Hit and Lead Discovery

More recently, the bottleneck of drug research has shifted from hit-and-lead discovery to lead optimization, and more specifically to PK lead optimization. Some major reasons are (i) the imperative to reduce as much as feasible the extremely costly rate of attrition prevailing in preclinical and clinical phases, and (ii) more stringent concerns for safety. The testing of ADME properties is now done much earlier, i.e. before a decision is taken to evaluate a compound in the clinic. 

The focus of this book is on methods and processes designed to predict drug-like properties, exposure and safety during hit and lead discovery. We do not intend to cover specific cultural considerations and marketing aspects [3]. What we will highlight is the need of a risk aware environment for drug discovery, where data-based integrated risk assessment is part of daily life of the team and drives the projects towards molecules with features fit for the description of an efficacious and safe medicine. 

The preceding discussion involves the elucidation of the primary hit and lead activity, obviously a crucial step in the drug discovery process. However, there are numerous other reasons a molecule with good primary activity may still fail... 

Bleicher, K.H., Bohm, H.J., Muller, K. and Alanine, A.I. (2003) Hit and lead generation beyond high-throughput screening. Nature Reviews Drug Discovery, 2, 369-378. 

Martis E.A. Radhakrishnan R. Badve R.R. High-throughput screening The hits and leads of drug discovery—An overview. Journal of Applied Pharmaceutical Science, 2011, 1, 2-10. 

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