Privileged structures inspire compound library design in medicinal chemistry. We performed a comprehensive analysis of 1.4 million bioactive compounds, with the aim of assessing the prevalence of certain molecular frameworks. We used the Shannon entropy formalism to quantify the promiscuity of the most frequently observed atom scaffolds across the annotated target families. This analysis revealed an apparent inverse relationship between hydrogen-bond-acceptor count of a scaffold and its potential promiscuity. The results further suggest that chemically easily accessible scaffolds can serve as templates for the generation of bespoke compound libraries with differing degrees of multiple target engagement, and heterocyclic, sp3 -rich frameworks are particularly suited for target-focused library design. The outcome of our study enables us to place some of the many narratives surrounding the concept of privileged structures into a critical context.
Keywords: Shannon entropy; cheminformatics; combinatorial chemistry; medicinal chemistry; polypharmacology.
© 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.