Leveraging HTS

Traditionally, high-throughput screening (HTS) has been employed excessively during early drug discovery to identify compounds binding to a single target of interest. Nowadays, we experience the shift in research and development toward modulating agents and, more prominently, on small molecules acting simultaneously on a variety of receptors to remedy an indication or disease of interest. In order to increase the outcome of HTS, novel approaches had to be and in fact have been developed. Accomplishing these goals may be attended by more detailed considerations of biological pathways and deeper integration with computational resources.

Identification of novel chemical entities is probably the hardest challenge in drug discovery we are facing today. Despite efforts in computational approaches to find chemical starting points with novel scaffolds, many still employ HTS (not exclusively though). Major initial obstacles, e.g. frequent hitter problem and scaffold-based enrichment, have been addressed and one can say that it has become more safe to perform HTS nowadays. In order to have an impact and use in future research projects, HTS (and maybe even the whole early development) has to adopt recent biological achievements and paradigm shifts, which were not present twenty years ago when HTS was rising to the method of choice for hit identification in drug discovery.

In this issue of Drug Discovery Today Editor’s Choice, we refer to three recent reviews with a focus on the development of novel HTS target platforms, integration of virtual screening techniques and the transformation toward chasing multitarget acting compounds.

Alexey Koval and Vladimir L. Katanaev summarize technologies enabling detection of antagonists of Wnt/Frizzled signaling in HTS campaigns. Wnt/Frizzled signaling pathways are involved in late stages of cancerogenesis and metastasis. The authors sub-divide various assay systems into those based on transcriptional or high-content readout, measuring ligand interaction, Ca2+ release, cAMP production, receptor dimerization and GTP-binding. Some of these technologies have been adapted for high-throughput screening enabling the discovery of Wnt/Frizzled antagonists for anticancer drug discovery. The authors admit that the effects measured in the primary HTS assay should occur upstream in the Wnt/Frizzled signaling pathway.

In our review with Björn Krüger entitled “The holistic integration of virtual screening in drug discovery”, we describe how virtual screening evolved from an isolated method to an integral part of early drug development going hand-in-hand with HTS. We provide examples of how both technologies can work together to drive hit and lead identification. Furthermore, a classification scheme for virtual screening campaigns is suggested documenting the characteristics of different integration levels. Future development in this area is encouraged, because computational re-processing of biological data is becoming of utmost importance for the future identification of mono- and polypharmalogically bioactive compound.

The review “Shifting from the single to the multitarget paradigm in drug discovery” by José L. Medina-Franco , Marc A. Giulianotti, Gregory S. Welmaker and Richard A. Houghten summarizes recent efforts in multitarget drug design. Multitarget drugs often exhibit improved efficacy, and discovery or design of polypharmacological compounds is in focus of current research efforts. The authors concentrate on methods for screening of compounds with polypharmacological activity, discussing the concepts of drug repurposing, chemogenomics and phenotype (including in vivo) screening. They suggest different sources for novel multitarget drugs, such as focused libraries, GRAS (“generally recognized as safe”) chemicals and natural products which can be screened in the mentioned systems.

We hope that you enjoy reading the articles presented in this newsletter. We believe they illustrate well how to derive more advantages of HTS by incorporation of sophisticated biological, in silico and multitarget approaches to enhance preclinical stages of drug discovery.

Ewgenij Proschak is a Junior-Professor for Drug Design at the Institute of Pharmaceutical Chemistry of the Goethe-University, Frankfurt (Germany). He and his group are working on computer-aided design and synthesis of multi-target anti-inflammatory and anti-diabetic agents. He received his PhD in 2008 in the working group of Prof. Dr. Gisbert Schneider. After a postdoctorial research period at the Institute of Pharmaceutical Chemistry he started an independent Junior Research group at the Lipid Signaling Forschungszentrum Frankfurt. Since 2007 he published more than 50 articles in peer-reviewed journals in the field of computational and medicinal chemistry and drug design.
Yusuf Tanrikulu is an expert in cheminformatics and computational chemistry in the Department of Chemical R&D at Merz Pharmaceuticals GmbH, Frankfurt (Germany). He currently drives hit identification and drug repurposing in the area of CNS diseases using cheminformatics and data mining techniques. Prior to that he was a post doc with Hoffmann-LaRoche in Nutley, NJ (USA), where he was involved with the analysis of in vitro bioactivity data focussing on binding affinity prediction based on small molecule activity profiles. In 2009 he completed his Ph.D. thesis at the molecular design lab at the Goethe University in Frankfurt (Germany) under the supervision of Prof. Dr. Gisbert Schneider, where he also received his diploma in bioinformatics in 2005. He is author of 23 research papers and contributed articles for two books.

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