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Microsecond MD Simulation and Multiple-Conformation Virtual Screening to Identify Potential Anti-COVID-19 Inhibitors Against SARS-CoV-2 Main Protease
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SYSNO ASEP 0539587 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Microsecond MD Simulation and Multiple-Conformation Virtual Screening to Identify Potential Anti-COVID-19 Inhibitors Against SARS-CoV-2 Main Protease Author(s) Selvaraj, C. (IN)
Panwar, U. (IN)
Dinesh, Dhurvas Chandrasekaran (UOCHB-X) ORCID
Bouřa, Evžen (UOCHB-X) ORCID
Singh, P. (IN)
Dubey, V. K. (IN)
Singh, S. K. (IN)Article number 595273 Source Title Frontiers in Chemistry. - : Frontiers Media - ISSN 2296-2646
Roč. 8, Jan 13 (2021)Number of pages 15 s. Language eng - English Country CH - Switzerland Keywords SARS-CoV-2 main protease ; COVID-19 ; TCM ; natural products ; molecular dynamics ; ensemble sampling OECD category Biochemistry and molecular biology R&D Projects EF16_019/0000729 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Method of publishing Open access Institutional support UOCHB-X - RVO:61388963 UT WOS 000612010100001 EID SCOPUS 85100261875 DOI 10.3389/fchem.2020.595273 Annotation 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 (Mpro/3CLpro), which can be a potential target inhibiting viral replication. Through this work, we have compiled the structural aspects of Mpro conformational changes, with molecular modeling and 1-μs 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 Mpro, 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 Mpro 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. Workplace Institute of Organic Chemistry and Biochemistry Contact asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Jana Procházková, Tel.: 220 183 418 Year of Publishing 2022 Electronic address https://doi.org/10.3389/fchem.2020.595273
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