The impact of SARS-CoV-2 3CL protease mutations on nirmatrelvir inhibitory efficiency. Computational insights into potential resistance mechanisms
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Otros documentos de la autoría: Ramos Guzmán, Carlos Alberto; Anđelković, Milorad; Zinovjev, Kirill; Ruiz-Pernía, José Javier; Tuñón, Iñaki
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Título
The impact of SARS-CoV-2 3CL protease mutations on nirmatrelvir inhibitory efficiency. Computational insights into potential resistance mechanismsAutoría
Fecha de publicación
2023-02-14Editor
The Royal Society of ChemistryCita bibliográfica
RAMOS-GUZMÁN, Carlos A., et al. The impact of SARS-CoV-2 3CL protease mutations on nirmatrelvir inhibitory efficiency. Computational insights into potential resistance mechanisms. Chemical Science, 2023, vol. 14, no 10, p. 2686-2697.Tipo de documento
info:eu-repo/semantics/articleVersión
info:eu-repo/semantics/publishedVersionPalabras clave / Materias
Resumen
The use of antiviral drugs can promote the appearance of mutations in the target protein that increase the resistance of the virus to the treatment. This is also the case of nirmatrelvir, a covalent inhibitor of the ... [+]
The use of antiviral drugs can promote the appearance of mutations in the target protein that increase the resistance of the virus to the treatment. This is also the case of nirmatrelvir, a covalent inhibitor of the 3CL protease, or main protease, of SARS-CoV-2. In this work we show how the by-residue decomposition of noncovalent interactions established between the drug and the enzyme, in combination with an analysis of naturally occurring mutations, can be used to detect potential mutations in the 3CL protease conferring resistance to nirmatrelvir. We also investigate the consequences of these mutations on the reaction mechanism to form the covalent enzyme-inhibitor complex using QM/MM methods. In particular, we show that the E166V variant of the protease displays smaller binding affinity to nirmatrelvir and larger activation free energy for the formation of the covalent complex, both factors contributing to the observed resistance to the treatment with this drug. The conclusions derived from our work can be used to anticipate the consequences of the introduction of nirmatrelvir in the fitness landscape of the virus and to design new inhibitors adapted to some of the possible resistance mechanisms. [-]
Entidad financiadora
MCIN/AEI/10.13039/501100011033 | Generalitat Valenciana | Ministerio de Ciencia, Innovación y Universidades, Spain | “la Caixa” Foundation
Código del proyecto o subvención
PID2021-123332OB-C22 | PROMETEO CIPROM/2021/079 | LCF/BQ/DR21/11880026
Título del proyecto o subvención
ERDF A way of making Europe
Derechos de acceso
© 2023 The Author(s). Published by the Royal Society of Chemistry
info:eu-repo/semantics/openAccess
info:eu-repo/semantics/openAccess
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