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

02 December 2022, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


A non-covalent oral drug targeting severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) main protease (Mpro), ensitrelvir (brand name Xocova), has been developed by Unoh et al. (J. Med. Chem. 2022, 65, 9, 6499–6512) using structure-based drug design (SBDD). To elucidate the factors responsible for the enhanced inhibitory activities from in silico screening hit compound to ensitrelvir, we analyzed interaction energies between the inhibitor and each residue of Mpro using fragment molecular orbital (FMO) calculations. This analysis reveals that functional group conversion for P1’ and P1 parts in the two inhibitors increases the strength of existing interactions with Mpro and also provides novel interactions for ensitrelvir. Moreover, the associated slight changes in the conformation of Mpro induce further interactions for ensitrelvir in other parts, including hydrogen bonds, a halogen bond, and π-orbital interactions. Thus, we shed light on the promising strategies of SBDD for leading ensitrelvir to get higher inhibitory activity against Mpro by elucidating microscopic interactions through FMO-based analysis. These detailed mechanism findings, including water cross-linkings, will give a powerful tool for further improvement in SBDD.


main protease
fragment molecular orbital (FMO)
Intermolecular interaction energy

Supplementary materials

Supporting information
S1. Computational Methods; S2. Intermolecular interaction of inhibitor with amino acid residues and water molecules (PDF)

Supplementary weblinks


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