Journal
FRONTIERS IN CHEMISTRY
Volume 8, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fchem.2020.595273
Keywords
SARS-CoV-2 main protease; COVID-19; TCM; natural products; molecular dynamics; ensemble sampling
Categories
Funding
- RUSA-Phase 2.0 Policy (TNmultiGen), Dept. of Edn, Govt. of India [F.24-51/2014-U]
- DST [CVD/2020/000031]
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The study analyzed the structural aspects of SARS-CoV-2 M-pro conformational changes through molecular modeling and 1-microsecond MD simulations, and screened potential compounds from Traditional Chinese Medicine database that could interact with the active site of M-pro, potentially inhibiting viral replication.
The recent pandemic outbreak of COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), raised global health and economic concerns. Phylogenetically, SARS-CoV-2 is closely related to SARS-CoV, and both encode the enzyme main protease (M-pro/3CL(pro)), which can be a potential target inhibiting viral replication. Through this work, we have compiled the structural aspects of M-pro conformational changes, with molecular modeling and 1-mu s MD simulations. Long-scale MD simulation resolves the mechanism role of crucial amino acids involved in protein stability, followed by ensemble docking which provides potential compounds from the Traditional Chinese Medicine (TCM) database. These lead compounds directly interact with active site residues (His41, Gly143, and Cys145) of M-pro, which plays a crucial role in the enzymatic activity. Through the binding mode analysis in the S1, S1 ', S2, and S4 binding subsites, screened compounds may be functional for the distortion of the oxyanion hole in the reaction mechanism, and it may lead to the inhibition of M-pro in SARS-CoV-2. The hit compounds are naturally occurring compounds; they provide a sustainable and readily available option for medical treatment in humans infected by SARS-CoV-2. Henceforth, extensive analysis through molecular modeling approaches explained that the proposed molecules might be promising SARS-CoV-2 inhibitors for the inhibition of COVID-19, subjected to experimental validation.
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