Quantum Chemical Interaction Analysis between SARS-CoV-2 Main Protease and Ensitrelvir Compared with Its Initial Screening Hit.
J Phys Chem Lett
; 14(15): 3609-3620, 2023 Apr 20.
Article
en En
| MEDLINE
| ID: mdl-37023394
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.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
COVID-19
Tipo de estudio:
Diagnostic_studies
/
Screening_studies
Límite:
Humans
Idioma:
En
Año:
2023
Tipo del documento:
Article