Targeting multiple conformations of SARS-CoV2 Papain-Like Protease for drug repositioning: An in-silico study

Muhammad I Ismail; Hanan M Ragab; Adnan A Bekhit; Tamer M Ibrahim

doi:10.1016/j.compbiomed.2021.104295

Targeting multiple conformations of SARS-CoV2 Papain-Like Protease for drug repositioning: An in-silico study

Comput Biol Med. 2021 Apr:131:104295. doi: 10.1016/j.compbiomed.2021.104295. Epub 2021 Feb 24.

Authors

Muhammad I Ismail¹, Hanan M Ragab², Adnan A Bekhit³, Tamer M Ibrahim⁴

Affiliations

¹ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, The British University in Egypt, Al-Sherouk City, Cairo-Suez Desert Road, 11837, Cairo, Egypt.
² Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt.
³ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt; Pharmacy Program, Allied Health Department, College of Health and Sport Sciences, University of Bahrain, P.O. Box 32038, Bahrain.
⁴ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, 33516, Egypt. Electronic address: Tamer_Mohamad@pharm.kfs.edu.eg.

Abstract

Papain-Like Protease (PLpro) is a key protein for SARS-CoV-2 viral replication which is the cause of the emerging COVID-19 pandemic. Targeting PLpro can suppress viral replication and provide treatment options for COVID-19. Due to the dynamic nature of its binding site loop, PLpro multiple conformations were generated through a long-range 1 micro-second molecular dynamics (MD) simulation. Clustering the MD trajectory enabled us to extract representative structures for the conformational space generated. Adding to the MD representative structures, X-ray structures were involved in an ensemble docking approach to screen the FDA approved drugs for a drug repositioning endeavor. Guided by our recent benchmarking study of SARS-CoV-2 PLpro, FRED docking software was selected for such a virtual screening task. The results highlighted potential consensus binders to many of the MD clusters as well as the newly introduced X-ray structure of PLpro complexed with a small molecule. For instance, three drugs Benserazide, Dobutamine and Masoprocol showed a superior consensus enrichment against the PLpro conformations. Further MD simulations for these drugs complexed with PLpro suggested the superior stability and binding of dobutamine and masoprocol inside the binding site compared to Benserazide. Generally, this approach can facilitate identifying drugs for repositioning via targeting multiple conformations of a crucial target for the rapidly emerging COVID-19 pandemic.

Keywords: COVID-19; Drug repositioning; Ensemble docking; Molecular dynamics; PLpro; VS.

MeSH terms

Binding Sites
Coronavirus 3C Proteases* / antagonists & inhibitors
Coronavirus 3C Proteases* / chemistry
Crystallography, X-Ray
Cysteine Proteinase Inhibitors / chemistry*
Drug Repositioning*
Enzyme Stability
Humans
Molecular Dynamics Simulation*
SARS-CoV-2 / enzymology*

Substances

Cysteine Proteinase Inhibitors
3C-like proteinase, SARS-CoV-2
Coronavirus 3C Proteases