Hit and lead

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 KH, Bohm HJ, Muller K, Alanine AI. Hit and lead generation beyond high-throughput screening. Nat Rev Drug Discov 2003 2 369-78. 

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. 

Although attempts to dock compounds in putative binding pockets in a model of the NBD1-NBD2 heterodimer have been published [38], more studies are required to provide the accuracy and resolution needed to guide hit and lead optimization efforts. 

The use of high-throughput screening (HTS) results in hits and leads that are more lipophilic than optimized drugs [24]... 

The uncontrolled use of parallel or combinatorial synthetic chemistry in hit and lead optimization (and in compound collection enhancement)... 

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. 

Medicinal chemists have always been adept in recognizing trends in physicochemical properties of molecules and relating them to molecular structure. With rapid increase in the number of hits and leads, computational tools have been proposed to calculate molecular properties that may predict potential absorption hurdles. For example, Lipinski s "Rule of 5"14 states that poor absorption or permeation are likely when ... 

While we do not use directly the above approach in this book, many chapters remind you that hit and lead profiling is close to detective work. It is equally exciting it carries a large volume of unknown elements which can only be dealt vdth using refined tools and protocols.. But what is most rewarding in this job is that correction, or to be precise, optimization is built into it. 

Hit and Lead Profiling. Edited by Bernard Faller and Laszlo Urban Copyright 2009 WILEY-VCH Verlag GmbH Co. KGaA, Weinheim ISBN 978-3-527-32331-9... 

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. 

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