Thermodynamic Parameters for the Association of Fluorinated Benzenesulfonamides with Bovine Carbonic Anhydrase II

This paper describes a calori- metric study of the association of a series of seven fluorinated benzenesul- fonamide ligands (C6HnF5� nSO2NH2) with bovine carbonic anhydrase II (BCA). Quantitative structure-activity relationships between the free energy, enthalpy, and entropy of binding and pKa and log P of the ligands allowed the evaluation of the thermodynamic parameters in terms of the two inde- pendent effects of fluorination on the ligand: its electrostatic potential and its hydrophobicity. The parameters were partitioned to the three different struc- tural interactions between the ligand and BCA: the Zn II cofactor-sulfon- A bond ( � 65 % of the free energy of binding), the hydrogen bonds be- tween the ligand and BCA ( � 10 %), and the contacts between the phenyl ring of the ligand and BCA ( � 25 %). Calorimetry revealed that all of the li- gands studied bind in a 1:1 stoichiome- try with BCA; this result was con- firmed by 19 F NMR spectroscopy and X-ray crystallography (for complexes with human carbonic anhydrase II).