Russian Chemical Bulletin, volume 70, issue 11, pages 2084-2089
Supercomputer simulation of the covalent inhibition of the main protease of SARS-CoV-2
Publication type: Journal Article
Publication date: 2021-11-01
Journal:
Russian Chemical Bulletin
Quartile SCImago
Q3
Quartile WOS
Q3
Impact factor: 1.7
ISSN: 10665285, 15739171
PubMed ID:
35068913
General Chemistry
Abstract
Molecular modeling tools were applied to design a potential covalent inhibitor of the main protease (Mpro) of the SARS-CoV-2 virus and to investigate its interaction with the enzyme. The compound includes a benzoisothiazolone (BZT) moiety of antimalarial drugs and a 5-fluoro-6-nitropyrimidine-2,4(1.H,3H)-dione (FNP) moiety mimicking motifs of inhibitors of other cysteine proteases. The BZT moiety provides a fair binding of the ligand on the protein surface, whereas the warhead FNP is responsible for efficient nucleophilic aromatic substitution reaction with the catalytic cysteine residue in the Mpro active site, leading to a stable covalent adduct. According to supercomputer calculations of the reaction energy profile using the quantum mechanics/molecular mechanics method, the energy of the covalent adduct is 21 kcal mol−1 below the energy of the reactants, while the highest barrier along the reaction pathway is 9 kcal mol−1. These estimates indicate that the reaction can proceed efficiently and can block the Mpro enzyme. The computed structures along the reaction path illustrate the nucleophilic aromatic substitution (SNAr) mechanism in enzymes. The results of this study are important for the choice of potential drugs blocking the development of coronavirus infection.
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Russian Chemical Bulletin
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Russian Chemical Bulletin
4 publications, 80%
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Journal of Chemical Physics
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Journal of Chemical Physics
1 publication, 20%
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Springer Nature
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Springer Nature
4 publications, 80%
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American Institute of Physics (AIP)
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American Institute of Physics (AIP)
1 publication, 20%
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Nemukhin A. V. et al. Supercomputer simulation of the covalent inhibition of the main protease of SARS-CoV-2 // Russian Chemical Bulletin. 2021. Vol. 70. No. 11. pp. 2084-2089.
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Nemukhin A. V., Grigorenko B. L., Lushchekina S. V., Varfolomeev S. D. Supercomputer simulation of the covalent inhibition of the main protease of SARS-CoV-2 // Russian Chemical Bulletin. 2021. Vol. 70. No. 11. pp. 2084-2089.
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TY - JOUR
DO - 10.1007/s11172-021-3319-8
UR - https://doi.org/10.1007%2Fs11172-021-3319-8
TI - Supercomputer simulation of the covalent inhibition of the main protease of SARS-CoV-2
T2 - Russian Chemical Bulletin
AU - Lushchekina, S V
AU - Nemukhin, A. V.
AU - Grigorenko, B. L.
AU - Varfolomeev, S. D.
PY - 2021
DA - 2021/11/01 00:00:00
PB - Springer Nature
SP - 2084-2089
IS - 11
VL - 70
PMID - 35068913
SN - 1066-5285
SN - 1573-9171
ER -
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@article{2021_Nemukhin,
author = {S V Lushchekina and A. V. Nemukhin and B. L. Grigorenko and S. D. Varfolomeev},
title = {Supercomputer simulation of the covalent inhibition of the main protease of SARS-CoV-2},
journal = {Russian Chemical Bulletin},
year = {2021},
volume = {70},
publisher = {Springer Nature},
month = {nov},
url = {https://doi.org/10.1007%2Fs11172-021-3319-8},
number = {11},
pages = {2084--2089},
doi = {10.1007/s11172-021-3319-8}
}
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Nemukhin, A. V., et al. “Supercomputer simulation of the covalent inhibition of the main protease of SARS-CoV-2.” Russian Chemical Bulletin, vol. 70, no. 11, Nov. 2021, pp. 2084-2089. https://doi.org/10.1007%2Fs11172-021-3319-8.
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