In Silico-Guided Identification of New Potent Inhibitors of Carbonic Anhydrases Expressed in Vibrio cholerae

Carbonic anhydrases from Vibrio cholerae (VchCAs) play a significant role in bacterial pathophysiological processes. Therefore, their inhibition leads to a reduction of gene expression virulence and bacterial growth impairment. Herein, we report the first ligand-based pharmacophore model as a computational tool to study selective inhibitors of the beta-class of VchCA. By a virtual screening on a collection of sulfonamides, we retrieved 9 compounds that were synthesized and evaluated for their inhibitory effects against VchCA beta as well as alpha- and gamma-classes of VchCAs and selectivity over human ubiquitous isoforms hCA I and IL Notably, all tested compounds were active inhibitors of VchCAs. The N-(4-sulfamoylbenzyl)-[1,1'-biphenyl]-4-carboxamide (20e) stood out as the most exciting inhibitor toward the beta-class (K-i = 95.6 nM), also showing a low affinity against the tested human isoforms. By applying docking procedures, we described the binding mode of the inhibitor 20e within the catalytic cavity of the modeled open conformation of VchCA beta.