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J Enzyme Inhib Med Chem. 2015 Apr;30(2):204-11. doi: 10.3109/14756366.2014.908291. Epub 2014 Apr 23.

Intrinsic thermodynamics of sulfonamide inhibitor binding to human carbonic anhydrases I and II.

Author information

1
Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Vilnius University , Vilnius , Lithuania and.

Abstract

Human carbonic anhydrase (CA) I and II are cytosolic proteins, where their expression disorders can cause diseases such as glaucoma, edema, epilepsy or cancer. There are numerous inhibitors that target these isozymes, but it is difficult to design compounds that could bind to one of these proteins specifically. The binding of sulfonamide inhibitor to a CA is linked to several protonation reactions, namely, deprotonation of the sulfonamide group, protonation of the active site zinc hydroxide and the compensating protonation-deprotonation of buffer. By performing binding experiments at various pHs and buffers, all those contributions were dissected and the "intrinsic" binding parameters were calculated. Intrinsic thermodynamic binding parameters to CA I and II were determined for such widely studied drugs as acetazolamide, ethoxzolamide, methazolamide, trifluoromethanesulfonamide and dichlorophenamide. The assignment of all contributions should enhance our understanding of the underlying energetics and increase our capability to design more potent and specific CA inhibitors.

KEYWORDS:

Carbonic anhydrase; ThermoFluor; enthalpy; fluorescent thermal shift assay; intrinsic parameters; isothermal titration calorimetry; ligand binding; thermal shift assay

PMID:
24758348
DOI:
10.3109/14756366.2014.908291
[Indexed for MEDLINE]

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