Bidentate Zinc chelators for alpha-carbonic anhydrases that produce a trigonal bipyramidal coordination geometry.

ChemMedChem
Johannes Schulze WischelerGerhard Klebe

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.

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Citations

Jan 6, 2012·Chemical Communications : Chem Comm·Fabrizio CartaClaudiu T Supuran
Jan 12, 2012·Journal of Enzyme Inhibition and Medicinal Chemistry·Sara R SchlesingerSung-Kun Kim
Sep 29, 2012·Bioorganic & Medicinal Chemistry·Tiziano TuccinardiClaudiu T Supuran
Aug 15, 2014·Journal of Medicinal Chemistry·David P MartinSeth M Cohen
Mar 19, 2014·Journal of the American Chemical Society·David P MartinSeth M Cohen
Aug 26, 2015·Journal of the American Chemical Society·Pamela A SontzF Akif Tezcan
Apr 9, 2017·Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry·Benjamin L DickSeth M Cohen
Aug 19, 2017·Journal of Medicinal Chemistry·Panagiotis K ChrysanthopoulosSally-Ann Poulsen

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