ArticleJournal of molecular graphics & modelling2022
Characterization of the non-covalent interaction between the PF-07321332 inhibitor and the SARS-CoV-2 main protease.
Article in Journal of molecular graphics & modelling, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed.
- Single- and multiple-dose pharmacokinetics and safety of the SARS-CoV-2 3CL protease inhibitor RAY1216: a phase 1 study in healthy participants.Antimicrobial agents and chemotherapy · 2025Trial
- Feasibility of the inhibitor development for SARS-CoV-2: a systematic approach for drug design.Journal of molecular modeling · 2025Article
- Machine Learning-Guided Screening and Molecular Docking for Proposing Naturally Derived Drug Candidates Against MERS-CoV 3CL Protease.International journal of molecular sciences · 2025Article
- Machine Learning in Enhancing Protein Binding Sites Predictions - What Has Changed Since Then?Combinatorial chemistry & high throughput screening · 2025Review
- Inhibitors of SARS-CoV-2 Main Protease (Mpro) as Anti-Coronavirus Agents.Biomolecules · 2024Review
- The inhibitory and inducing effects of ritonavir on hepatic and intestinal CYP3A and other drug-handling proteins.Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 2023Review
- Characteristics of COVID-19 vaccinated and unvaccinated patients admitted to Careggi University Hospital, Florence, Italy.Internal and emergency medicine · 2023Observational
- SARS-CoV-2 neutralizing antibody therapies: an early retrospective cohort study of 26 hospitalized patients treated with bamlanivimab or casirivimab/imdevimab.International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases · 2023Article
- Stabilization of the Dimeric State of SARS-CoV-2 Main Protease by GC376 and Nirmatrelvir.International journal of molecular sciences · 2023Article
- Molecular dynamics studies reveal structural and functional features of the SARS-CoV-2 spike protein.BioEssays : news and reviews in molecular, cellular and developmental biology · 2022Review
- The Mechanism-Based Inactivation of CYP3A4 by Ritonavir: What Mechanism?International journal of molecular sciences · 2022Review
- Interaction of the new inhibitor paxlovid (PF-07321332) and ivermectin with the monomer of the main protease SARS-CoV-2: A volumetric study based on molecular dynamics, elastic networks, classical thermodynamics and SPT.Computational biology and chemistry · 2022Article
- Developing New Treatments for COVID-19 through Dual-Action Antiviral/Anti-Inflammatory Small Molecules and Physiologically Based Pharmacokinetic Modeling.International journal of molecular sciences · 2022Review
- [Nirmatrelvir plus ritonavir (Paxlovid) a potent SARS-CoV-2 3CLpro protease inhibitor combination].Revista espanola de quimioterapia : publicacion oficial de la Sociedad Espanola de Quimioterapia · 2022Review
- Synthesis and Biochemical Evaluation of 8Molecules (Basel, Switzerland) · 2022Article
- Multiple protonation states in ligand-free SARS-CoV-2 main protease revealed by large-scale quantum molecular dynamics simulations.Chemical physics letters · 2022Article
- Nirmatrelvir Plus Ritonavir: First Approval.Drugs · 2022Review
- Potential Resistance of SARS-CoV-2 Main Protease (Mpro) against Protease Inhibitors: Lessons Learned from HIV-1 Protease.International journal of molecular sciences · 2022Review
- Article
- Molecular Insights of SARS-CoV-2 Antivirals Administration: A Balance between Safety Profiles and Impact on Cardiovascular Phenotypes.Biomedicines · 2022Review
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Authors and funding
3 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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