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Network Biology, 2024, 14(4): 266-292
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Article

Identification of the most potent bioactive natural compound as main protease inhibitor of SARS-CoV-2: Molecular docking, molecular dynamics simulations and MM-PBSA studies

Sana Begum1, Vishal K. Singh2, Priyanka Kumari1, Anup Som1
1Centre of Bioinformatics, Institute of Interdisciplinary Studies, University of Allahabad, Prayagraj - 211002, India
2Department of Chemistry, Institute of Science, Banaras Hindu University, Varanasi - 221005, India

Received 22 July 2024;Accepted 31 August 2024;Published online 15 September 2024;Published 1 December 2024
IAEES

Abstract
Emergence of COVID-19 and thereafter intensive research on bioactive natural compounds against SARS-CoV-2, identified a large number of phytochemicals (i.e., plants-derived) and mycochemicals (i.e., fungi-derived) as potential inhibitors with proven antiviral properties against SARS-CoV-2, but there are no comparative study on the reported compounds. A comparative study among the previously identified/reported main protease (Mpro) inhibitors of SARS-CoV-2 can lead to the most potent compound that eventually helps to make an effective drug lead against SARS-CoV-2. Through manual literature curation, we selected 57 potential bioactive compounds and screened them against Mpro protein of SARS-CoV-2. A series of in silico screening such as binding affinity, drug-like properties, pharmacokinetic, physicochemical, and ADMET studies identified top ten compounds as potential Mpro inhibitors. Further, docking studies prioritized the top two compounds namely Norquinadoline A and Quinadoline B, based on their predicted affinity for the target protein. Binding free energy calculations further emphasized them as top candidates for effective Mpro inhibitors that hold promise for drug development against COVID-19. In-depth molecular dynamics studies and MM/PBSA analysis culminated in the recognition of Norquinadoline A as the most potent Mpro inhibitor of SARS-CoV-2. Thus, Norquinadoline A can be used as lead compound in further drug discovery process after in vitro and in vivo experimental studies.

Keywords COVID-19;SARS-CoV-2;main protease;phytochemicals;mycochemicals;molecular docking;drug-likeness;toxicity;MD simulations;MM-PBSA analyses.


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