Abstract
Human ubiquitin carboxyl-terminal hydrolase-2 (USP2) inhibitors, such as thiopurine analogs, have been reported to inhibit SARS-CoV papain-like proteases (PLpro). The PLpro have significant functional implications in the innate immune response during SARS-CoV-2 infection and considered an important antiviral target. Both proteases share strikingly similar USP fold with right-handed thumb-palm-fingers structural scaffold and conserved catalytic triad Cys-His-Asp/Asn. In this urgency situation of COVID-19 outbreak, there is a lack of in-vitro facilities readily available to test SARS-CoV-2 inhibitors in whole-cell assays. Therefore, we adopted an alternate route to identify potential USP2 inhibitor through integrated in-silico efforts. After an extensive virtual screening protocol, the best compounds were selected and tested. The compound Z93 showed significant IC 50 value against Jurkat (9.67 μM) and MOTL-4 cells (11.8 μM). The binding mode of Z93 was extensively analyzed through molecular docking, followed by MD simulations, and molecular interactions were compared with SARS-CoV-2. The relative binding poses of Z93 fitted well in the binding site of both proteases and showed consensus π-π stacking and H-bond interactions with histidine and aspartate/asparagine residues of the catalytic triad. These results led us to speculate that compound Z93 might be the first potential chemical lead against SARS-CoV-2 PLpro, which warrants in-vitro evaluations.
Keywords: COVID-19; Deubiquitination; Leukemia; SARS-CoV-2 papain-like protease (PLpro); Ubiquitin-specific protease 2 (USP2).
【저자키워드】 COVID-19, leukemia, Deubiquitination, SARS-CoV-2 papain-like protease (PLpro), Ubiquitin-specific protease 2 (USP2)., 【초록키워드】 SARS-CoV-2, protocol, innate immune response, SARS-CoV, SARS-COV-2 infection, Human, molecular docking, Virtual screening, protease, inhibitors, MD simulations, binding site, Papain-like protease, COVID-19 outbreak, Proteases, in-silico, PLPro, inhibitor, antiviral target, leukemia, binding, In-vitro, lead, histidine, followed by, best, Consensus, asparagine, residue, Compound, aspartate, Papain, urgency, molecular interaction, implication, Cell, carboxyl, USP2, selected, tested, analyzed, identify, lack, conserved, reported, assays, inhibit, functional, adopted, catalytic, H-bond interaction, USP, 【제목키워드】 Treatment, SARS-CoV-2, protease, inhibitor, identification, inhibiting,