ArticleChemical science2023
The impact of SARS-CoV-2 3CL protease mutations on nirmatrelvir inhibitory efficiency. Computational insights into potential resistance mechanisms.
Article in Chemical science, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed.
- Structure-Based Design of Covalent SARS-CoV‑2 Main Protease Inhibitors Targeting the Nirmatrelvir-Resistant E166 Mutants.JACS Au · 2026Article
- Inhibitor-induced dimerization mediates lufotrelvir resistance in mutants of SARS-CoV-2 3C-like protease.Protein science : a publication of the Protein Society · 2025Article
- Strategy to overcome a nirmatrelvir resistance mechanism in the SARS-CoV-2 nsp5 protease.Science advances · 2025Article
- A Reflection on the Use of Molecular Simulation to Respond to SARS-CoV-2 Pandemic Threats.The journal of physical chemistry letters · 2025Review
- An Investigation of Nirmatrelvir (Paxlovid) Resistance in SARS-CoV-2 MACS bio & med chem Au · 2024Article
- Molecular Insights into Structural Dynamics and Binding Interactions of Selected Inhibitors Targeting SARS-CoV-2 Main Protease.International journal of molecular sciences · 2024Article
- Computational Insights into SARS-CoV-2 Main Protease Mutations and Nirmatrelvir Efficacy: The Effects of P132H and P132H-A173V.Journal of chemical information and modeling · 2024Article
- Perspectives on Computational Enzyme Modeling: From Mechanisms to Design and Drug Development.ACS omega · 2024Review
- Article
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Authors and funding
5 authors.
Funding
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Abstract
The use of antiviral drugs can promote the appearance of mutations in the target protein that increase the resistance of the virus to the treatment. This is also the case of nirmatrelvir, a covalent inhibitor of the 3CL protease, or main protease, of SARS-CoV-2. In this work we show how the by-residue decomposition of noncovalent interactions established between the drug and the enzyme, in combination with an analysis of naturally occurring mutations, can be used to detect potential mutations in the 3CL protease conferring resistance to nirmatrelvir. We also investigate the consequences of these mutations on the reaction mechanism to form the covalent enzyme-inhibitor complex using QM/MM methods. In particular, we show that the E166V variant of the protease displays smaller binding affinity to nirmatrelvir and larger activation free energy for the formation of the covalent complex, both factors contributing to the observed resistance to the treatment with this drug. The conclusions derived from our work can be used to anticipate the consequences of the introduction of nirmatrelvir in the fitness landscape of the virus and to design new inhibitors adapted to some of the possible resistance mechanisms.
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Registered trials
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