Comments on the design of chemical libraries for screening

Abstract

Different representations of molecules, based on distinct sets of properties can yield different perspectives of the issues involved in library design. In particular, different chemical representations can give rise to very different estimates of required library sizes. We provide a preliminary mathematical framework that examines the size of libraries required to adequately sample the spaces corresponding to some commonly used property sets. Introduction of conformational flexibility is also discussed as a means of increasing coverage of chemical libraries, while at the same time considering the thermodynamic consequences of flexibility upon detectable activity. Our theoretical analysis reveals that the property spaces currently in use are extremely large and unlikely to provide adequate discrimination among compounds.