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Article

Binding of SARS-CoV Covalent Non-Covalent Inhibitors to the SARS-CoV-2 Papain-Like Protease and Ovarian Tumor Domain Deubiquitinases

Molecular Simulations and Design Group, Max Planck Institute for Dynamics of Complex Technical Systems, Sandtorstrasse 1, 39106 Magdeburg, Germany
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Author to whom correspondence should be addressed.
Current address: R&D Center, Pharmcadd, 221, 17 APEC-ro, Haeundae-gu, Busan 48060, Korea.
Academic Editors: Alejandro Speck-Planche and Mark S. Johnson
Biomolecules 2021, 11(6), 802; https://doi.org/10.3390/biom11060802
Received: 17 March 2021 / Revised: 26 May 2021 / Accepted: 26 May 2021 / Published: 28 May 2021
The urgent need for novel and effective drugs against the SARS-CoV-2 coronavirus pandemic has stimulated research worldwide. The Papain-like protease (PLpro), which is essential for viral replication, shares a similar active site structural architecture to other cysteine proteases. Here, we have used representatives of the Ovarian Tumor Domain deubiquitinase family OTUB1 and OTUB2 along with the PLpro of SARS-CoV-2 to validate and rationalize the binding of inhibitors from previous SARS-CoV candidate compounds. By forming a new chemical bond with the cysteine residue of the catalytic triad, covalent inhibitors irreversibly suppress the protein’s activity. Modeling covalent inhibitor binding requires detailed knowledge about the compounds’ reactivities and binding. Molecular Dynamics refinement simulations of top poses reveal detailed ligand-protein interactions and show their stability over time. The recently discovered selective OTUB2 covalent inhibitors were used to establish and validate the computational protocol. Structural parameters and ligand dynamics are in excellent agreement with the ligand-bound OTUB2 crystal structures. For SARS-CoV-2 PLpro, recent covalent peptidomimetic inhibitors were simulated and reveal that the ligand-protein interaction is very dynamic. The covalent and non-covalent docking plus subsequent MD refinement of known SARS-CoV inhibitors into DUBs and the SARS-CoV-2 PLpro point out a possible approach to target the PLpro cysteine protease from SARS-CoV-2. The results show that such an approach gives insight into ligand-protein interactions, their dynamic character, and indicates a path for selective ligand design. View Full-Text
Keywords: deubiquitinase; OTUB2; papain-like protease; SARS-CoV-2; drug design; molecular dynamics; covalent docking deubiquitinase; OTUB2; papain-like protease; SARS-CoV-2; drug design; molecular dynamics; covalent docking
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MDPI and ACS Style

Sivakumar, D.; Stein, M. Binding of SARS-CoV Covalent Non-Covalent Inhibitors to the SARS-CoV-2 Papain-Like Protease and Ovarian Tumor Domain Deubiquitinases. Biomolecules 2021, 11, 802. https://doi.org/10.3390/biom11060802

AMA Style

Sivakumar D, Stein M. Binding of SARS-CoV Covalent Non-Covalent Inhibitors to the SARS-CoV-2 Papain-Like Protease and Ovarian Tumor Domain Deubiquitinases. Biomolecules. 2021; 11(6):802. https://doi.org/10.3390/biom11060802

Chicago/Turabian Style

Sivakumar, Dakshinamurthy, and Matthias Stein. 2021. "Binding of SARS-CoV Covalent Non-Covalent Inhibitors to the SARS-CoV-2 Papain-Like Protease and Ovarian Tumor Domain Deubiquitinases" Biomolecules 11, no. 6: 802. https://doi.org/10.3390/biom11060802

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