Mirza, M.U.; Ahmad, S.; Abdullah, I.; Froeyen, M. Identification of Novel Human USP2 Inhibitor: Might Involve in SARS-CoV-2 Papain-Like (PLpro) Protease Deubiquitination Activity. Preprints2020, 2020050136. https://doi.org/10.20944/preprints202005.0136.v1
Mirza, M.U., Ahmad, S., Abdullah, I., & Froeyen, M. (2020). Identification of Novel Human USP2 Inhibitor: Might Involve in SARS-CoV-2 Papain-Like (PLpro) Protease Deubiquitination Activity. Preprints. https://doi.org/10.20944/preprints202005.0136.v1
Mirza, M.U., Iskandar Abdullah and Matheus Froeyen. 2020 "Identification of Novel Human USP2 Inhibitor: Might Involve in SARS-CoV-2 Papain-Like (PLpro) Protease Deubiquitination Activity" Preprints. https://doi.org/10.20944/preprints202005.0136.v1
The ubiquitin-specific protease 2 (USP) belongs to the family of deubiquitinases and plays a critical role in tumors cells’ survival and therefore signifies an important therapeutic target. Previous studies have indicated promising efficacies of potent human USP2 inhibitors including, thiopurine analogues against 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 structure-based virtual screening efforts. After a subsequent virtual screening protocol, the best compounds were selected and tested. The compound Z93 showed significant IC50 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.
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