overcoming ADMET-related issues of drug-like compounds

The availability of high resolution x-ray structures of ADMET relevant proteins might extend the application of structure-based drug design from potency to ADMET prediction. It is however a long way to go and involves an even better understanding of these proteins than is available today.

Intestinal delivery of non-viral gene therapeutics: physiological barriers and preclinical models

The future of nucleic acid-based therapeutics is dependent on achieving successful delivery. Recently, there has been an increasing interest in delivery via the gastrointestinal tract. Gene therapy via this route has many advantages, including non-invasive access and the versatility to treat local diseases, such as inflammatory bowel disease, as well as systemic diseases, such as haemophilia.

Lyotropic liquid crystal systems in drug delivery

Lyotropic liquid crystal systems, such as reversed bicontinuous cubic and hexagonal mesophases, are attracting more and more attention because of their unique microstructures and physicochemical properties.

Calcium phosphate biomaterials as bone drug delivery systems: a review

A short review is proposed on the existing literature for the research performed in calcium phosphate (CaP) biomaterials used as drug delivery systems. In the first part, a brief update is given on the performance of both CaP ceramics and CaP cements. Second, a review of the research and clinical situation is developed for CaP materials already used as drug delivery systems.

Foundation review: Antiangiogenic therapy using nanotechnological-based delivery system

Of the many approaches for the treatment of cancer, angiogenesis and the additional promotion of apoptosis in cancer stem cells by using combinatorial therapy is usually the most recommended. There has been increased interest in the use of antiapoptotic and antiangiogenic biomolecules, such as antiangiogenic microRNA, small interfering RNA, inhibitor of apoptosis protein-binding peptides and Von Hippel-Lindau tumor suppressors, as well as targeting ligands, such as aptamers. Therefore, it is tempting to suggest that such molecules could be used for anticancer therapy.

Disease-specific target selection: a critical first step down the right road

Relevance of a drug target for a disease is often inferred with strong belief but fragile evidence. Here, a program for early identification of human diseasespecific drug targets using high-throughput genetic associations is described

Identifying and validating novel targets with in vivo disease models: Guidelines for study design

In vivo studies are an important tool for the identification and validation of novel drug targets in medicine; however, the interpretation of submitted and published data is often compromised by inadequate study design.

Target discovery from data mining approaches

Data mining of available biomedical data and information has greatly boosted target discovery in the ‘omics’ era. Target discovery is the key step in the biomarker and drug discovery pipeline to diagnose and fight human diseases.

Outsourcing lead optimization: constant change is here to stay

Since last reviewed in 2004, the market for outsourcing lead optimization has continued to grow and to change. Here, I review some of the key events that have taken place in this time, particularly merger and acquisition activity, and also seek to delineate some of the emerging trends.

Modelling iterative compound optimisation using a self-avoiding walk

The optimisation phase is a crucial step in the process of drug development, yet the mechanics of the projects that make it up are poorly understood. Weak documentation of failed projects makes statistical analysis of the factors affecting project performance challenging, so a better approach may be the development of an underlying theory of how projects work.

Thermodynamics guided lead discovery and optimization

We hypothesize that entropy-driven optimizations might be responsible for the undesirable trend observed in physicochemical properties. Consequently, we suggest that enthalpydriven optimizations are preferred because they provide better quality compounds.

Drug Discovery: an Industrial Process

How are drugs discovered and developed?

Epigenetic therapies for non-oncology indications

Chronic and degenerative disorders are a major, and growing, human health burden, and current treatments are in many cases inadequate or very expensive. Epigenetic therapies are attractive options for treating such disorders because they manipulate the processes that maintain cells in an abnormal transcriptional state.

Advances in the computational development of DNA methyltransferase inhibitors

This review covers three main areas. Current DNMT inhibitors are discussed first, followed by molecular modeling studies toward the understanding of the mechanism of action of known DNMT inhibitors at the molecular level. Finally, successful virtual screening studies to identify novel small molecule inhibitors are reviewed.

Making medicinal chemistry more effective—application of Lean Sigma to improve processes, speed and quality

The pharmaceutical industry, particularly the small molecule domain, faces unprecedented challenges of escalating costs, high attrition as well as increasing competitive pressure from other companies and from new treatment modes such as biological products. In other industries, process improvement approaches, such as Lean Sigma, have delivered benefits in speed, quality and cost of delivery. Examining the medicinal chemistry contributions to the iterative improvement process of design-make-test-analyse from a Lean Sigma perspective revealed that major improvements could be made. Thus, the cycle times of synthesis, as well as compound analysis and purification, were reduced dramatically. Improvements focused on team, rather than individual, performance. These new ways of working have consequences for staff engagement, goals, rewards and motivation, which are also discussed.

