期刊
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
卷 30, 期 2, 页码 204-211出版社
TAYLOR & FRANCIS LTD
DOI: 10.3109/14756366.2014.908291
关键词
Carbonic anhydrase; enthalpy; fluorescent thermal shift assay; intrinsic parameters; isothermal titration calorimetry; ligand binding; thermal shift assay; ThermoFluor
资金
- European Social Fund [VP1-3.1.SMM-07-K-02-009]
- COST project [TD0905, CM0804]
- FP7-REGPOT-1 grant 'MoBiLi' [245721]
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.
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