Discovery of natural‐derived Mpro inhibitors as therapeutic candidates for COVID‐19: Structure‐based pharmacophore screening combined with QSAR analysis

Abstract

AbstractThe main protease (Mpro) is an essential enzyme for the life cycle of SARS‐CoV‐2 and a validated target for treatment of COVID‐19 infection. Structure‐based pharmacophore modeling combined with QSAR calculations were employed to identify new chemical scaffolds of Mpro inhibitors from natural products repository. Hundreds of pharmacophore models were manually built from their corresponding X‐ray crystallographic structures. A pharmacophore model that was validated by receiver operating characteristic (ROC) curve analysis and selected using the statistically optimum QSAR equation was implemented as a 3D‐search tool to mine AnalytiCon Discovery database of natural products. Captured hits that showed the highest predicted inhibitory activities were bioassayed. Three active Mpro inhibitors (pseurotin A, lactupicrin, and alpinetin) were successfully identified with IC50 values in low micromolar range.