title: Structural analysis of inhibitor binding to human carbonic anhydrase II.
abstract: X-ray crystal structures of carbonic anhydrase II (CAII) complexed with sulfonamide inhibitors illuminate the structural determinants of high affinity binding in the nanomolar regime. The primary binding interaction is the coordination of a primary sulfonamide group to the active site zinc ion. Secondary interactions fine-tune tight binding in regions of the active site cavity >5 A away from zinc, and this work highlights three such features: (1) advantageous conformational restraints of a bicyclic thienothiazene-6-sulfonamide-1,1-dioxide inhibitor skeleton in comparison with a monocyclic 2,5-thiophenedisulfonamide skeleton; (2) optimal substituents attached to a secondary sulfonamide group targeted to interact with hydrophobic patches defined by Phe131, Leu198, and Pro202; and (3) optimal stereochemistry and configuration at the C-4 position of bicyclic thienothiazene-6-sulfonamides; the C-4 substituent can interact with His64, the catalytic proton shuttle. Structure-activity relationships rationalize affinity trends observed during the development of brinzolamide (Azopt), the newest carbonic anhydrase inhibitor approved for the treatment of glaucoma.
authors.affiliation: Department of Chemistry, University of Pennsylvania, Philadelphia 19104-6323, USA.
authors.forename: P A
authors.initials: PA
authors.lastname: Boriack-Sjodin
authors.forename: S
authors.initials: S
authors.lastname: Zeitlin
authors.forename: H H
authors.initials: HH
authors.lastname: Chen
authors.forename: L
authors.initials: L
authors.lastname: Crenshaw
authors.forename: S
authors.initials: S
authors.lastname: Gross
authors.forename: A
authors.initials: A
authors.lastname: Dantanarayana
authors.forename: P
authors.initials: P
authors.lastname: Delgado
authors.forename: J A
authors.initials: JA
authors.lastname: May
authors.forename: T
authors.initials: T
authors.lastname: Dean
authors.forename: D W
authors.initials: DW
authors.lastname: Christianson
mesh_terms: D001665:Binding Sites; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry* / Q000378:metabolism*; D002256:Carbonic Anhydrases / Q000737:chemistry* / Q000378:metabolism*; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D013449:Sulfonamides; D002256:Carbonic Anhydrases