Ring systems in natural products: structural diversity, physicochemical properties, and coverage by synthetic compounds

Abstract

Covering: up to 2021

The structural core of most small-molecule drugs is formed by a ring system, often derived from natural products. However, despite the importance of natural product ring systems in bioactive small molecules, there is still a lack of a comprehensive overview and understanding of natural product ring systems and how their full potential can be harnessed in drug discovery and related fields. Herein, we present a comprehensive cheminformatic analysis of the structural and physicochemical properties of 38 662 natural product ring systems, and the coverage of natural product ring systems by readily purchasable, synthetic compounds that are commonly explored in virtual screening and high-throughput screening. The analysis stands out by the use of comprehensive, curated data sets, the careful consideration of stereochemical information, and a robust analysis of the 3D molecular shape and electrostatic properties of ring systems. Among the key findings of this study are the facts that only about 2% of the ring systems observed in NPs are present in approved drugs but that approximately one in two NP ring systems are represented by ring systems with identical or related 3D shape and electrostatic properties in compounds that are typically used in (high-throughput) screening.