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 (Mpro), 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 Mpro 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 Mpro and also provides novel interactions for ensitrelvir; the associated 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 illuminate the promising strategies of SBDD for leading ensitrelvir to get higher activity against Mpro by elucidating microscopic interactions through FMO-based analysis. These detailed mechanism findings, including water cross-linkings, will help to design novel inhibitors in SBDD.

Special Features of COVID-19 in the FMODB: Fragment Molecular Orbital Calculations and Interaction Energy Analysis of SARS-CoV-2-Related Proteins.

SARS-CoV-2 is the causative agent of coronavirus (known as COVID-19), the virus causing the current pandemic. There are ongoing research studies to develop effective therapeutics and vaccines against COVID-19 using various methods and many results have been published. The structure-based drug design of SARS-CoV-2-related proteins is promising, however, reliable information regarding the structural and intra- and intermolecular interactions is required. We have conducted studies based on the fragment molecular orbital (FMO) method for calculating the electronic structures of protein complexes and analyzing their quantitative molecular interactions. This enables us to extensively analyze the molecular interactions in residues or functional group units acting inside the protein complexes. Such precise interaction data are available in the FMO database (FMODB) (https://drugdesign.riken.jp/FMODB/). Since April 2020, we have performed several FMO calculations on the structures of SARS-CoV-2-related proteins registered in the Protein Data Bank. We have published the results of 681 structures, including three structural proteins and 11 nonstructural proteins, on the COVID-19 special page (as of June 8, 2021). In this paper, we describe the entire COVID-19 special page of the FMODB and discuss the calculation results for various proteins. These data not only aid the interpretation of experimentally determined structures but also the understanding of protein functions, which is useful for rational drug design for COVID-19.