http://www.drugdiscoverytoday.com/ Copyright Elsevier Ltd Intuitiv Ltd (www.intuitiv.net) Wed, 22 May 2013 07:05:53 GMT http://www.drugdiscoverytoday.com/ http://www.drugdiscoverytoday.com/_common/img/template/ddt/site-logo.gif http://www.drugdiscoverytoday.com/download/1135/ 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. Tue, 14 May 2013 00:00:00 GMT http://www.drugdiscoverytoday.com/download/1135/ http://www.drugdiscoverytoday.com/download/1136/ 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. Tue, 14 May 2013 00:00:00 GMT http://www.drugdiscoverytoday.com/download/1136/ http://www.drugdiscoverytoday.com/download/1137/ 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. Tue, 14 May 2013 00:00:00 GMT http://www.drugdiscoverytoday.com/download/1137/ http://www.drugdiscoverytoday.com/download/1138/ 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. Tue, 14 May 2013 00:00:00 GMT http://www.drugdiscoverytoday.com/download/1138/ http://www.drugdiscoverytoday.com/download/1105/ 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. Mon, 25 Mar 2013 00:00:00 GMT http://www.drugdiscoverytoday.com/download/1105/ http://www.drugdiscoverytoday.com/download/1102/ In this article, Zhichao Liu et al. propose the key bioinformatics steps essential for discovering valuable repositioning methods. Wed, 20 Mar 2013 00:00:00 GMT http://www.drugdiscoverytoday.com/download/1102/ http://www.drugdiscoverytoday.com/download/1103/ In this review, Julie Blatt and Seth J. Corey explore the scope of drug repurposing in pediatric hematology oncology and in pediatrics in general. Wed, 20 Mar 2013 00:00:00 GMT http://www.drugdiscoverytoday.com/download/1103/ http://www.drugdiscoverytoday.com/download/1104/ In this article Ramaiah Muthyala discusses new approaches to developing therapeutic options for orphan diseases. Wed, 20 Mar 2013 00:00:00 GMT http://www.drugdiscoverytoday.com/download/1104/ http://www.drugdiscoverytoday.com/download/1078/ 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. Tue, 05 Mar 2013 00:00:00 GMT http://www.drugdiscoverytoday.com/download/1078/ http://www.drugdiscoverytoday.com/download/1079/ 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. Tue, 05 Mar 2013 00:00:00 GMT http://www.drugdiscoverytoday.com/download/1079/ http://www.drugdiscoverytoday.com/download/1074/ 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. Fri, 01 Mar 2013 00:00:00 GMT http://www.drugdiscoverytoday.com/download/1074/ http://www.drugdiscoverytoday.com/download/1075/ 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. Fri, 01 Mar 2013 00:00:00 GMT http://www.drugdiscoverytoday.com/download/1075/ http://www.drugdiscoverytoday.com/download/1030/ 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. Fri, 18 Jan 2013 00:00:00 GMT http://www.drugdiscoverytoday.com/download/1030/ http://www.drugdiscoverytoday.com/download/1031/ 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). Fri, 18 Jan 2013 00:00:00 GMT http://www.drugdiscoverytoday.com/download/1031/ http://www.drugdiscoverytoday.com/download/1032/ 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. Fri, 18 Jan 2013 00:00:00 GMT http://www.drugdiscoverytoday.com/download/1032/ http://www.drugdiscoverytoday.com/download/1025/ This article provides new insights into the different strategy paths or business models currently being implemented by Canadian biopharma companies. Mon, 07 Jan 2013 00:00:00 GMT http://www.drugdiscoverytoday.com/download/1025/ http://www.drugdiscoverytoday.com/download/1017/ 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. Wed, 19 Dec 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/1017/ http://www.drugdiscoverytoday.com/download/1018/ 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. Wed, 19 Dec 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/1018/ http://www.drugdiscoverytoday.com/download/1019/ 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. Wed, 19 Dec 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/1019/ http://www.drugdiscoverytoday.com/download/991/ 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. Thu, 29 Nov 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/991/ http://www.drugdiscoverytoday.com/download/987/ 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. Tue, 27 Nov 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/987/ http://www.drugdiscoverytoday.com/download/988/ 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. Tue, 27 Nov 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/988/ http://www.drugdiscoverytoday.com/download/969/ 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. Mon, 19 Nov 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/969/ http://www.drugdiscoverytoday.com/download/975/ 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. Mon, 19 Nov 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/975/ http://www.drugdiscoverytoday.com/download/979/ 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. Mon, 19 Nov 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/979/ http://www.drugdiscoverytoday.com/download/980/ In the past decade there has been a growing interest in lipid-based formulations to deliver challenging compounds such as lipophilic drugs. Mon, 19 Nov 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/980/ http://www.drugdiscoverytoday.com/download/966/ 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. Wed, 31 Oct 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/966/ http://www.drugdiscoverytoday.com/download/961/ 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. Wed, 24 Oct 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/961/ http://www.drugdiscoverytoday.com/download/963/ 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. Wed, 24 Oct 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/963/ http://www.drugdiscoverytoday.com/download/964/ 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. Wed, 24 Oct 