Carbonic Anhydrase Inhibitors: Binding of Indanesulfonamides to the Human Isoform II

Abstract

Indanesulfonamides are interesting lead compounds for designing selective inhibitors of the different isoforms of the zinc enzyme Carbonic Anhydrase (CA). Herein, we report for the first time the X-ray crystal structure of two such derivatives, namely indane-5-sulfonamide and indane-2-valproylamido-5-sulfonamide, in complex with the physiologically dominant human isoform II. The structural analysis reveals that, although these two inhibitors have quite similar chemical structures, the arrangement of their indane ring within the enzyme active site is significantly diverse. Thus, our findings suggest that the introduction of bulky substituents on the indane-sulfonamide ring may alter the binding mode of this potent class of CA inhibitors, although retaining good inhibitory properties. Accordingly, the introduction of bulky tail moieties on the indane-sulfonamide scaffold may represent a powerful strategy to induce a desired physicochemical property to an aromatic sulfonamide or to obtain inhibitors with diverse inhibition profiles and selectivity for various mammalian CAs.

Structural Basis for the Interaction Between Carbonic Anhydrase and 1,2,3,4-tetrahydroisoquinolin-2-ylsulfonamides

“…Welldefined, non-protein electron densities indicated the binding of an inhibitor molecule into the primary binding site in the enzyme active site and the secondary inhibitor binding site on the surface of the protein molecule near the N-terminus. The secondary binding site, also reported for other hCA II-inhibitor crystal structures (e.g., PDB codes 3HS4 15 and 2QOA 16 ), most likely has no biological relevance and represents a crystallization artifact caused by high concentrations of the inhibitor used in the cocrystallization experiments.…”

Thermodynamic, kinetic, and structural parameterization of human carbonic anhydrase interactions toward enhanced inhibitor design

“…Indanesulfonamide-based series of human CA inhibitors was analyzed (D'Ambrosio et al ., 2008 b ) with two crystal structures of CA II. Indane rings oriented differently in these structures due to the different substituents.…”

Identification of 3,4-Dihydroisoquinoline-2(1H)-sulfonamides as Potent Carbonic Anhydrase Inhibitors: Synthesis, Biological Evaluation, and Enzyme−Ligand X-ray Studies

“…10 Most of known CAIs contain a sulfonamide/sulfamate moiety able to coordinate the zinc ion of catalytic binding site (e.g., acetazolamide, zonisamide, and topiramate, Chart 1), inhibiting in this way the enzymatic activity. [11][12][13][14][15][16][17][18] These inhibitors bear specific functional groups that interact with important amino acid residues, thus driving the selectivity against the different isoforms as confirmed by X-ray *To whom correspondence should be addressed. Phone: 00390906766413.…”