Bioisosteric replacement of molecular scaffolds: From natural products to synthetic compounds

Abstract

Natural products often contain scaffolds or core structures that prevent immediate synthetic accessibility. It is, therefore, desirable to find isosteric chemotypes that allow for scaffold-hopping or re-scaffolding. The idea is to obtain simpler chemotypes that are synthetically feasible and exhibit either the same or similar bioactivity as the original natural product or reference compound. We developed and applied a virtual screening technique that represents a molecular scaffold by its side-chain attachment points (exit-vectors) and properties of the side-chain substituents. The technique was validated by retrospective screening for beta-turn mimetics and HMG-CoA inhibitors. A prospective application aimed at finding new chemotypes of PPAR-alpha agonists. Two such compounds were found in a commercially available screening compound library yielding EC50 values in the low micromolar range. This study demonstrates the applicability of exit-vector based virtual screening to scaffold-hopping tasks.