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/964/ http://www.drugdiscoverytoday.com/download/917/ 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. Tue, 18 Sep 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/917/ http://www.drugdiscoverytoday.com/download/919/ 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. Tue, 18 Sep 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/919/ http://www.drugdiscoverytoday.com/download/920/ 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. Tue, 18 Sep 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/920/ http://www.drugdiscoverytoday.com/download/921/ 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. Tue, 18 Sep 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/921/ http://www.drugdiscoverytoday.com/download/916/ 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. Thu, 13 Sep 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/916/ http://www.drugdiscoverytoday.com/download/900/ Orphan drug incentives have stimulated research into diseases with significant unmet medical need. Wed, 15 Aug 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/900/ http://www.drugdiscoverytoday.com/download/897/ Matthew A. Cooper outlines the progress of optical label-free in the drug discovery technology markets. Tue, 14 Aug 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/897/ http://www.drugdiscoverytoday.com/download/898/ Ye Fang outlines how label-free biosensors provide a new dimension for elucidating receptor biology and for facilitating drug discovery. Tue, 14 Aug 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/898/ http://www.drugdiscoverytoday.com/download/899/ Clay W Scott and Matthew F. Peters review emerging data evaluating impedance- and optical-based label-free instruments for GPCR drug discovery. Tue, 14 Aug 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/899/ http://www.drugdiscoverytoday.com/download/880/ Sarah Rickwood and Carolyn Gauntlett from the European Thought Leadership Group IMS Health discuss the market for non-insulin diabetes treatments. Wed, 08 Aug 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/880/ http://www.drugdiscoverytoday.com/download/881/ 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. Wed, 08 Aug 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/881/ http://www.drugdiscoverytoday.com/download/862/ 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. Tue, 17 Jul 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/862/ http://www.drugdiscoverytoday.com/download/863/ 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. Tue, 17 Jul 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/863/ http://www.drugdiscoverytoday.com/download/864/ 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. Tue, 17 Jul 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/864/ http://www.drugdiscoverytoday.com/download/865/ 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. Tue, 17 Jul 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/865/ http://www.drugdiscoverytoday.com/download/866/ 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. Tue, 17 Jul 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/866/ http://www.drugdiscoverytoday.com/download/861/ 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. Fri, 06 Jul 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/861/ http://www.drugdiscoverytoday.com/download/831/ 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. Fri, 15 Jun 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/831/ http://www.drugdiscoverytoday.com/download/832/ 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. Fri, 15 Jun 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/832/ http://www.drugdiscoverytoday.com/download/833/ 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. Fri, 15 Jun 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/833/ http://www.drugdiscoverytoday.com/download/816/ 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. Tue, 29 May 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/816/ http://www.drugdiscoverytoday.com/download/817/ 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. Tue, 29 May 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/817/ http://www.drugdiscoverytoday.com/download/818/ 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. Tue, 29 May 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/818/ http://www.drugdiscoverytoday.com/download/819/ 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. Tue, 29 May 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/819/ http://www.drugdiscoverytoday.com/download/783/ 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. Thu, 26 Apr 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/783/ http://www.drugdiscoverytoday.com/download/784/ 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. Thu, 26 Apr 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/784/ http://www.drugdiscoverytoday.com/download/785/ In this article Daniela Schuster highlights the concept, recent applications and caveats of pharmacophore-based activity profiling. Thu, 26 Apr 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/785/ http://www.drugdiscoverytoday.com/download/762/ 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. Wed, 28 Mar 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/762/ http://www.drugdiscoverytoday.com/download/764/ 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. Wed, 28 Mar 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/764/ http://www.drugdiscoverytoday.com/download/765/ 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. Wed, 28 Mar 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/765/ http://www.drugdiscoverytoday.com/download/766/ 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. Wed, 28 Mar 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/766/ http://www.drugdiscoverytoday.com/download/715/ 