Mechanism of inhibition of SARS-CoV-2 Mpro by N3 peptidyl Michael acceptor explained by QM/MM simulations and design of new derivatives with tunable chemical reactivity
![Thumbnail](/xmlui/bitstream/handle/10234/191528/73092.pdf.jpg?sequence=5&isAllowed=y)
Visualitza/
Impacte
![Google Scholar](/xmlui/themes/Mirage2/images/uji/logo_google.png)
![Microsoft Academico](/xmlui/themes/Mirage2/images/uji/logo_microsoft.png)
Metadades
Mostra el registre complet de l'elementcomunitat-uji-handle:10234/9
comunitat-uji-handle2:10234/7013
comunitat-uji-handle3:10234/8638
comunitat-uji-handle4:
INVESTIGACIONMetadades
Títol
Mechanism of inhibition of SARS-CoV-2 Mpro by N3 peptidyl Michael acceptor explained by QM/MM simulations and design of new derivatives with tunable chemical reactivityAutoria
Data de publicació
2021Editor
Royal Society of ChemistryISSN
2041-6520; 2041-6539Cita bibliogràfica
K. Arafet, N. Serrano-Aparicio, A. Lodola, A. J. Mulholland, F. V. González, K. Świderek and V. Moliner. Mechanism of inhibition of SARS-CoV-2 Mpro by N3 peptidyl Michael acceptor explained by QM/MM simulations and design of new derivatives with tunable chemical reactivity. , Chem. Sci., 2021, 2041-6520Tipus de document
info:eu-repo/semantics/articleVersió de l'editorial
https://pubs.rsc.org/en/content/articlehtml/2021/sc/d0sc06195fVersió
info:eu-repo/semantics/publishedVersionParaules clau / Matèries
Resum
The SARS-CoV-2 main protease (Mpro) is essential for replication of the virus responsible for the COVID-19 pandemic, and one of the main targets for drug design. Here, we simulate the inhibition process of SARS-CoV-2 ... [+]
The SARS-CoV-2 main protease (Mpro) is essential for replication of the virus responsible for the COVID-19 pandemic, and one of the main targets for drug design. Here, we simulate the inhibition process of SARS-CoV-2 Mpro with a known Michael acceptor (peptidyl) inhibitor, N3. The free energy landscape for the mechanism of the formation of the covalent enzyme-inhibitor product is computed with QM/MM molecular dynamics methods. The simulations show a two-step mechanism, and give structures and calculated barriers in good agreement with experiment. Using these results and information from our previous investigation on the proteolysis reaction of SARS-CoV-2 Mpro, we design two new, synthetically accessible N3-analogues as potential inhibitors, in which the recognition and warhead motifs are modified. QM/MM modelling of the mechanism of inhibition of Mpro by these novel compounds indicates that both may be promising candidates as drug leads against COVID-19, one as an irreversible inhibitor and one as a potential reversible inhibitor. [-]
Publicat a
Chemical Science, 2021Drets d'accés
info:eu-repo/semantics/openAccess
Apareix a les col.leccions
- INAM_Articles [531]
- QFA_Articles [829]
Els següents fitxers sobre la llicència estan associats a aquest element: