In search of RdRp and Mpro inhibitors against SARS CoV-2: Molecular docking, molecular dynamic simulations and ADMET analysis

Normi D Gajjar; Tejas M Dhameliya; Gaurang B Shah

doi:10.1016/j.molstruc.2021.130488

In search of RdRp and Mpro inhibitors against SARS CoV-2: Molecular docking, molecular dynamic simulations and ADMET analysis

J Mol Struct. 2021 Sep 5:1239:130488. doi: 10.1016/j.molstruc.2021.130488. Epub 2021 Apr 21.

Authors

Normi D Gajjar¹, Tejas M Dhameliya¹, Gaurang B Shah¹

Affiliation

¹ L.M. College of Pharmacy, Navrangpura, Ahmedabad 380 009, Gujarat, India.

Abstract

Corona Virus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome coronavirus (SARS CoV-2) has been declared a worldwide pandemic by WHO recently. The complete understanding of the complex genomic structure of SARS CoV-2 has enabled the use of computational tools in search of SARS CoV-2 inhibitors against the multiple proteins responsible for its entry and multiplication in human cells. With this endeavor, 177 natural, anti-viral chemical entities and their derivatives, selected through the critical analysis of the literatures, were studied using pharmacophore screening followed by molecular docking against RNA dependent RNA polymerase and main protease. The identified hits have been subjected to molecular dynamic simulations to study the stability of ligand-protein complexes followed by ADMET analysis and Lipinski filters to confirm their drug likeliness. It has led to an important start point in the drug discovery and development of therapeutic agents against SARS CoV-2.

Keywords: 3CLpro, 3-chymotrypsin-like protease; ACE, Angiotensin converting enzyme; ADMET, Absorption, distribution, metabolism, excretion, and toxicity; ASL, Atom specification language; COVID-19, Corona virus disease-2019; Dscore, Druggability score; EM, Electron microscopy; HB, Hydrogen bond; MD simulation; MD simulation, Molecular dynamic simulation; Molecular docking; Mpro; Mpro, Main protease; Natural products; PLpro, Papain-like protease; RMSD, Root mean square deviation; RMSF, Root mean square fluctuation; RdRP, RNA-dependent RNA polymerase; RdRp; RoG, Radius of gyration; SARS CoV-2; SARS CoV-2, Severe acute respiratory syndrome coronavirus 2; SASA, Solvent accessible surface area; SP, Standard precision; WHO, World health organization; nsp, Non-structural protein.