A Combined in Silico and Structural Study Opens New Perspectives on Aliphatic Sulfonamides, a Still Poorly Investigated Class of CA Inhibitors

Simple Summary Carbonic anhydrases are a family of enzymes that catalyze an essential physiological reaction for living organisms: the reversible conversion of CO2 to bicarbonate ion. In humans, these enzymes impact many physiological and pathological processes including respiration, pH and CO2 homeostasis, electrolyte secretion, gluconeogenesis, ureagenesis, lipogenesis, bone resorption, and tumorigenicity. For this reason, several human carbonic anhydrases have become therapeutic targets for the treatment of many disorders. In recent years, a huge number of carbonic anhydrase inhibitors have been developed for therapeutics aims, such as diuretic, antiglaucoma, antiobesity, and anticonvulsant agents, and for the diagnosis and treatment of cancer diseases. The authors report a combined crystallographic and computational study on a promising class of carbonic anhydrase inhibitors to clarify their mechanism of action and to obtain useful information for the drug design of new effective and selective molecules. Aliphatic sulfonamides are an interesting class of carbonic anhydrase inhibitors (CAIs) proven to be effective for several carbonic anhydrase (CA) isoforms involved in pathologic states. Here we report the crystallographic structures of hCA II in complex with two aliphatic sulfonamides incorporating coumarin rings, which showed a good inhibition and selectivity for this isoform. Although these two molecules have a very similar chemical structure, differing only in the substitution of the two aliphatic hydrogen atoms with two fluorine atoms, they adopt a significantly different binding mode within the enzyme active site. Theoretical binding free energy calculations, performed to rationalize these data, showed that a delicate balance of electrostatic and steric effects modulate the protein-ligand interactions. Data presented here can be fruitfully used for the rational design of novel and effective isozyme-specific inhibitor molecules.