Abstract
Papain-like protease (nsp-3; non-structural protein) of novel corona virus is an ideal target for developing drugs as it plays multiple important functions for viral growth and replication. For instance, role of nsp-3 has been recognized in cleavage of viral polyprotein; furthermore, in infected host it weakens the immune system via downregulating the production of type I interferon. This downregulation is promoted by removal of ubiquitin-like interferon-stimulated gene 15 protein (ISG15) from interferon-responsive factor 3 (IRF3) protein. Among known inhibitors of SARS-CoV-PLpro GRL0617 is by far the most effective inhibitor. As PLpro of SARS-CoV2 is having more than 80% similarity with SARS-CoV-PLpro, GRL0617 is reported to be effective even against SARS-CoV2. Owing to this similarity, certain key amino acids remain the same/conserved in both proteins. Among conserved amino acids Tyr268 for SARS-CoV2 and Tyr269 for SARS-CoV produce important hydrophobic interactions with aromatic rings of GRL0617. Here, in this study antibacterial compounds were collected from ZINC database, and they were filtered to select compounds that are having similar structural features as GRL0617. This filtered library of compound was then docked with SARS-CoV and CoV2-PLpro. Five hits were noted that were able to interact with Tyr268 (SARS-CoV2) and Tyr269 (SARS-CoV). Further, best hit 2-(2-((benzofuran-2-carboxamido)methyl)-5-methoxy-1H-indol-1-yl)acetic acid (ZINC44459905) was studied using molecular dynamic simulation where stability of protein-ligand complex as well as stability of produced interactions was noted.
Keywords: Antibacterial compounds; GRL0617; Molecular dynamics simulation; Papain-like protease (PLpro); SARS-CoV-2 novel corona virus.
【저자키워드】 Molecular dynamics simulation, Papain-like protease (PLpro), Antibacterial compounds, GRL0617, SARS-CoV-2 novel corona virus., 【초록키워드】 SARS-CoV-2, Zinc, SARS-CoV2, SARS-CoV, interferon, Proteins, drug, molecular dynamics, immune system, protease, type I interferon, ZINC database, Molecular dynamics simulation, Replication, Papain-like protease, Protein, stability, Viral, amino acids, non-structural protein, Antibacterial, cleavage, IRF3, molecular, PLPro, inhibitor, novel corona virus, function, Amino acid, Interaction, ISG15, similarity, best, aromatic rings, acetic acid, key amino acids, complex, Compound, removal, Papain, downregulation, hydrophobic, effective inhibitor, indol, benzofuran, viral growth, interferon-stimulated gene, Host, feature, effective, produced, collected, conserved, reported, promoted, docked, downregulating, filtered, hydrophobic interaction, key amino acid, protein-ligand, 【제목키워드】 molecular docking, repurposing, drug, MD simulation, binding energy,