Computational quantum chemistry and adaptive ligand modeling in mechanistic QSAR

This article deals with the application of computational quantum chemistry to drug design and discovery.

The future of discovery chemistry: quo vadis? Academic to industrial – the maturation of medicinal chemistry to chemical biology

The article deals with how medicinal chemistry must diversify at pace and in line with the increasing understanding of chemical biology, in order to provide the necessary innovation that the industry requires.

Current applications and future potential for bioinorganic chemistry in the development of anticancer drugs

This article is concerned with the progress of bioinorganic chemistry particularly in the field of cancer.

Medicinal chemistry strategies in follow-on drug discovery

This article discusses the medicinal chemistry strategies that have been utilized by the pharmaceutical industry to exploit validated therapeutic targets.

Use of functional assays to detect and quantify functional selectivity

Drug selectivity is arguably a critical concern for drug development. Recently, experimental evidence suggests that drugs have more selectivity than that afforded by differential affinity for different receptor subtypes. Drugs, acting at a single receptor, can selectively and differentially activate each of the multiple signaling pathways coupled to a receptor. This type of selectivity has been termed functional selectivity. Understanding functional selectivity and how to measure it will be important for new drug development

Label-free receptor assays

Label-free biosensors offer integrated, kinetic and multi-parametric measures of receptor biology and ligand pharmacology in whole cells. Being highly sensitive and pathway-unbiased, label-free receptor assays can be used to probe the systems cell biology including pleiotropic signaling of receptors, and to characterize the functional selectivity and phenotypic pharmacology of ligand molecules. These assays provide a new dimension for elucidating receptor biology and for facilitating drug discovery.

Image-based high-content reporter assays: limitations and advantages

Transcription factors are promising targets in many therapeutic areas, and reporter assays represent a mainstay of the cellular approaches utilized to study their functions. Traditional reporter assays lend themselves to screening applications, but do suffer from some disadvantages. During the past decade, the development of image-based high-content reporter assays has boosted transcription factor drug discovery and contributed to the understanding of their functions and molecular dynamics. This review summarizes and discusses the technical approaches currently employed in high-content reporter assays.

Epigenetics: tools and technologies

Epigenetics refers to heritable changes that control how the genome is accessed in different cell-types and during development and differentiation. Even though each cell contains essentially the same genetic code, epigenetic mechanisms permit specialization of function between cells. The state of chromatin, the complex of histone proteins, RNA and DNA that efficiently package the genome, is largely regulated by specific modifications to histone proteins and DNA, and the recognition of these marks by other proteins and protein complexes. The enzymes that produce these modifications (the ‘writers’), the proteins that recognize them (the ‘readers’), and the enzymes that remove them (the ‘erasers’) are crucial targets for manipulation to further understand the histone code and its role in biology and human disease.

Epigenetic control of the immune system: histone demethylation as a target for drug discovery

In recent years significant progress has been made in ourunderstanding of epigenetic control of a wide range of cellular processes. This has come about both through the concerted effort of the research community and through the development of technologies essential to the area. The importance of the epigenetic control of the immune system is becoming increasingly clear, and therefore epigenetics presents itself as an attractive, and potentially ground-breaking, entry point to tackle immune-mediated conditions. The advances in our understanding are in part due to the development of next generation sequencing technologies and chromatin immunoprecipitation. When combined, these approaches have allowed studies at the chromatin level

An industrial perspective on positive allosteric modulation as a means to discover safe and selective drugs

Positive allosteric modulation is an innovative strategy for the discovery of drugs acting at 7-transmembrane receptors. Screening has led to the identification of numerous starting points for medicinal chemistry typified by novel mechanisms of action. The progression of compounds through hit-to-candidate phases and preclinical animal models, however, proves very challenging. In this review, we discuss advances in the area and interrogate the mechanistic profiling required to support drug discovery programs and fully exploit the therapeutic potential of positive allosteric modulators.

Thermodynamics guided lead discovery and optimisation

This article outlines how medicinal chemistry approaches in lead discovery and optimisation can be guided using a thermodynamics approach.

Two ‘Golden Ratio’ indices in fragment-based drug discovery

Ligand efficiency, library design and the uses of the 'Golden Ratio'

Data structures and computational tools for the extraction of SAR information from large compound sets

Compound data analysis and computational tools sor SAR mining of large compound data sets.

