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

Abstract

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.

Structural Stability and Binding Ability of SARS-CoV-2 Main Protease with GC376: A Stereoisomeric Covalent Ligand Analysis by FMO calculation

“…Since B1S has a higher protein binding strength than K36, a bond with His41 contributes to the difference in the protein binding strength between B1S and K36. The results of this study, along with analysis of the interaction patterns between M pro and various ligands registered in FMODB [8,15], can be useful for structure-based drug design of the inhibitors of M pro .…”

Use of caps in the auxiliary basis set formulation of the fragment molecular orbital method

“…For unconnected dimers without a detached covalent bond between the two monomers, the effect of caps cancels out (see Figure 1) because each cap in a dimer IJ is present in one of the two monomers I or J . In the applications of FMO to molecular binding, only PIEs of unconnected dimers are commonly used 34,35 …”

Comprehensive Review on the Synthetic Strategies toward Anti-SARS-CoV-2 Drug Ensitrelvir

“…The drug showed the anti-SARS-CoV-2 activity by inhibiting the main protease target, which is similar to the first generation of oral anti-SARS-CoV-2 drug paxlovid, a combination of nirmatrelvir and ritonavir. In contrast to paxlovid, ensitrelvir does not need to be taken in combination with other drugs, which decreases the virus in lungs and nasal turbinates, and exhibits good drug metabolism and pharmacokinetic (DMPK) profiles. , …”