Combinatorial library design from reagent pharmacophore fingerprints

Abstract

Combinatorial and parallel chemical synthesis technologies are powerful tools in early drug discovery projects. Over the past couple of years an increased emphasis on targeted lead generation libraries and focussed screening libraries in the pharmaceutical industry has driven a surge in computational methods to explore molecular frameworks to establish new chemical equity. In this chapter we describe a complementary technique in the library design process, termed ProSAR, to effectively cover the accessible pharmacophore space around a given scaffold. With this method reagents are selected such that each R-group on the scaffold has an optimal coverage of pharmacophoric features. This is achieved by optimising the Shannon entropy, i.e. the information content, of the topological pharmacophore distribution for the reagents. As this method enumerates compounds with a systematic variation of user-defined pharmacophores to the attachment point on the scaffold, the enumerated compounds may serve as a good starting point for deriving a structure-activity relationship (SAR).