Carbonic anhydrase inhibitors: X-ray crystallographic structure of the adduct of human isozyme II with the antipsychotic drug sulpiride

Abstract

The X-ray crystal structure for the adduct of human carbonic anhydrase (hCA) II with sulpiride, a sulfonamide derivative clinically used as antipsychotic drug, has been resolved at a resolution of 1.6 Å. This compound is an effective inhibitor of the physiologically most relevant isozyme hCA II ( K i of 40 nM), being only a moderate or moderate-weak inhibitor of the cytosolic isozyme hCA I ( K i of 1200 nM) and the membrane-bound isozyme hCA IV ( K i of 620 nM). Sulpiride shows CA inhibitory properties of the same magnitude as dichlorophenamide, a clinically used antiglaucoma sulfonamide, or valdecoxib, a COX-2 selective inhibitor recently shown to inhibit CA. The binding of sulpiride to the hCA II active site is similar to that of other sulfonamide inhibitors, considering the interactions of the sulfonamide zinc anchoring group, but differs considerably when the organic scaffold of the molecule is analyzed. Indeed, one unprecedented hydrogen bond involving the imino moiety of the carboxamido group of sulpiride and a water molecule was observed, together with a unique stacking interaction of the N-methyl-pyrrolidine ring of the inhibitor and the aromatic ring of Phe 131 of the enzyme active site, which has been observed only recently in another CA–sulfonamide complex.