Drug repurposing studies targeting SARS-nCoV2: An ensemble docking approach on drug target 3C-like protease (3CLpro)

Shruti Koulgi, Vinod Jani, Mallikarjunachari Uppuladinne, Uddhavesh Sonavane, A. K. Nath, Hemant Darbari, Rajendra Joshi

10.1080/07391102.2020.1792344

Research curated

Abstract

The COVID-19 pandemic has been responsible for several deaths worldwide. The causative agent behind this disease is the Severe Acute Respiratory Syndrome – novel Coronavirus 2 (SARS- nCoV2). SARS-nCoV2 belongs to the category of RNA viruses. The main protease, responsible for the cleavage of the viral polyprotein is considered as one of the hot targets for treating COVID- 19. Earlier reports suggest the use of HIV anti-viral drugs for targeting the main protease of SARS- CoV, which caused SARS in the year 2002-03. Hence, drug repurposing approach may prove to be useful in targeting the main protease of SARS-nCoV2. The high-resolution crystal structure of main protease of SARS-nCoV2 (PDB ID: 6LU7) was used as the target. The Food and Drug Administration (FDA) approved and SWEETLEAD database of drug molecules were screened. The apo form of the main protease was simulated for a cumulative of 150 ns and 10 μs open source simulation data was used, to obtain conformations for ensemble docking. The representative structures for docking were selected using RMSD-based clustering and Markov State Modeling analysis. This ensemble docking approach for main protease helped in exploring the conformational variation in the drug binding site of the main protease leading to efficient binding of more relevant drug molecules. The drugs obtained as best hits from the ensemble docking possessed anti-bacterial and anti-viral properties. Small molecules with these properties may prove to be useful to treat symptoms exhibited in COVID-19. This in-silico ensemble docking approach would support identification of potential candidates for repurposing against COVID-19.

Source: ChemRxiv

Related molecules

Name	Synonyms	Genes
3C-like protease	3CLpro, Mpro, SARS coronavirus main peptidase, 3CLpro-SARS-CoV-2	rep, ORF1a-1b
Ivermectin	IVERMECTIN, Ivermectin B1a, Dihydroavermectin B1a, 70288-86-7, 22-23-Dihydroavermectin B1a
Neomycin	Neo-rx
Amprenavir
Indinavir

Related interactions

Target	Drug	Type	Result
3C-like protease	Amprenavir	Computational	negative
3C-like protease	Indinavir	Computational	negative
3C-like protease	Ivermectin	Computational	positive
3C-like protease	Neomycin	Computational	positive