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.