title: Bidentate Zinc chelators for alpha-carbonic anhydrases that produce a trigonal bipyramidal coordination geometry.
abstract: A series of new zinc binding groups (ZBGs) has been evaluated kinetically on 13 carbonic anhydrase (CA) isoforms. The fragments show affinity for all isoforms with IC(50) values in the range of 2-11 microM. The crystal structure of hCA II in complex with one such fragment reveals a bidentate binding mode with a trigonal-bipyramidal coordination geometry at the Zn(2+) center. The fragment also interacts with Thr199 and Thr200 through hydrogen bonding and participates in a water network. Further development of this ZBG should increase the binding affinity leading to a structurally distinct and promising class of CA inhibitors.
authors.affiliation: Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 6, 35032 Marburg, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Schulze Wischeler
authors.forename: Alessio
authors.initials: A
authors.lastname: Innocenti
authors.forename: Daniela
authors.initials: D
authors.lastname: Vullo
authors.forename: Arpita
authors.initials: A
authors.lastname: Agrawal
authors.forename: Seth M
authors.initials: SM
authors.lastname: Cohen
authors.forename: Andreas
authors.initials: A
authors.lastname: Heine
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
authors.forename: Gerhard
authors.initials: G
authors.lastname: Klebe
mesh_terms: D001665:Binding Sites; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry*; D002256:Carbonic Anhydrases / Q000737:chemistry* / Q000378:metabolism; D002614:Chelating Agents / Q000737:chemistry*; D018360:Crystallography, X-Ray; D006801:Humans; D011485:Protein Binding; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D015032:Zinc / Q000737:chemistry*
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D002614:Chelating Agents; D020033:Protein Isoforms; D002256:Carbonic Anhydrases; D015032:Zinc