Molecular modeling and structure-activity relationship of a natural o-hydroxybenzoate derivative as a potent inhibitor of SARS-CoV-2 dual NSP3 and NSP12: an in silico study

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J Biomol Struct Dyn. 17:1-19 Jan 2022. doi: 10.1080/07391102.2022.2026818. Online ahead of print.


The nsp3 macrodomain and nsp12 (RdRp) enzymes are strongly implicated in the virulent regulation of the host immune response and viral replication of SARS-CoV-2, making them plausible therapeutic targets for mitigating infectivity . Remdesivir remains the only FDA-approved small molecule inhibitor of nsp12 in clinical conditions while none have yet been approved for the nsp3 macrodomain. In this study, 69,067 natural compounds from the IBScreen database were screened for effective potentials with mechanistic multitarget inhibitory pharmacology against dual targets using silicone approaches. Maestro Glide Docking standard and additional precision (SP and XP) assays were used to assess their inhibitory interactions against enzymes. Four compounds, STOCK1N-45901, 03804, 83408, 08377 consistently showed high XP scores against respective targets and interacted strongly with pharmacologically essential amino acid and RNA residues, in better terms than standard inhibitors co -crystallized, GS-441524 and remdesivir. Further evaluations through ADMET and mutagenicity predictions singled out STOCK1N-45901, a naturally occurring derivative of o-hydroxybenzoate as the most promising candidate. The ligand maintained good conformational and thermodynamic stability in complex with the enzymes throughout the 100 ns molecular dynamics trajectories, indicated by RMSD, RMSF and radius of gyration. Its binding free energy, MM-GBSA, was recorded at -54.24 and -31.77 kcal/mol against the respective enzyme, while its structure-activity relationships confer high probabilities as an active antiviral, anti-inflammatory, anti-infective, antitussive and peroxidase inhibitor. IBScreen’s natural product, STOCK1N-45901 (2,3,4,5,6-pentahydroxyhexyl oh-hydroxybenzoate) is therefore recommended as a potent inhibitor of both nsp3 and nsp12 of SARS-CoV-2 for further study. Communicated by Ramaswamy H. Sarma.

PMID:35037841 | DO I:10.1080/07391102.2022.2026818

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