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Open Access Research article

Intrinsic thermodynamics of ethoxzolamide inhibitor binding to human carbonic anhydrase XIII

Lina Baranauskienė and Daumantas Matulis*

Author Affiliations

Department of Biothermodynamics and Drug Design, Vilnius University Institute of Biotechnology, Graičiūno 8, Vilnius LT-02241, Lithuania

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BMC Biophysics 2012, 5:12  doi:10.1186/2046-1682-5-12

Published: 7 June 2012

Abstract

Background

Human carbonic anhydrases (CAs) play crucial role in various physiological processes including carbon dioxide and hydrocarbon transport, acid homeostasis, biosynthetic reactions, and various pathological processes, especially tumor progression. Therefore, CAs are interesting targets for pharmaceutical research. The structure-activity relationships (SAR) of designed inhibitors require detailed thermodynamic and structural characterization of the binding reaction. Unfortunately, most publications list only the observed thermodynamic parameters that are significantly different from the intrinsic parameters. However, only intrinsic parameters could be used in the rational design and SAR of the novel compounds.

Results

Intrinsic binding parameters for several inhibitors, including ethoxzolamide, trifluoromethanesulfonamide, and acetazolamide, binding to recombinant human CA XIII isozyme were determined. The parameters were the intrinsic Gibbs free energy, enthalpy, entropy, and the heat capacity. They were determined by titration calorimetry and thermal shift assay in a wide pH and temperature range to dissect all linked protonation reaction contributions.

Conclusions

Precise determination of the inhibitor binding thermodynamics enabled correct intrinsic affinity and enthalpy ranking of the compounds and provided the means for SAR analysis of other rationally designed CA inhibitors.