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Bidentate Zinc Chelators for α‐Carbonic Anhydrases that Produce a Trigonal Bipyramidal Coordination Geometry
Author(s) -
Schulze Wischeler Johannes,
Innocenti Alessio,
Vullo Daniela,
Agrawal Arpita,
Cohen Seth M.,
Heine Andreas,
Supuran Claudiu T.,
Klebe Gerhard
Publication year - 2010
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201000200
Subject(s) - trigonal bipyramidal molecular geometry , denticity , chemistry , carbonic anhydrase , coordination geometry , zinc , pentagonal bipyramidal molecular geometry , crystallography , hydrogen bond , stereochemistry , crystal structure , carbonic anhydrase ii , binding site , gene isoform , molecule , enzyme , biochemistry , gene , organic chemistry
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 μ M . 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.