Open Access High Throughput Drug Discovery in the Public Domain: A Mount Everest in the Making

Abstract

High throughput screening (HTS) facilitates screening large numbers of compounds against a biochemical target of interest using validated biological or biophysical assays. In recent years, a significant number of drugs in clinical trails originated from HTS campaigns, validating HTS as a bona fide mechanism for hit finding. In the current drug discovery landscape, the pharmaceutical industry is embracing open innovation strategies with academia to maximize their research capabilities and to feed their drug discovery pipeline. The goals of academic research have therefore expanded from target identification and validation to probe discovery, chemical genomics, and compound library screening. This trend is reflected in the emergence of HTS centers in the public domain over the past decade, ranging in size from modestly equipped academic screening centers to well endowed Molecular Libraries Probe Centers Network (MLPCN) centers funded by the NIH Roadmap initiative. These centers facilitate a comprehensive approach to probe discovery in academia and utilize both classical and cutting-edge assay technologies for executing primary and secondary screening campaigns. The various facets of academic HTS centers as well as their implications on technology transfer and drug discovery are discussed, and a roadmap for successful drug discovery in the public domain is presented. New lead discovery against therapeutic targets, especially those involving the rare and neglected diseases, is indeed a Mount Everestonian size task, and requires diligent implementation of pharmaceutical industry’s best practices for a successful outcome.

Recent Trends in Collaborative, Open Source Drug Discovery

“…An ideal probe is a small molecule that is novel and drug like with submicromolar affinity and selective to the therapeutic target, and has the potential to be the starting point for lead optimization studies. Alternatively, the probe may be used to study challenging refractory biology [14]. Other desirable aspects of a new probe include a proven chemical identity with a defined structure, a clear and quantifiable structureactivity relationship over a 2-3 log drug concentration range, identification of more than one chemotype with an analogous activity profile and a proven efficacy and potency around 3 orders of magnitude.…”

Pyrazolyl-Tetrazoles and Imidazolyl-Pyrazoles as Potential Anticoagulants and their Integrated Multiplex Analysis Virtual Screening

“…4,5 The ability of specialized virtual screening algorithms to filter molecular libraries into a manageable number of compounds for biological assays is the driving force for finding novel ligands. 5,6 When the structural information of the target protein is unknown, the screening file is made as diverse as possible and ligand-based approaches are employed to scan the compound library. 7,8 On the other hand, when structural information on the target or target family is available, the strategy switches to a target-based approach, such as molecular docking, in an attempt to predominantly screen compounds that can be expected to modulate the target and improve them using fragment-based optimization.…”

Finding new scaffolds of JAK3 inhibitors in public database: 3D-QSAR models & shape-based screening

“…However, this technology also produces false positive hits or identifies undesirable hits in view of drug likeness (e.g., stability, solubility, and toxicity; Feng et al 2005;Hughes et al 2011;Macarron et al 2011). Therefore, drug repositioning combined with conventional HTS technology holds great promise for efficient drug development while avoiding undesirable DMPK (drug metabolism and pharmacokinetics) profiles (Ashburn and Thor 2004;Roy et al 2010). Even though not all chemicals in public chemical databases are successful drugs, a portion of them may present a physicochemical profile (stability, solubility, logD etc.)…”