Computational Insights into SARS-CoV-2 Main Protease Mutations and Nirmatrelvir Efficacy: The Effects of P132H and P132H-A173V

Authors

Yuan-Ling Xia
Wen-Wen Du
Yong-Ping Li
Yan Tao
Zhi-Bi Zhang
Song-Ming Liu
Yun-Xin Fu
Ke-Qin Zhang
Shu-Qun Liu

Language

English

Publication Date

7-8-2024

Journal

Journal of Chemical Information and Modeling

DOI

10.1021/acs.jcim.4c00334

PMID

38913174

PMCID

PMC11235099

PubMedCentral® Posted Date

6-24-2024

PubMedCentral® Full Text Version

Post-print

Abstract

Nirmatrelvir, a pivotal component of the oral antiviral Paxlovid for COVID-19, targets the SARS-CoV-2 main protease (Mpro) as a covalent inhibitor. Here, we employed combined computational methods to explore how the prevalent Omicron variant mutation P132H, alone and in combination with A173V (P132H-A173V), affects nirmatrelvir’s efficacy. Our findings suggest that P132H enhances the noncovalent binding affinity of Mpro for nirmatrelvir, whereas P132H-A173V diminishes it. Although both mutants catalyze the rate-limiting step more efficiently than the wild-type (WT) Mpro, P132H slows the overall rate of covalent bond formation, whereas P132H-A173V accelerates it. Comprehensive analysis of noncovalent and covalent contributions to the overall binding free energy of the covalent complex suggests that P132H likely enhances Mpro sensitivity to nirmatrelvir, while P132H-A173V may confer resistance. Per-residue decompositions of the binding and activation free energies pinpoint key residues that significantly affect the binding affinity and reaction rates, revealing how the mutations modulate these effects. The mutation-induced conformational perturbations alter drug–protein local contact intensities and the electrostatic preorganization of the protein, affecting noncovalent binding affinity and the stability of key reaction states, respectively. Our findings inform the mechanisms of nirmatrelvir resistance and sensitivity, facilitating improved drug design and the detection of resistant strains.

Keywords

SARS-CoV-2, Coronavirus 3C Proteases, Mutation, Antiviral Agents, Humans, COVID-19 Drug Treatment, Molecular Dynamics Simulation, Protease Inhibitors, Leucine, Thermodynamics, Sulfonamides, Protein Binding, Succinates, Lactams, Nitriles, Proline

Published Open-Access

yes

Recommended Citation

Xia, Yuan-Ling; Du, Wen-Wen; Li, Yong-Ping; et al., "Computational Insights into SARS-CoV-2 Main Protease Mutations and Nirmatrelvir Efficacy: The Effects of P132H and P132H-A173V" (2024). Faculty, Staff and Student Publications. 1238.
https://digitalcommons.library.tmc.edu/uthsph_docs/1238