Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 51, Issue -, Pages 259-270Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2012.02.050
Keywords
Carbonic anhydrase isozymes; Isothermal titration calorimetry; Thermal shift assay; ThermoFluor (R); Sulfonamides as CA inhibitors
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Funding
- Research Council of Lithuania [LIG-16/2010, C-01/2008, C-08027]
- European Community [26716]
- FP7-REGPOT-2009-1 program [245721 MoBiLi]
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A series of [(2-pyrimidinylthio)acetyl]benzenesulfonamides were designed and synthesized. Their binding affinities as inhibitors of several recombinant human carbonic anhydrase (CA) isozymes were determined by isothermal titration calorimetry (ITC) and thermal shift assay (TSA). A group of compounds containing a chlorine atom in the benzenesulfonamide ring were found to exhibit higher selectivity but lower binding affinity toward tested CAs. The crystal structures of selected compounds in complex with CA II were determined to atomic resolution. Docking studies were performed to compare the binding modes of experimentally determined crystallographic structures with computational prediction of the pyrimidine derivative binding to CA II. Several compounds bound to select CAs with single-digit nanomolar affinities and could be used as leads for inhibitor development toward a select CA isozyme. (C) 2012 Elsevier Masson SAS. All rights reserved.
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