Molecular characterization of ebselen binding activity to SARS-CoV-2 main protease

Abstract

There is an urgent need to repurpose drugs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Recent computational-experimental screenings have identified several existing drugs that could serve as effective inhibitors of the virus’ main protease, Mpro, which is involved in gene expression and replication. Among these, ebselen (2-phenyl-1,2-benzoselenazol-3-one) appears to be particularly promising. Here, we examine, at a molecular level, the potential of ebselen to decrease Mpro activity. We find that it exhibits a distinct affinity for the catalytic region. Our results reveal a higher-affinity, previously unknown binding site localized between the II and III domains of the protein. A detailed strain analysis indicates that, on such a site, ebselen exerts a pronounced allosteric effect that regulates catalytic site access through surface-loop interactions, thereby inducing a reconfiguration of water hotspots. Together, these findings highlight the promise of ebselen as a repurposed drug against SARS-CoV-2.

Anin silicoanalysis of Ibuprofen enantiomers in high concentrations of sodium chloride with SARS-CoV-2 main protease

“…It is important to point out that it was found that R(-)Ibuprofen interacts with residues of the Linker loop region (185–200) that links the domain (I + II) with domain III, a region that is being studied for its fundamental role in the control of dimerization and enzymatic activity (Bzówka et al, 2020 ; Menéndez et al, 2020 ). Therefore, this interaction with these residues could be significant for the activity.…”

DINC-COVID: A webserver for ensemble docking with flexible SARS-CoV-2 proteins

“…Altogether, these features make our server of interest even for advanced users, adding robustness to docking analysis. Currently, DINC-COVID offers ensemble docking for the catalytic binding site of SARS-CoV-2 Main protease (Mpro), Papain-like protease (PLpro) and RNA-dependent RNA polymerase (RdRp) (Zhu et al, 2020;Aftab et al, 2020;Faheem et al, 2020), as well as the allosteric binding site of Mpro (Menéndez et al, 2020). Ensembles of other SARS-CoV-2 proteins are under process (e.g., spike protein) and will be added to the webserver, which also enables users to make requests.…”

Identification of potential SARS-CoV-2 Mpro inhibitors integrating molecular docking and water thermodynamics

“…Two covalent protease inhibitors of ketoamide category boceprevir and GC376 exhibited strong in vitro activity against SARS-CoV-2 M pro (Fu et al, 2020). An organoselenium compound ebselen has recently emerged as a promising drug lead candidate in cell-based assays which targets this crucial enzyme Menendez et al, 2020). In this study, we focused on viral M pro to identify molecules with potential to bind the active site of the SARS-CoV-2 M pro structure (PDB ID -5R82).…”