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. Tue, 21 Feb 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/715/ http://www.drugdiscoverytoday.com/download/716/ 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. Tue, 21 Feb 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/716/ http://www.drugdiscoverytoday.com/download/717/ 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. Tue, 21 Feb 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/717/ http://www.drugdiscoverytoday.com/download/718/ 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. Tue, 21 Feb 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/718/ http://www.drugdiscoverytoday.com/download/701/ Drug repurposing from an academic perspective; featured article from Drug Discovery Today: Therapeutic Strategies, Winter 2011 Mon, 13 Feb 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/701/ http://www.drugdiscoverytoday.com/download/703/ Highlight from Drug Discovery Today: Therapeutic Strategies, Winter 2011 Mon, 13 Feb 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/703/ http://www.drugdiscoverytoday.com/download/704/ Highlight from the Winter 2011 issue of Drug Discovery Today: Therapeutic Strategies Mon, 13 Feb 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/704/ http://www.drugdiscoverytoday.com/download/705/ Highlight from the Winter 2011 issue of Drug Discovery Today: Therapeutic Strategies Mon, 13 Feb 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/705/ http://www.drugdiscoverytoday.com/download/706/ This is a highlight of the Winter 2011 issue of Drug Discovery Today: Therapeutic Strategies Mon, 13 Feb 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/706/ http://www.drugdiscoverytoday.com/download/707/ A highlight of the Winter 2011 issue of Drug Discovery Today: Therapeutic Strategies Mon, 13 Feb 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/707/ http://www.drugdiscoverytoday.com/download/686/ 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. Mon, 23 Jan 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/686/ http://www.drugdiscoverytoday.com/download/687/ Neil Jones and Almut Schultz discuss how targeting cancer cell metabolism has emerged as a new area for anticancer drug discovery. Mon, 23 Jan 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/687/ http://www.drugdiscoverytoday.com/download/688/ 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. Mon, 23 Jan 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/688/ http://www.drugdiscoverytoday.com/download/689/ 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. Mon, 23 Jan 2012 00:00:00 GMT http://www.drugdiscoverytoday.com/download/689/ http://www.drugdiscoverytoday.com/download/671/ 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. Mon, 12 Dec 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/671/ http://www.drugdiscoverytoday.com/download/667/ 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. Fri, 09 Dec 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/667/ http://www.drugdiscoverytoday.com/download/668/ 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. Fri, 09 Dec 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/668/ http://www.drugdiscoverytoday.com/download/669/ This article reviews progress in the development of computational methods, tools and databases used for organizing and extracting biological meaning from antimicrobial research. Fri, 09 Dec 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/669/ http://www.drugdiscoverytoday.com/download/653/ 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. Wed, 23 Nov 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/653/ http://www.drugdiscoverytoday.com/download/654/ 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. Wed, 23 Nov 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/654/ http://www.drugdiscoverytoday.com/download/655/ 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. Wed, 23 Nov 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/655/ http://www.drugdiscoverytoday.com/download/656/ 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. Wed, 23 Nov 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/656/ http://www.drugdiscoverytoday.com/download/629/ Pavan K Battiprolu et al. discuss insights into mechanisms and molecular events involved in the pathogenesis of diabetic cardiomyopathy. Tue, 18 Oct 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/629/ http://www.drugdiscoverytoday.com/download/630/ 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. Tue, 18 Oct 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/630/ http://www.drugdiscoverytoday.com/download/631/ 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. Tue, 18 Oct 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/631/ http://www.drugdiscoverytoday.com/download/623/ 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. Wed, 21 Sep 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/623/ http://www.drugdiscoverytoday.com/download/624/ 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. Wed, 21 Sep 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/624/ http://www.drugdiscoverytoday.com/download/620/ 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?’ Tue, 20 Sep 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/620/ http://www.drugdiscoverytoday.com/download/622/ Hudson and Orviska discuss the views of pharmacogenetics and gene therapy across European countries. Tue, 20 Sep 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/622/ http://www.drugdiscoverytoday.com/download/616/ These are the instructions to authors for submission of articles to Drug Discovery Today Tue, 13 Sep 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/616/ http://www.drugdiscoverytoday.com/download/617/ 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. Tue, 13 Sep 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/617/ http://www.drugdiscoverytoday.com/download/599/ 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. Thu, 01 Sep 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/599/ http://www.drugdiscoverytoday.com/download/600/ This review focuses on the approaches of cancer nanotechnology in the advancement of cancer therapy. Thu, 01 Sep 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/600/ http://www.drugdiscoverytoday.com/download/602/ 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. Thu, 01 Sep 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/602/ http://www.drugdiscoverytoday.com/download/604/ 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. Thu, 01 Sep 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/604/ http://www.drugdiscoverytoday.com/download/605/ 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. Thu, 01 Sep 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/605/ http://www.drugdiscoverytoday.com/download/589/ 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. Mon, 15 Aug 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/589/ http://www.drugdiscoverytoday.com/download/591/ In this review molecular mechanisms governing transendothelial migration of the diabetogenic effector cells are discussed and resulting pharmacological strategies are considered. Mon, 15 Aug 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/591/ http://www.drugdiscoverytoday.com/download/569/ 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. Fri, 22 Jul 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/569/ http://www.drugdiscoverytoday.com/download/559/ 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. Wed, 13 Jul 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/559/ http://www.drugdiscoverytoday.com/download/560/ 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. Wed, 13 Jul 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/560/ http://www.drugdiscoverytoday.com/download/539/ This review describes the biological technology of using Lactococcus lactis containing the nisin-modifying enzymes for producing thioether-stabilized therapeutic peptides. Mon, 13 Jun 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/539/ http://www.drugdiscoverytoday.com/download/541/ 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. Mon, 13 Jun 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/541/ http://www.drugdiscoverytoday.com/download/534/ 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. Fri, 10 Jun 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/534/ http://www.drugdiscoverytoday.com/download/535/ 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. Fri, 10 Jun 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/535/ http://www.drugdiscoverytoday.com/download/517/ 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. Fri, 13 May 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/517/ http://www.drugdiscoverytoday.com/download/518/ 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. Fri, 13 May 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/518/ http://www.drugdiscoverytoday.com/download/519/ 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. Fri, 13 May 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/519/ http://www.drugdiscoverytoday.com/download/520/ This article reviews the various approaches that have been used to represent ADME related molecule properties graphically in the context of oral drug-likeness. Fri, 13 May 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/520/ http://www.drugdiscoverytoday.com/download/521/ 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. Fri, 13 May 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/521/ http://www.drugdiscoverytoday.com/download/504/ 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. Thu, 21 Apr 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/504/ http://www.drugdiscoverytoday.com/download/505/ 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. Thu, 21 Apr 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/505/ http://www.drugdiscoverytoday.com/download/506/ 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. Thu, 21 Apr 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/506/ http://www.drugdiscoverytoday.com/download/507/ 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. Thu, 21 Apr 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/507/ http://www.drugdiscoverytoday.com/download/488/ 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 Wed, 06 Apr 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/488/ http://www.drugdiscoverytoday.com/download/489/ 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. Wed, 06 Apr 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/489/ http://www.drugdiscoverytoday.com/download/490/ 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. Wed, 06 Apr 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/490/ http://www.drugdiscoverytoday.com/download/491/ 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. Wed, 06 Apr 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/491/ http://www.drugdiscoverytoday.com/download/492/ 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. Wed, 06 Apr 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/492/ http://www.drugdiscoverytoday.com/download/493/ 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. Wed, 06 Apr 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/493/ http://www.drugdiscoverytoday.com/download/494/ How are drugs discovered and developed? Wed, 06 Apr 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/494/ http://www.drugdiscoverytoday.com/download/481/ 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. Tue, 29 Mar 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/481/ http://www.drugdiscoverytoday.com/download/483/ 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. Tue, 29 Mar 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/483/ http://www.drugdiscoverytoday.com/download/461/ 