title: Saccharin: a lead compound for structure-based drug design of carbonic anhydrase IX inhibitors.
abstract: Carbonic anhydrase IX (CA IX) is a key modulator of aggressive tumor behavior and a prognostic marker and target for several cancers. Saccharin (SAC) based compounds may provide an avenue to overcome CA isoform specificity, as they display both nanomolar affinity and preferential binding, for CA IX compared to CA II (>50-fold for SAC and >1000-fold when SAC is conjugated to a carbohydrate moiety). The X-ray crystal structures of SAC and a SAC-carbohydrate conjugate bound to a CA IX-mimic are presented and compared to CA II. The structures provide substantial new insight into the mechanism of SAC selective CA isoform inhibition.
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Box 100245, Gainesville, FL 32610, USA.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Mahon
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Box 100245, Gainesville, FL 32610, USA.
authors.forename: Alex M
authors.initials: AM
authors.lastname: Hendon
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Box 100245, Gainesville, FL 32610, USA.
authors.forename: Jenna M
authors.initials: JM
authors.lastname: Driscoll
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Nathan, Queensland 4111, Australia.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Rankin
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Nathan, Queensland 4111, Australia.
authors.forename: Sally-Ann
authors.initials: SA
authors.lastname: Poulsen
authors.affiliation: Polo Scientifico, Neurofarba Department and Laboratorio di Chimica Bioinorganica, Università degli Studi di Firenze, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy.
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Box 100245, Gainesville, FL 32610, USA. Electronic address: rmckenna@ufl.edu.
authors.forename: Robert
authors.initials: R
authors.lastname: McKenna
mesh_terms: D000951:Antigens, Neoplasm / Q000737:chemistry / Q000378:metabolism*; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000737:chemistry / Q000378:metabolism*; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D012439:Saccharin / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000951:Antigens, Neoplasm; D002257:Carbonic Anhydrase Inhibitors; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; D012439:Saccharin
keywords: CA IX-mimic; Carbonic anhydrase IX; Metalloenzyme; Saccharin; Structure-based drug design