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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
dc.contributor.author | Arafet Cruz, Kemel | |
dc.contributor.author | Serrano Aparicio, Natalia | |
dc.contributor.author | Lodola, Alessio | |
dc.contributor.author | Mulholland, Adrian J. | |
dc.contributor.author | González, Florenci | |
dc.contributor.author | Świderek, Katarzyna | |
dc.contributor.author | Moliner, Vicent | |
dc.date.accessioned | 2021-01-26T13:13:03Z | |
dc.date.available | 2021-01-26T13:13:03Z | |
dc.date.issued | 2021 | |
dc.identifier.citation | 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, 2041-6520 | ca_CA |
dc.identifier.issn | 2041-6520 | |
dc.identifier.issn | 2041-6539 | |
dc.identifier.uri | http://hdl.handle.net/10234/191528 | |
dc.description.abstract | 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. | ca_CA |
dc.format.extent | 12 p. | ca_CA |
dc.format.mimetype | application/pdf | ca_CA |
dc.language.iso | eng | ca_CA |
dc.publisher | Royal Society of Chemistry | ca_CA |
dc.relation.isPartOf | Chemical Science, 2021 | ca_CA |
dc.rights | Atribución-NoComercial 4.0 Internacional | * |
dc.rights.uri | http://creativecommons.org/licenses/by-nc/4.0/ | * |
dc.subject | SARS-CoV-2 | ca_CA |
dc.subject | COVID-19 | ca_CA |
dc.subject | main protease | ca_CA |
dc.title | 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 | ca_CA |
dc.type | info:eu-repo/semantics/article | ca_CA |
dc.identifier.doi | https://doi.org/10.1039/D0SC06195F | |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | ca_CA |
dc.relation.publisherVersion | https://pubs.rsc.org/en/content/articlehtml/2021/sc/d0sc06195f | ca_CA |
dc.contributor.funder | This work was supported by the Spanish Ministerio de Ciencia, Innovación y Universidades (Grant PGC2018-094852-B-C21 and PID2019-107098RJ-I00), Generalitat Valenciana (Grant AICO/2019/195 and SEJI/2020/007) Universitat Jaume I (UJI B2017-31, UJI B2018-41, UJI-A2019-04 and SomUJIContraCovid crowdfunding campaign), KŚ thanks the Spanish Ministerio de Ciencia, Innovación y Universidades for a Juan de la Cierva – Incorporación (ref. IJCI-2016-27503) contract. K. A. thanks Universitat Jaume I (POSDOC-A/2018/30) and Generalitat Valenciana (APOSTD/2020/015) for post-doctoral contracts. NS thanks the MINECO for doctoral FPI grant (BES-2016-078029). The authors thankfully acknowledge the computer resources at Pirineus and the technical support provided at Pirineus and by Barcelona Supercomputing Center (QSB-2020-2-0004), as well as the local computational resources of the Servei d’Informàtica of Universitat Jaume I. AJM thanks EPSRC for support (CCP-BioSim, grant number EP/M022609/1) and also the British Society for Antimicrobial Chemotherapy (grant number BSAC-COVID-30). | ca_CA |
dc.type.version | info:eu-repo/semantics/publishedVersion | ca_CA |
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