Chapter 4 - Step IIIb: The Drug-Like Chemical Diversity Pool: Diverse and Targeted Compound Collections

Abstract

Hit discovery requires to access medium-large collections/libraries containing biologically active small molecules. The first section covers modern methods to synthesize them (combinatorial and parallel synthesis) and their formats (discretes, pools from mix and split synthesis); describes the physicochemical filters used to design and select a drug-like molecule (Lipinski rule of 5, fragment-directed rule of 3); and the identification of recurrent false positives (PAINS compounds) in HTS campaigns. The following section deals with an example of HD, in which most of the described biology- and chemistry-based methods (vHTS and HTS campaigns, FBDD, NMR, X-ray crystallography) were used to find drug-like hits against HSP90. The last section deals with noncanonical, biologically active chemical diversity, introducing extended- and beyond rule of 5 compounds; with the impact of natural products in drug discovery and on medicinal chemistry (function-oriented and biology-oriented synthesis); and particularly of macrocycles, covered through their unique properties and their accessibility via chemical synthesis (macrocycle libraries) and biosynthesis (DNA-encoded chemistry).