Carbonic anhydrase inhibitors, interaction of boron derivatives with isozymes I and II: A new binding site for hydrophobic inhibitors at the entranceof the active site as shown by docking studies

The interaction of human carbonic anhydrase (hCA) isozymes I and II with bo ron derivatives was investigated by kinetic and spectroscopic studies. Thes e derivatives, tested as new inhibitors of carbonic anhydrase, are sulfonam ide and non-sulfonamide boron derivatives and some of them proved to be mod erately efficient inhibitors of hCA I and hCA II, their activities being co mparable to those of the unsubstituted sulfonamides, the classical inhibito rs of these zinc enzymes. Ph2BOH, one of the compounds with the highest aff inity for hCA II in the present study, has been docked within the active si te. After minimisation it was found situated at 7.9 Angstrom from zinc, wit hin the hydrophobic half of the active site, in Van der Waals contacts with the amino acid residues: Val 121, Phe 130, Val 135, Leu 141, Val 143, Val 207 and Pro 201. This is the first time that a CA inhibitor has been found to bind at the edge of the active site cavity, similarly to the CA activato r histamine, which binds on the hydrophilic half. This finding may be of im portance also for the design of novel types of inhibitors with increased af finity for the different CA isozymes.