SARS-CoV-2 Mpro inhibitors: identification of anti-SARS-CoV-2 Mpro compounds from FDA approved drugs

Shiv Bharadwaj, Esam Ibraheem Azhar, Mohammad Amjad Kamal, Leena Hussein Bajrai, Amit Dubey, Kanupriya Jha, Umesh Yadava, Sang Gu Kang, Vivek Dhar Dwivedi

10.1080/07391102.2020.1842807

Research curated

Abstract

Recent outbreak of COVID-19 pandemic caused by severe acute respiratory syndrome-Coronavirus-2 (SARS-CoV-2) has raised serious global concern for public health. The viral main 3-chymotrypsin-like cysteine protease (Mpro), known to control coronavirus replication and essential for viral life cycle, has been established as an essential drug discovery target for SARS-CoV-2. Herein, we employed computationally screening of Druglib database containing FDA approved drugs against active pocket of SARS-CoV-2 Mpro using MTiopen screen web server, yields a total of 1051 FDA approved drugs with docking energy >−7 kcal/mol. The top 10 screened potential compounds against SARS-CoV-2 Mpro were then studied by re-docking, binding affinity, intermolecular interaction, and complex stability via 100 ns all atoms molecular dynamics (MD) simulation followed by post-simulation analysis, including end point binding free energy, essential dynamics, and residual correlation analysis against native crystal structure ligand N3 inhibitor. Based on comparative molecular simulation and interaction profiling of the screened drugs with SARS-CoV-2 Mpro revealed R428 (−10.5 kcal/mol), Teniposide (−9.8 kcal/mol), VS-5584 (−9.4 kcal/mol), and Setileuton (−8.5 kcal/mol) with stronger stability and affinity than other drugs and N3 inhibitor; and hence, these drugs are advocated for further validation using in vitro enzyme inhibition and in vivo studies against SARS-CoV-2 infection.

Source: PubMed

Related molecules

Name	Synonyms	Genes
MK-3207
Setileuton	910656-27-8, MK-0633, UNII-0U2750935P, 0U2750935P
Cep-11981
Orvepitant	GW823296
VS-5584
Teniposide
Etoposide	Toposar
3C-like protease	3CLpro, Mpro, SARS coronavirus main peptidase, 3CLpro-SARS-CoV-2	rep, ORF1a-1b
R-428	Bemcentinib
Tadalafil

Related interactions

Target	Drug	Type	Result
3C-like protease	MK-3207	Computational	positive
3C-like protease	Cep-11981	Computational	positive
3C-like protease	Orvepitant	Computational	positive
3C-like protease	VS-5584	Computational	positive
3C-like protease	Setileuton	Computational	positive
3C-like protease	Teniposide	Computational	positive
3C-like protease	Etoposide	Computational	positive
3C-like protease	Tadalafil	Computational	positive
3C-like protease	R-428	Computational	positive