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

Abstract The main protease (M pro ) 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 M pro 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 M pro inhibitors (pseurotin A, lactupicrin, and alpinetin) were successfully identified with IC 50 values in low micromolar range.