The term ‘privileged scaffold’, as defined by Evans in 1988, is a simple structural subunit common to several structures providing high-affinity ligands to different receptors. This definition can be interpreted in various ways, though the idea is that certain structural features may produce a particular biological effect more often than others, reflecting promiscuity in drug-like chemical space. Despite common reference in medicinal chemistry, the validity of the concept is often debated.<br/><br/>In this study, we aim to identify and characterize ‘privileged scaffolds’ for 5 super families: protein kinases, GPCR, ligand-gated ion channels, voltage-gated ion channels, and nuclear hormone receptors. We employ a scaffold network based approach and a novel scaffold efficiency Index (ScafEI) calculated based on the molecular structures and their bioactivities taken from ChEMBL. The Kolmogorov–Smirnov statistic is also used. Our privileged scaffolds are likely to have a maximum impact on the overall bioactivity of a subset of compounds for a protein family. This differentiation is also reflected by a calculated p-value significance score. Some validations will be shown and our results will provide useful information for future scaffold development in drug discovery.

Classification and analysis of privileged scaffolds in protein families

2019 Fall National Meeting

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