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.

Fig. (1)

Drug discovery project progression from basic research to probe development.

Fig. (2)

Generalization of Academia vs. Industry in terms of (1) risk tolerance vs. (2) affected patient population. Each dot represents an HTS campaign. This is a hypothetical generalization of the relationship between risk and reward against investment, not based on actual data. Black dot = Private domain HTS, Grey dot = Public domain HTS. Size of dot = Dollars spent or resources allocated on a project.

Fig. (3)

Industry level drug discovery in the public domain. The Molecular Libraries Probe Centers Network (MLPCN) has brought together critical facets of the drug discovery process to the public, giving open access to comprehensive compound screening and probe development, advancing research through public data sharing via Pubchem.

Fig. (4)

Example assay comparison for determining assay sensitivity for high throughput screening (HTS), Tetrazolium-based MTS versus ATP quantitation of cell viability. Breast adenocarcinoma cells (MCF-7 derivative) were seeded at a range of 4–125,000 cells per well, followed by cell viability assessment by MTS and ATP quantitation assays. The characteristics of the homogenous ATP-based assay were superior to the MTS assay, and the improved sensitivity for measuring low numbers of cells (below 2,000 cells/well) confirmed that the ATP-based assay method was more suitable for HTS.