Characterization of the non-covalent interaction between the PF-07321332 inhibitor and the SARS-CoV-2 main protease

• Published in: Journal of molecular graphics & modelling Vol. 110; p. 108042
• Main Authors: Macchiagodena, Marina, Pagliai, Marco, Procacci, Piero
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2022
• Subjects: 3CL-PRO; 3CL-PRO inhibitor; Antiviral Agents - therapeutic use; Coronavirus; Coronavirus 3C Proteases; Coronavirus main protease; COVID-19; Humans; Lactams; Leucine; Molecular Docking Simulation; Molecular dynamics; Molecular Dynamics Simulation; Nitriles; PF-07321332; Pfizer; Proline; Protease Inhibitors; SARS-CoV-2; COVID-19; SARS-CoV-2; Coronavirus; Pfizer; Molecular dynamics; 3CL-PRO inhibitor; 3CL-PRO; PF-07321332; Coronavirus main protease
• ISSN: 1093-3263; 1873-4243
• DOI: 10.1016/j.jmgm.2021.108042

We have studied the non-covalent interaction between PF-07321332 and SARS-CoV-2 main protease at the atomic level using a computational approach based on extensive molecular dynamics simulations with explicit solvent. PF-07321332, whose chemical structure has been recently disclosed, is a promising oral antiviral clinical candidate with well-established anti-SARS-CoV-2 activity in vitro. The drug, currently in phase III clinical trials in combination with ritonavir, relies on the electrophilic attack of a nitrile warhead to the catalytic cysteine of the protease. Nonbonded interaction between the inhibitor and the residues of the binding pocket, as well as with water molecules on the protein surface, have been characterized using two different force fields and the two possible protonation states of the main protease catalytic dyad HIS41-CYS145. When the catalytic dyad is in the neutral state, the non-covalent binding is likely to be stronger. Molecular dynamics simulations seems to lend support for an inhibitory mechanism in two steps: a first non-covalent addition with the dyad in neutral form and then the formation of the thiolate-imidazolium ion pair and the ligand relocation for finalising the electrophilic attack. [Display omitted] •Study of the non-covalent interaction between PF-07321332 and SARS-CoV-2 main protease using a computational approach.•The catalytic dyad HIS41-CYS145 has been characterized using two different force fields (AMBER and OPLS-AA) and the two possible protonation states.•Molecular dynamics simulations seem to lend support for an inhibitory mechanism in two steps.