ArticleChemical science2021
A microscopic description of SARS-CoV-2 main protease inhibition with Michael acceptors. Strategies for improving inhibitor design.
Article in Chemical science, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 65 citations in OpenAlex.
- Artificial intelligence and ultra-high performance computing methods and experiments for drug discovery: virtual screening, deep learning, molecular dynamics simulations, ADMET modelling, and experimental validation.Molecular biomedicine · 2026Review
- Systematic Modeling of Covalent Inhibitors of SARS-CoV-2 Main Protease and Its Mutants.ACS catalysis · 2026Article
- Template-Based Docking Using Automated Maximum Common Substructure Identification with EnzyDock: Mechanistic and Inhibitor Docking.Journal of chemical information and modeling · 2025Article
- 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
- Mechanistic Insights into Nitrile and Alkyne Covalent Inhibitors of the SARS-CoV-2 Main Protease.ACS catalysis · 2025Article
- Catalytic Mechanism of SARS-CoV-2 3-Chymotrypsin-Like Protease as Determined by Steady-State and Pre-Steady-State Kinetics.ACS catalysis · 2024Article
- Article
- Perspectives on Computational Enzyme Modeling: From Mechanisms to Design and Drug Development.ACS omega · 2024Review
- 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
- Targeting SARS-CoV-2 Main Protease for Treatment of COVID-19: Covalent Inhibitors Structure-Activity Relationship Insights and Evolution Perspectives.Journal of medicinal chemistry · 2022Review
- Methodology-Centered Review of Molecular Modeling, Simulation, and Prediction of SARS-CoV-2.Chemical reviews · 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
- New insights into the catalytic mechanism of the SARS-CoV-2 main protease: an ONIOM QM/MM approach.Molecular diversity · 2022Article
- Multiple protonation states in ligand-free SARS-CoV-2 main protease revealed by large-scale quantum molecular dynamics simulations.Chemical physics letters · 2022Article
- Applications of density functional theory in COVID-19 drug modeling.Drug discovery today · 2022Review
- SERS-PCR assays of SARS-CoV-2 target genes using Au nanoparticles-internalized Au nanodimple substrates.Biosensors & bioelectronics · 2022Article
- Insights into the binding and covalent inhibition mechanism of PF-07321332 to SARS-CoV-2 MRSC advances · 2022Article
- Michael acceptor molecules in natural products and their mechanism of action.Frontiers in pharmacology · 2022Review
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The irreversible inhibition of the main protease of SARS-CoV-2 by a Michael acceptor known as N3 has been investigated using multiscale methods. The noncovalent enzyme-inhibitor complex was simulated using classical molecular dynamics techniques and the pose of the inhibitor in the active site was compared to that of the natural substrate, a peptide containing the Gln-Ser scissile bond. The formation of the covalent enzyme-inhibitor complex was then simulated using hybrid QM/MM free energy methods. After binding, the reaction mechanism was found to be composed of two steps: (i) the activation of the catalytic dyad (Cys145 and His41) to form an ion pair and (ii) a Michael addition where the attack of the Sγ atom of Cys145 to the Cβ atom of the inhibitor precedes the water-mediated proton transfer from His41 to the Cα atom. The microscopic description of protease inhibition by N3 obtained from our simulations is strongly supported by the excellent agreement between the estimated activation free energy and the value derived from kinetic experiments. Comparison with the acylation reaction of a peptide substrate suggests that N3-based inhibitors could be improved by adding chemical modifications that could facilitate the formation of the catalytic dyad ion pair.
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