The crystal structures of 2-(4-benzhydrylpiperazin-1-yl)-N-(4-sulfamoylphenyl)acetamide in complex with human carbonic anhydrase II and VII provide insights into selective CA inhibitor development

2-(4-Benzhydrylpiperazin-1-yl)-N-(4-sulfamoylphenyl)acetamide is an effective human carbonic anhydrase (hCA) inhibitor designed through the tail approach using the acetamide moiety as linker and the benzhydrylpiperazine group as tail. Here we report the crystal structures of this compound in complex both with the ubiquitous hCA II and the brain-associated hCA VII, showing that in agreement with the previously reported inhibition constants, the inhibitor is stabilized by a higher number of polar and hydrophobic interactions in the active site of hCA VII compared to hCA II. Results point out the conformational flexibility of the linker and the tail length as fundamental features to establish significant differences in the number of favorable enzyme/inhibitor interactions and consequently in the inhibition selectivity against the two hCA isoforms.