Quantum Chemical Interaction Analysis between SARS-CoV-2 Main Protease and Ensitrelvir Compared with Its Initial Screening Hit

A non-covalent oral drug targeting SARS-CoV-2 main protease (M pro ), ensitrelvir (Xocova), has been developed using structure-based drug design (SBDD). To elucidate the factors responsible for enhanced inhibitory activities from an in silico screening hit compound to ensitrelvir, we analyzed the interaction energies of the inhibitors with each residue of M pro using fragment molecular orbital (FMO) calculations. This analysis reveals that functional group conversion for P1′ and P1 parts in the inhibitors increases the strength of existing interactions with M pro and also provides novel interactions for ensitrelvir; the associated changes in the conformation of M pro induce further interactions for ensitrelvir in other parts, including hydrogen bonds, a halogen bond, and π-orbital interactions. Thus, we illuminate the promising strategies of SBDD for leading ensitrelvir to get higher activity against M pro by elucidating microscopic interactions through FMO-based analysis. These detailed mechanism findings, including water cross-linkings, will help to design novel inhibitors in SBDD.