Rational approach toward COVID-19 main protease inhibitors via molecular docking, molecular dynamics simulation and free energy calculation.

Seketoulie Keretsu, Swapnil P Bhujbal, Seung Joo Cho

Journal: Scientific reports 2020;10(1):17716

PMID: 33077821

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Abstract

In the rapidly evolving coronavirus disease (COVID-19) pandemic, repurposing existing drugs and evaluating commercially available inhibitors against druggable targets of the virus could be an effective strategy to accelerate the drug discovery process. The 3C-Like proteinase (3CL) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been identified as an important drug target due to its role in viral replication. The lack of a potent 3CL inhibitor and the availability of the X-ray crystal structure of 3CL (PDB-ID 6LU7) motivated us to perform computational studies to identify commercially available potential inhibitors. A combination of modeling studies was performed to identify potential 3CL inhibitors from the protease inhibitor database MEROPS ( https://www.ebi.ac.uk/merops/index.shtml ). Binding energy evaluation identified key residues for inhibitor design. We found 15 potential 3CL inhibitors with higher binding affinity than that of an α-ketoamide inhibitor determined via X-ray structure. Among them, saquinavir and three other investigational drugs aclarubicin, TMC-310911, and faldaprevir could be suggested as potential 3CL inhibitors. We recommend further experimental investigation of these compounds.

Address: Department of Biomedical Sciences, College of Medicine, Chosun University, Gwangju, 501-759, Republic of Korea.; Department of Biomedical Sciences, College of Medicine, Chosun University, Gwangju, 501-759, Republic of Korea. [email protected].; Department of Cellular Molecular Medicine, College of Medicine, Chosun University, 375 Seosuk-dong, Dong-gu, Gwangju, 501-759, Republic of Korea. [email protected].

DOI: 10.1038/s41598-020-74468-0

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https://assays.cancer.gov/CPTAC-438

MeSH Terms: Aclarubicin, Aminoisobutyric Acids, Betacoronavirus, Binding Sites, COVID-19, Coronavirus 3C Proteases, Coronavirus Infections, Cysteine Endopeptidases, Databases, Factual, Humans, Hydrogen Bonding, Leucine, Molecular Docking Simulation, Molecular Dynamics Simulation, Oligopeptides, Pandemics, Pneumonia, Viral, Proline, Protease Inhibitors, Quinolines, SARS-CoV-2, Thermodynamics, Thiazoles, Viral Nonstructural Proteins