Microsecond MD Simulation and Multiple-Conformation Virtual Screening to Identify Potential Anti-COVID-19 Inhibitors Against SARS-CoV-2 Main Protease

0539587 - ÚOCHB 2022 RIV CH eng J - Journal Article
Selvaraj, C. - Panwar, U. - Dinesh, Dhurvas Chandrasekaran - Bouřa, Evžen - Singh, P. - Dubey, V. K. - Singh, S. K.
Microsecond MD Simulation and Multiple-Conformation Virtual Screening to Identify Potential Anti-COVID-19 Inhibitors Against SARS-CoV-2 Main Protease.
Frontiers in Chemistry. Roč. 8, Jan 13 (2021), č. článku 595273. ISSN 2296-2646. E-ISSN 2296-2646
R&D Projects: GA MŠMT(CZ) EF16_019/0000729
Grant - others:AV ČR(CZ) L200551951
Institutional support: RVO:61388963
Keywords : SARS-CoV-2 main protease * COVID-19 * TCM * natural products * molecular dynamics * ensemble sampling
OECD category: Biochemistry and molecular biology
Impact factor: 5.545, year: 2021
Method of publishing: Open access
https://doi.org/10.3389/fchem.2020.595273

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.
Permanent Link: http://hdl.handle.net/11104/0318116