title: Carbonic anhydrase inhibitors. The X-ray crystal structure of human isoform II in adduct with an adamantyl analogue of acetazolamide resides in a less utilized binding pocket than most hydrophobic inhibitors.
abstract: We investigated the inhibitory activity of several 1,3,4-thiadiazole-sulfonamides against all catalytically active CA (EC 4.2.1.1), CA I-XV. The tail derivatizing the 5-position in the 1,3,4-thiadiazole-2-sulfonamide scaffold was observed to be critical as an inhibitory determinant of these compounds. The high resolution X-ray crystal structure of hCA II in complex with 5-(1-adamantylcarboxamido)-1,3,4-thiadiazole-2-sulfonamide, showed the adamantyl moiety of the inhibitor residing in a less utilized binding pocket than that of most hydrophobic inhibitors, lined by the amino acid residues Ile91, Val121 and Phe131. This binding site may explain the diverse inhibition profiles of 5-carboxamide- and sufonamide-derivatized 1,3,4-thiadiazole-2-sulfonamides and offers a hot spot for designing isoform selective inhibitors, considering that residues 91 and 131 are highly variable among the 13 catalytically active isoforms.
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Box Gainesville, FL 32610, USA.
authors.forename: Balendu Sankara
authors.initials: BS
authors.lastname: Avvaru
authors.forename: Jason M
authors.initials: JM
authors.lastname: Wagner
authors.forename: Alfonso
authors.initials: A
authors.lastname: Maresca
authors.forename: Andrea
authors.initials: A
authors.lastname: Scozzafava
authors.forename: Arthur H
authors.initials: AH
authors.lastname: Robbins
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
authors.forename: Robert
authors.initials: R
authors.lastname: McKenna
mesh_terms: D000086:Acetazolamide / Q000031:analogs & derivatives*; D000818:Animals; D001665:Binding Sites; D024402:Carbonic Anhydrase II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D020033:Protein Isoforms; D013449:Sulfonamides; D024402:Carbonic Anhydrase II; D000086:Acetazolamide