Multiple Binding Modes of Inhibitors to Carbonic Anhydrases: How to Design Specific Drugs Targeting 15 Different Isoforms?

A description of the structural studies on α-Carbonic anhydrases (α-CA) is presented. Main structural features of the catalytically active α-CA isozymes are described and the current state of the art on complexes of hCA II with the principal classes of inhibitors is summarized. Studies have demonstrated that cyanamide acts as a weak inhibitor of the esterase activity of hCA II, interacting with the zinc ion within the enzyme active site. Crystallographic studies have shown that inorganic anions can bind within the CA II active site, either coordinating the catalytic Zn2+ ion or not coordinating it, but being located in its close proximity in a nonmetal site. The effect of the presence of a positive, negative or neutral substituent on benzenesulfonamide CAIs has been investigated to understand the effect of different charges in the CA I and CA II active sites, to discriminate the binding to these two isoforms.