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

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-CoV-2-PLpro (and Tyr269 of SARS-CoVPLpro) 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. [GRAPHICS] .

Automated summary

The non-structural protein (nsp)-3 of SARS-CoV2, also known as papain-like protease (PLpro), is considered as an essential target protein for inhibiting the replication of the virus. Studies have identified GRL0617 and Fonsecin as potent inhibitors for PLpro, which may help in boosting the immune response.