Identifying structural–functional analogue of GRL0617, the only well-established inhibitor for papain-like protease (PLpro) of SARS-CoV2 from the pool of fungal metabolites using docking and molecular dynamics simulation

Abstract

The non-structural protein (nsp)-3 of SARS-CoV2 coronavirus is sought to be an essential target protein which is also named as papain-like protease (PLpro). This protease cleaves the viral polyprotein, but importantly in human host it also removes ubiquitin-like interferon-stimulated gene 15 protein (ISG15) from interferon responsive factor 3 (IRF3) protein which ultimately downregulates the production of type I interferon leading to weakening of immune response. GRL0617 is the most potent known inhibitor for PLpro that was initially developed for SARS outbreak of 2003. The PLpro of SARS-CoV and CoV2 share 83% sequence identity but interestingly have several identical conserved amino acids that suggests GRL0617 to be an effective inhibitor for PLpro of SARS-CoV2. GRL0617 is a naphthalene-based molecule and interacts with Tyr268 of SARS-CoV2-PLpro (and Tyr269 of SARS-CoV-PLpro). To identify PLpro inhibitors, we prepared a library of secondary metabolites from fungi with aromatic nature and docked them with PLpro of SARS-CoV and SARS-CoV2. We found six hits which interacts with Tyr268 of SARS-CoV2-PLpro (and Tyr269 of SARS-CoV-PLpro). More surprisingly the top hit, Fonsecin, has naphthalene moiety in its structure, which recruits Tyr268 of SARS-CoV2-PLpro (and Tyr269 of SARS-CoV-PLpro) and has binding energy at par with control (GRL0617). Molecular dynamics (MD) simulation showed Fonsecin to interact with Tyr268 of SARS-CoV2-PLpro more efficiently than control (GRL0617) and interacting with a greater number of amino acids in the binding cleft of PLpro. Graphic abstract

SARS-CoV-2: from its discovery to genome structure, transcription, and replication

“…But all viral encoded proteins are potential targets for inhibition of SARS-CoV-2 infection. Inhibitors of proteases are currently in the pipeline [107][108][109][110]. We hope that inhibitors targeting necessary protein-protein interactions beyond viral enzymes will be developed as well.…”

Meticulous assessment of natural compounds from NPASS database for identifying analogue of GRL0617, the only known inhibitor for SARS-CoV2 papain-like protease (PLpro) using rigorous computational workflow

“…Lately, our research team recently predicted Pyranonigrin A and Flaviolin to have the prospects to interfere with Mpro of SARS-CoV2 to inhibit its function [46]. Further we have recently proposed we have postulated Fonsecin, a fungal metabolite to be the structural-functional analogue of GRL0617 and current version of manuscript is an extension of our work in search for structure-function analogue of GRL0167 [16]. A sizable portion of the approach for distinguishing the inhibitors of viral proteins uses atomic docking and MD reenactments as the primary strategies for computational assessment, and by using these methods a few lead compounds are perceived to intrude with the organic chemistry driven by viral proteins of SARS-CoV2.…”

“…This qualitative similarity suggests similar assessment of activity of GRL0617 towards either substrate of SARS [15]. Recently we have postulated Fonsecin, a fungal metabolite to be the structural-functional analogue of GRL0617 [16]. However, the current manuscript is the extension of our previous study and the detailed rationale for undertaking current theoretical study is expressed as follows.…”

Sterenin M as a potential inhibitor of SARS-CoV-2 main protease identified from MeFSAT database using molecular docking, molecular dynamics simulation and binding free energy calculation

“…A wide range of metabolites from various natural sources such as plants, bacteria and fungi have been investigated to check its potential as inhibitor of virus essential proteins. For instance, molecular docking and simulation studies of the fungal metabolite, Flaviolin indicate that it interacts with PLpro and Mpro proteases and can inhibit key processes for completion of SARS-CoV2 life cycle [ 15 , 31 ]. Similarly, a plant metabolite Lepidine E along with a polyphenol Hispidin found in a variety of plants and fungi has been tested against Mpro of the SARS-CoV2 virus [ 32 ].…”

“…Nowadays, incremental advancement of computer hardware and software technology has increased the odds of discovering new drugs from metagenomic databases of natural small molecules. Number of studies have been employed the use of advance computational tools including docking, molecular dynamics simulation, and combination of developed in silico methods for providing natural compounds as potential lead molecule against SARS-CoV-2 virus [ [13] , [14] , [15] , [16] , [17] ].…”