Supercomputer simulation of the covalent inhibition of the main protease of SARS-CoV-2.
Russ Chem Bull
; 70(11): 2084-2089, 2021.
Article
in English
| MEDLINE | ID: covidwho-1626439
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.
Full text:
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Collection:
International databases
Database:
MEDLINE
Language:
English
Journal:
Russ Chem Bull
Year:
2021
Document Type:
Article
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