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

• Published in: Molecular diversity Vol. 26; no. 1; pp. 309 - 329
• Main Authors: Rao, Priyashi, Patel, Rohit, Shukla, Arpit, Parmar, Paritosh, Rawal, Rakesh M., Saraf, Meenu, Goswami, Dweipayan
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.02.2022; Springer Nature B.V
• Subjects: Amino acids; Aniline Compounds; Benzamides; Biochemistry; Biomedical and Life Sciences; COVID-19 - drug therapy; Fungi - metabolism; Humans; Interferon; Life Sciences; Metabolites; Molecular Docking Simulation; Molecular Dynamics Simulation; Naphthalenes; Organic Chemistry; Original; Original Article; Papain - chemistry; Papain - metabolism; Peptide Hydrolases - metabolism; Pharmacy; Polymer Sciences; Proteins; RNA, Viral; SARS-CoV-2; GRL0617; Fungal metabolites; Papain-like protease (PLpro); SARS-CoV2 novel coronavirus; Molecular dynamics simulation
• ISSN: 1381-1991; 1573-501X; 1573-501X
• DOI: 10.1007/s11030-021-10220-8

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