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

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