Clinical and biological data integration for biomarker discovery

Marco D. Sorani, Ward A. Ortmann, Erik P. Bierwagen and Timothy W. Behrens describe a data integration strategy and show how data integration could be used to develop predictive biomarkers.

From biomarker strategies to biomarker activities and back

Here, Alain J. van Gool, Brian Henry and Erik D. Sprengers outline a rational, question-based drug development strategy in which biomarker data drive decisions on which drug candidates to progress to clinical testing.

Use of biomarkers in the discovery of novel anti-schizophrenia drugs

Jens D. Mikkelsen, Morten S. Thomsen, Henrik H. Hansen and Jacek Lichota take a look at the current validity of biomarkers in the identification of novel anti-schizophrenic drug candidates.

Fit-for-purpose biomarker method validation in anticancer drug development

In this article, Jeffrey Cummings, Tim H. Ward and Caroline Dive aim to clarify the issues surrounding biomarker method validation and the analysis of samples and to provide clear guidance on validation strategies.

Can molecular biomarker-based patient selection in phase I trials accelerate anticancer drug development?

A suggestion for a new model of early clinical trial design from Craig P. Carden, Debashis Sarker, Sophie Postel-Vinay, Timothy A. Yap, Gerthardt Attard, Udai Banerji, Michelle D. Garrett, George V. Thomas, Paul Workman, Stan B. Kaye and Johann S. de Bono.

Pharmacogenetics – pivotal to the future of the biopharmaceutical industry

Elizabeth Foot, Dominique Kleyn and Emma Palmer Foster comment on the debate over the place of pharmacogenetics in the future of drug development, as discussed at the inaugural London Genetics Pharmacogenetic Conference.

Sir David Weatherall reflects on genetics and personalized medicine

In this interview, conducted by Ulrike Knies-Bamforth, Sir David Weatherall tells Drug Discovery Today about the long-term prospects of personalized medicine, personalized medicine in the third world, and much more.

Criteria for the selection of single nucleotide polymorphisms in pathway pharmacogenetics: TNF inhibitors as a case study

Wouter M. Kooloos, Judith A.M. Wessels, Tahar van der Straaten, Tom W.J. Huizinga and Henk-Jan Guchelaar present selection criteria for the pathway pharmacogenetic approach, using adalimumab as a case study.

Pharmacogenetics of EGFR and VEGF inhibition

Jan Pander, Hans Gelderblom and Henk-Jan Guchelaar provide an overview of germ-line variations in genes that are potentially involved in the pharmacodynamics of the monoclonal antibodies cetuximab, panitumumab and bevacizumab.

The impact of pharmacogenetics on the development and use of antipsychotic drugs

Gavin P. Reynolds discusses genetic variation in responses to antipsychotic drugs and asks whether pharmacogenetics will prove valuable in their discovery.

Progress towards personalized medicine

Stewart Bates discusses improved genomic tools and other progress towards a new paradigm in drug development, asking: how close is personalized medicine to delivering on its promise?

Non-coding RNAs and new opportunities for the private sector

Fabrício F. Costa argues that the private sector should start paying more attention to non-coding RNAs to improve the pipeline for drug discovery and drug development and to facilitate the identification of new diagnostic and prognostic markers.

Targeted genetic and viral therapy for advanced head and neck cancers

Head and neck cancers usually present with advanced disease, and novel therapies are urgently needed. Here, Pin-I Huang, Ju-Fang Chang, David H. Kirn and Ta-Chiang Liu summarize the available clinical data and discuss challenges and future directions.

siRNAs: their potential as therapeutic agents – Part II. Methods of delivery

Sunit Kumar Singh and Praveensingh B. Hajeri discuss the challenges associated with siRNA and the full potential of RNAi for the development of therapeutic tools and drugs.

siRNAs: their potential as therapeutic agents – Part I. Designing of siRNAs

Developing precise tools for designing siRNAs can achieve the most efficient knockdown of target genes and reduce off-target effects. Here, Praveensingh B. Hajeri and Sunit Kumar Singh discuss the strategies and parameters required for effective siRNA designing and synthesis.

Aptocine-Mediated Systemic Immune Tumor Destruction: An Emerging Intratumoral Whole Cell Autologous Vaccine

This is a white paper addressing the immunotherapeutic potential of the development product Aptocine and puts it in the context of current treatments and other 'cancer vaccines' in development.

The shrinking of the knowledge base – what is the impact of this on the speed and security of drug development?

Paul Branthwaite discusses the implication of reducing the Pharmaceutical industry knowledge base as a result of mergers, acquisitions and a drive to reduce cost base. He specificaly deals with the impact of these changes on the ability to produce innovative pharmaceuticals and the time required so to do.