title: Structure-Activity Relationship for Sulfonamide Inhibition of Helicobacter pylori α-Carbonic Anhydrase.
abstract: α-Carbonic anhydrase of Helicobacter pylori (HpαCA) plays an important role in the acclimation of this oncobacterium to the acidic pH of the stomach. Sulfonamide inhibitors of HpαCA possess anti-H. pylori activity. The crystal structures of complexes of HpαCA with a family of acetazolamide-related sulfonamides have been determined. Analysis of the structures revealed that the mode of sulfonamide binding correlates well with their inhibitory activities. In addition, comparisons with the corresponding inhibitor complexes of human carbonic anhydrase II (HCAII) indicated that HpαCA possesses an additional, alternative binding site for sulfonamides that is not present in HCAII. Furthermore, the hydrophobic pocket in HCAII that stabilizes the apolar moiety of sulfonamide inhibitors is replaced with a more open, hydrophilic pocket in HpαCA. Thus, our analysis identified major structural features can be exploited in the design of selective and more potent inhibitors of HpαCA that may lead to novel antimicrobials.
authors.affiliation: Department of Microbiology, Monash University , Clayton, Victoria 3800, Australia.|Infection and Immunity Program, Monash Biomedicine Discovery Institute, Monash University , Clayton, Victoria 3800, Australia.
authors.forename: Joyanta K
authors.initials: JK
authors.lastname: Modak
authors.affiliation: Department of Microbiology, Monash University , Clayton, Victoria 3800, Australia.
authors.forename: Yu C
authors.initials: YC
authors.lastname: Liu
authors.affiliation: Laboratorio di Chimica Bioinorganica, Polo Scientifico, Università degli Studi di Firenze , Via della Lastruccia 3, Sesto Fiorentino, Florence 50019, Italy.|Neurofarba Department, Sezione di Scienze Farmaceutiche, Università degli Studi di Firenze , Via U. Schiff 6, Sesto Fiorentino, Florence 50019, Italy.
authors.forename: Claudiu T
authors.identifier: 0000-0003-4262-0323
authors.initials: CT
authors.lastname: Supuran
authors.affiliation: Department of Microbiology, Monash University , Clayton, Victoria 3800, Australia.|Infection and Immunity Program, Monash Biomedicine Discovery Institute, Monash University , Clayton, Victoria 3800, Australia.|Department of Biochemistry and Molecular Biology, Monash University , Clayton, Victoria 3800, Australia.
authors.forename: Anna
authors.identifier: 0000-0001-8478-4751
authors.initials: A
authors.lastname: Roujeinikova
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000378:metabolism*; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D016480:Helicobacter pylori / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D002257:Carbonic Anhydrase Inhibitors; D013449:Sulfonamides; D002256:Carbonic Anhydrases