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Wiley, ChemMedChem, 9(5), p. 1609-1615, 2010

DOI: 10.1002/cmdc.201000200

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Bidentate Zinc Chelators for α-Carbonic Anhydrases that Produce a Trigonal Bipyramidal Coordination Geometry

Journal article published in 2010 by Johannes Schulze Wischeler, Johannes Schulze Wischeler, Alessio Innocenti, Daniela Vullo, Arpita Agrawal, Seth M. Cohen ORCID, Andreas Heine, Claudiu T. Supuran, Gerhard Klebe
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This paper is available in a repository.

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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.