{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Ngo ST"],"funding":["National Foundation for Science and Technology Development"],"pagination":["3729-3737"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC8979274"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["12(6)"],"pubmed_abstract":["The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been causing the COVID-19 pandemic, resulting in several million deaths being reported. Numerous investigations have been carried out to discover a compound that can inhibit the biological activity of the SARS-CoV-2 main protease, which is an enzyme related to the viral replication. Among these, PF-07321332 (Nirmatrelvir) is currently under clinical trials for COVID-19 therapy. Therefore, in this work, atomistic and electronic simulations were performed to unravel the binding and covalent inhibition mechanism of the compound to M<sup>pro</sup>. Initially, 5 μs of steered-molecular dynamics simulations were carried out to evaluate the ligand-binding process to SARS-CoV-2 M<sup>pro</sup>. The successfully generated <i>bound</i> state between the two molecules showed the important role of the PF-07321332 pyrrolidinyl group and the residues Glu166 and Gln189 in the ligand-binding process. Moreover, from the MD-refined structure, quantum mechanics/molecular mechanics (QM/MM) calculations were carried out to unravel the reaction mechanism for the formation of the thioimidate product from SARS-CoV-2 M<sup>pro</sup> and the PF-07321332 inhibitor. We found that the catalytic triad Cys145-His41-Asp187 of SARS-CoV-2 M<sup>pro</sup> plays an important role in the activation of the PF-07321332 covalent inhibitor, which renders the deprotonation of Cys145 and, thus, facilitates further reaction. Our results are definitely beneficial for a better understanding of the inhibition mechanism and designing new effective inhibitors for SARS-CoV-2 M<sup>pro</sup>."],"journal":["RSC advances"],"pubmed_title":["Insights into the binding and covalent inhibition mechanism of PF-07321332 to SARS-CoV-2 M<sup>pro</sup>."],"pmcid":["PMC8979274"],"funding_grant_id":["104.99-2019.57"],"pubmed_authors":["Ngo ST","Tung NT","Nguyen TH","Mai BK"],"additional_accession":[]},"is_claimable":false,"name":"Insights into the binding and covalent inhibition mechanism of PF-07321332 to SARS-CoV-2 M<sup>pro</sup>.","description":"The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been causing the COVID-19 pandemic, resulting in several million deaths being reported. Numerous investigations have been carried out to discover a compound that can inhibit the biological activity of the SARS-CoV-2 main protease, which is an enzyme related to the viral replication. Among these, PF-07321332 (Nirmatrelvir) is currently under clinical trials for COVID-19 therapy. Therefore, in this work, atomistic and electronic simulations were performed to unravel the binding and covalent inhibition mechanism of the compound to M<sup>pro</sup>. Initially, 5 μs of steered-molecular dynamics simulations were carried out to evaluate the ligand-binding process to SARS-CoV-2 M<sup>pro</sup>. The successfully generated <i>bound</i> state between the two molecules showed the important role of the PF-07321332 pyrrolidinyl group and the residues Glu166 and Gln189 in the ligand-binding process. Moreover, from the MD-refined structure, quantum mechanics/molecular mechanics (QM/MM) calculations were carried out to unravel the reaction mechanism for the formation of the thioimidate product from SARS-CoV-2 M<sup>pro</sup> and the PF-07321332 inhibitor. We found that the catalytic triad Cys145-His41-Asp187 of SARS-CoV-2 M<sup>pro</sup> plays an important role in the activation of the PF-07321332 covalent inhibitor, which renders the deprotonation of Cys145 and, thus, facilitates further reaction. Our results are definitely beneficial for a better understanding of the inhibition mechanism and designing new effective inhibitors for SARS-CoV-2 M<sup>pro</sup>.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Jan","modification":"2026-05-31T06:59:51.884Z","creation":"2025-02-19T01:55:10.839Z"},"accession":"S-EPMC8979274","cross_references":{"pubmed":["35425393"],"doi":["10.1039/d1ra08752e"]}}