In silico prediction of potential inhibitors for the main protease of SARS-CoV-2 using molecular docking and dynamics simulation based drug-repurposing

Yogesh Kumara, Harvijay Singh, Chirag N.Patel

10.1016/j.jiph.2020.06.016

Research curated

Abstract

Background The rapidly enlarging COVID-19 pandemic caused by the novel SARS-corona virus-2 is a global public health emergency of an unprecedented level. Unfortunately no treatment therapy or vaccine is yet available to counter the SARS-CoV-2 infection, which substantiates the need to expand research efforts in this direction. The indispensable function of the main protease in virus replication makes this enzyme a promising target for inhibitors screening and drug discovery to treat novel coronavirus infection. The recently concluded α-ketoamide ligand-bound X-ray crystal structure of SARS-CoV-2 Mpro (PDB ID: 6Y2F) from Zhang et al. has revealed the potential inhibitor binding mechanism and the molecular determinants responsible for substrate binding. Methods For the study, we have targeted the SARS-CoV-2 Mpro for the screening of FDA approved antiviral drugs and carried out molecular docking based virtual screening. Further molecular dynamic simulation studies of the top three selected drugs carried out to investigated for their binding affinity and stability in the SARS-CoV-2 Mpro active site. The phylogenetic analysis was also performed to know the relatedness between the SARS-CoV-2 genomes isolated from different countries. Results The phylogenetic analysis of the SARS-CoV-2 genome reveals that the virus is closely related to the Bat-SL-CoV and does not exhibit any divergence at the genomic level. Molecular docking studies revealed that among the 77 drugs, screened top ten drugs shows good binding affinities, whereas the top three drugs: Lopinavir–Ritonavir, Tipranavir, and Raltegravir were undergone for molecular dynamics simulation studies for their conformational stability in the active site of the SARS-CoV-2 Mpro protein. Conclusions In the present study among the library of FDA approved antiviral drugs, the top three inhibitors Lopinavir–Ritonavir, Tipranavir, and Raltegravir show the best molecular interaction with the main protease of SARS-CoV-2. However, the in-vitro efficacy of the drug molecules screened in this study further needs to be corroborated by carrying out a biochemical and structural investigation.

Source: PubMed

Related molecules

Name	Synonyms	Genes
Tenofovir disoproxil	Tenofovir disoproxil fumarate
Tipranavir
Raltegravir
Baloxavir Marboxil
Maraviroc
Nelfinavir
3C-like protease	3CLpro, Mpro, SARS coronavirus main peptidase, 3CLpro-SARS-CoV-2	rep, ORF1a-1b
Dolutegravir
Letermovir
Lopinavir & Ritonavir

Related interactions

Target	Drug	Type	Result
3C-like protease	Lopinavir & Ritonavir	Computational	positive
3C-like protease	Tipranavir	Computational	positive
3C-like protease	Nelfinavir	Computational	positive
3C-like protease	Tenofovir disoproxil	Computational	positive
3C-like protease	Baloxavir Marboxil	Computational	positive
3C-like protease	Letermovir	Computational	positive
3C-like protease	Raltegravir	Computational	positive
3C-like protease	Maraviroc	Computational	positive
3C-like protease	Dolutegravir	Computational	positive