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

Chandrabose Selvaraj; Umesh Panwar; Dhurvas Chandrasekaran Dinesh; Evzen Boura; Poonam Singh; Vikash Kumar Dubey; Sanjeev Kumar Singh

doi:10.3389/fchem.2020.595273

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

Front Chem. 2021 Jan 13:8:595273. doi: 10.3389/fchem.2020.595273. eCollection 2020.

Authors

Chandrabose Selvaraj¹, Umesh Panwar¹, Dhurvas Chandrasekaran Dinesh², Evzen Boura², Poonam Singh³, Vikash Kumar Dubey⁴, Sanjeev Kumar Singh¹

Affiliations

¹ Computer Aided Drug Design and Molecular Modeling Lab, Department of Bioinformatics, Alagappa University, Karaikudi, India.
² Section of Molecular Biology and Biochemistry, Institute of Organic Chemistry and Biochemistry AS CR, v.v.i., Prague, Czechia.
³ Corrosion and Materials Protection Division, Council of Scientific and Industrial Research (CSIR)-Central Electrochemical Research Institute, Karaikudi, India.
⁴ School of Biochemical Engineering, Indian Institute of Technology (BHU), Varanasi, India.

Abstract

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-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 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.

Keywords: COVID-19; SARS-CoV-2 main protease; TCM; ensemble sampling; molecular dynamics; natural products.