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.

Keywords: Fungal metabolites; GRL0617; Molecular dynamics simulation; Papain-like protease (PLpro); SARS-CoV2 novel coronavirus.

Fig. 1

Illustration depicting function of IRF3 in production of INF1 and its inhibition by PLpro along with showing other functions involved in viral replication

Fig. 2

a Superimposition of PLpro of SARS-CoV and SARS-CoV2 b Multiple sequence alignment of sequences of PLpro’s of MERS-CoV, SARS-CoV and SARS-CoV2

Fig. 3

Interaction profile of GRL0617 and top six fungal metabolites docked with SARS-CoV-PLpro (PDB: 3E9S)

Fig. 4

Interaction profile of GRL0617 and top six fungal metabolites docked with SARS-CoV2-PLpro (PDB: 7CMD)

Fig. 5

MD simulation Protein–ligand interaction root-mean-square deviation (RMSD) profile of a SARS-CoV2-PLpro-GRL0617 b SARS-CoV2-PLpro-Fonsecin

Fig. 6

MD simulation Protein–ligand interaction root-mean-square fluctuation (RMSF) profile of a SARS-CoV2-PLpro-GRL0617 b SARS-CoV2-PLpro-Fonsecin

Fig. 7

Protein–Ligand interaction profile during the course of MD simulation of SARS-CoV2-PLpro-GRL0617 complex a interaction profile of crucial interacting amino acids b Ligand interaction diagram showing percent of total time a particular interaction is involved in

Fig. 8

Protein–Ligand interaction profile during the course of MD simulation of SARS-CoV2-PLpro-Fonsecin complex a interaction profile of crucial interacting amino acids b Ligand interaction diagram showing percent of total time a particular interaction is involved in

Fig. 9

Timeline representation of the interactions of ligand with amino acids for the complex a SARS-CoV2-PLpro-GRL0617 b SARS-CoV2-PLpro-Fonsecin