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. Fri, 25 Feb 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/461/ http://www.drugdiscoverytoday.com/download/463/ This article deals with the application of computational quantum chemistry to drug design and discovery. Fri, 25 Feb 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/463/ http://www.drugdiscoverytoday.com/download/464/ 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. Fri, 25 Feb 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/464/ http://www.drugdiscoverytoday.com/download/465/ This article is concerned with the progress of bioinorganic chemistry particularly in the field of cancer. Fri, 25 Feb 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/465/ http://www.drugdiscoverytoday.com/download/466/ This article discusses the medicinal chemistry strategies that have been utilized by the pharmaceutical industry to exploit validated therapeutic targets. Fri, 25 Feb 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/466/ http://www.drugdiscoverytoday.com/download/432/ 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 Wed, 19 Jan 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/432/ http://www.drugdiscoverytoday.com/download/435/ 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. Wed, 19 Jan 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/435/ http://www.drugdiscoverytoday.com/download/436/ 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. Wed, 19 Jan 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/436/ http://www.drugdiscoverytoday.com/download/437/ 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. Wed, 19 Jan 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/437/ http://www.drugdiscoverytoday.com/download/438/ 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 Wed, 19 Jan 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/438/ http://www.drugdiscoverytoday.com/download/439/ 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. Wed, 19 Jan 2011 00:00:00 GMT http://www.drugdiscoverytoday.com/download/439/ http://www.drugdiscoverytoday.com/download/415/ This article outlines how medicinal chemistry approaches in lead discovery and optimisation can be guided using a thermodynamics approach. Mon, 29 Nov 2010 00:00:00 GMT http://www.drugdiscoverytoday.com/download/415/ http://www.drugdiscoverytoday.com/download/417/ Ligand efficiency, library design and the uses of the 'Golden Ratio' Mon, 29 Nov 2010 00:00:00 GMT http://www.drugdiscoverytoday.com/download/417/ http://www.drugdiscoverytoday.com/download/418/ Compound data analysis and computational tools sor SAR mining of large compound data sets. Mon, 29 Nov 2010 00:00:00 GMT http://www.drugdiscoverytoday.com/download/418/ http://www.drugdiscoverytoday.com/download/389/ 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. Fri, 29 Oct 2010 00:00:00 GMT http://www.drugdiscoverytoday.com/download/389/ http://www.drugdiscoverytoday.com/download/390/ 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. Fri, 29 Oct 2010 00:00:00 GMT http://www.drugdiscoverytoday.com/download/390/ http://www.drugdiscoverytoday.com/download/391/ 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. Fri, 29 Oct 2010 00:00:00 GMT http://www.drugdiscoverytoday.com/download/391/ http://www.drugdiscoverytoday.com/download/392/ 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. Fri, 29 Oct 2010 00:00:00 GMT http://www.drugdiscoverytoday.com/download/392/ http://www.drugdiscoverytoday.com/download/393/ 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. Fri, 29 Oct 2010 00:00:00 GMT http://www.drugdiscoverytoday.com/download/393/ http://www.drugdiscoverytoday.com/download/367/ 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. Thu, 23 Sep 2010 00:00:00 GMT http://www.drugdiscoverytoday.com/download/367/ http://www.drugdiscoverytoday.com/download/368/ 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. Thu, 23 Sep 2010 00:00:00 GMT http://www.drugdiscoverytoday.com/download/368/ http://www.drugdiscoverytoday.com/download/370/ 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. Thu, 23 Sep 2010 00:00:00 GMT http://www.drugdiscoverytoday.com/download/370/ http://www.drugdiscoverytoday.com/download/371/ 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. Thu, 23 Sep 2010 00:00:00 GMT http://www.drugdiscoverytoday.com/download/371/ http://www.drugdiscoverytoday.com/download/372/ Gavin P. Reynolds discusses genetic variation in responses to antipsychotic drugs and asks whether pharmacogenetics will prove valuable in their discovery. Thu, 23 Sep 2010 00:00:00 GMT http://www.drugdiscoverytoday.com/download/372/ http://www.drugdiscoverytoday.com/download/374/ 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? Thu, 23 Sep 2010 00:00:00 GMT http://www.drugdiscoverytoday.com/download/374/ http://www.drugdiscoverytoday.com/download/347/ 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. Mon, 23 Aug 2010 00:00:00 GMT http://www.drugdiscoverytoday.com/download/347/ http://www.drugdiscoverytoday.com/download/344/ 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. Fri, 20 Aug 2010 00:00:00 GMT http://www.drugdiscoverytoday.com/download/344/ http://www.drugdiscoverytoday.com/download/346/ 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. Thu, 19 Aug 2010 00:00:00 GMT http://www.drugdiscoverytoday.com/download/346/ http://www.drugdiscoverytoday.com/download/345/ 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. Wed, 18 Aug 2010 00:00:00 GMT http://www.drugdiscoverytoday.com/download/345/ http://www.drugdiscoverytoday.com/download/250/ 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. Mon, 08 Mar 2010 00:00:00 GMT http://www.drugdiscoverytoday.com/download/250/ http://www.drugdiscoverytoday.com/download/171/ 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. Tue, 02 Feb 2010 00:00:00 GMT http://www.drugdiscoverytoday.com/download/171/