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J Chem Inf Model ; 64(13): 5207-5218, 2024 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-38913174

RESUMO

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.


Assuntos
Antivirais , Proteases 3C de Coronavírus , Mutação , SARS-CoV-2 , SARS-CoV-2/enzimologia , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/genética , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases 3C de Coronavírus/metabolismo , Proteases 3C de Coronavírus/química , Proteases 3C de Coronavírus/genética , Antivirais/farmacologia , Antivirais/química , Humanos , Tratamento Farmacológico da COVID-19 , Simulação de Dinâmica Molecular , Inibidores de Proteases/farmacologia , Inibidores de Proteases/química , Inibidores de Proteases/metabolismo , Leucina/química , Termodinâmica , Sulfonamidas/farmacologia , Sulfonamidas/química , Sulfonamidas/metabolismo , Ligação Proteica , Succinatos/química , Succinatos/farmacologia , Succinatos/metabolismo , Lactamas , Nitrilas , Prolina
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