ArticleAngewandte Chemie (International ed. in English)2021
Inhibition Mechanism of SARS-CoV-2 Main Protease with Ketone-Based Inhibitors Unveiled by Multiscale Simulations: Insights for Improved Designs*.
Article in Angewandte Chemie (International ed. in English), 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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15 citing papers in PubMed, 48 citations in OpenAlex.
- Systematic Modeling of Covalent Inhibitors of SARS-CoV-2 Main Protease and Its Mutants.ACS catalysis · 2026Article
- A Reflection on the Use of Molecular Simulation to Respond to SARS-CoV-2 Pandemic Threats.The journal of physical chemistry letters · 2025Review
- CHARMM-GUIJournal of chemical theory and computation · 2025Article
- Review
- Perspectives on Computational Enzyme Modeling: From Mechanisms to Design and Drug Development.ACS omega · 2024Review
- Anti-infection effects of heparin on SARS-CoV-2 in a diabetic mouse model.Zoological research · 2023Article
- Unraveling the catalytic mechanism of SARS-CoV-2 papain-like protease with allosteric modulation of C270 mutation using multiscale computational approaches.Chemical science · 2023Article
- Unveiling the Mechanistic Singularities of Caspases: A Computational Analysis of the Reaction Mechanism in Human Caspase-1.ACS catalysis · 2023Article
- Electrostatic Embedding of Machine Learning Potentials.Journal of chemical theory and computation · 2023Article
- The impact of SARS-CoV-2 3CL protease mutations on nirmatrelvir inhibitory efficiency. Computational insights into potential resistance mechanisms.Chemical science · 2023Article
- The SARS-CoV-2 main protease (MMedComm · 2022Review
- Testing Affordable Strategies for the Computational Study of Reactivity in Cysteine Proteases: The Case of SARS-CoV-2 3CL Protease Inhibition.Journal of chemical theory and computation · 2022Article
- Review of preclinical data of PF-07304814 and its active metabolite derivatives against SARS-CoV-2 infection.Frontiers in pharmacology · 2022Review
- Characterization of the non-covalent interaction between the PF-07321332 inhibitor and the SARS-CoV-2 main protease.Journal of molecular graphics & modelling · 2022Article
- Inhibition Mechanism of SARS-CoV-2 Main Protease with Ketone-Based Inhibitors Unveiled by Multiscale Simulations: Insights for Improved Designs*.Angewandte Chemie (International ed. in English) · 2021Article
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3 authors at 1 institution in 1 country.
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Abstract
We present the results of classical and QM/MM simulations for the inhibition of SARS-CoV-2 3CL protease by a hydroxymethylketone inhibitor, PF-00835231. 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-P3 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' 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 Sγ atom on the carbonyl carbon atom of the inhibitor and a proton transfer from His41 to the carbonyl oxygen atom mediated by the P1' hydroxyl group. Computational simulations show that the addition of a chloromethyl substituent to the P1' group may lower the activation free energy for covalent inhibition.
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