{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T07:05:35Z","timestamp":1792739135839,"version":"4.5.0"},"reference-count":22,"publisher":"Wiley","issue":"49","license":[{"start":{"date-parts":[[2021,11,3]],"date-time":"2021-11-03T00:00:00Z","timestamp":1635897600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003359","name":"Generalitat Valenciana","doi-asserted-by":"publisher","award":["GVCOV19\/Decreto180\/2020"],"award-info":[{"award-number":["GVCOV19\/Decreto180\/2020"]}],"id":[{"id":"10.13039\/501100003359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011033","name":"Agencia Estatal de Investigaci\u00f3n","doi-asserted-by":"publisher","award":["PGC2018-094852-B-C22"],"award-info":[{"award-number":["PGC2018-094852-B-C22"]}],"id":[{"id":"10.13039\/501100011033","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Angew Chem Int Ed"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>We present the results of classical and QM\/MM simulations for the inhibition of SARS\u2010CoV\u20102 3CL protease by a hydroxymethylketone inhibitor, PF\u201000835231. In the noncovalent complex the carbonyl oxygen atom of the warhead is placed in the oxyanion hole formed by residues 143 to 145, while P1\u2013P3 groups are accommodated in the active site with interactions similar to those observed for the peptide substrate. According to alchemical free energy calculations, the P1\u2032 hydroxymethyl group also contributes to the binding free energy. Covalent inhibition of the enzyme is triggered by the proton transfer from Cys145 to His41. This step is followed by the nucleophilic attack of the S\u03b3 atom on the carbonyl carbon atom of the inhibitor and a proton transfer from His41 to the carbonyl oxygen atom mediated by the P1\u2032 hydroxyl group. Computational simulations show that the addition of a chloromethyl substituent to the P1\u2032 group may lower the activation free energy for covalent inhibition<\/jats:p>","DOI":"10.1002\/anie.202110027","type":"journal-article","created":{"date-parts":[[2021,9,28]],"date-time":"2021-09-28T05:41:03Z","timestamp":1632807663000},"page":"25933-25941","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Inhibition Mechanism of SARS\u2010CoV\u20102 Main Protease with Ketone\u2010Based Inhibitors Unveiled by Multiscale Simulations: Insights for Improved Designs**"],"prefix":"10.1002","volume":"60","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7701-377X","authenticated-orcid":false,"given":"Carlos A.","family":"Ramos\u2010Guzm\u00e1n","sequence":"first","affiliation":[{"name":"Departamento de Qu\u00edmica F\u00edsica Universidad de Valencia  46100 Burjassot Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4640-0419","authenticated-orcid":false,"given":"J. 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