Thermodynamic parameters for the association of fluorinated benzenesulfonamides with bovine carbonic anhydrase II

This paper describes a calorimetric study of the association of a series of seven fluorinated benzenesulfonamide ligands (C6HnF5-nSO2NH2) with bovine carbonic anhydrase II (BCA). Quantitative structure-activity relationships between the free energy, enthalpy, and entropy of binding and pK(a) and logP of the ligands allowed the evaluation of the thermodynamic parameters in terms of the two independent effects of fluorination on the ligand: its electrostatic potential and its hydrophobicity. The parameters were partitioned to the three different structural interactions between the ligand and BCA: the Zn-II cofactor-sulfonamide bond ( approximate to 65% of the free energy of binding), the hydrogen bonds between the ligand and BCA (approximate to 10%), and the contacts between the phenyl ring of the ligand and BCA (approximate to 25%). Calorimetry revealed that all of the ligands studied bind in a 1:1 stoichiometry with BCA; this result was confirmed by (FNMR)-F-19 spectroscopy and X-ray crystallography (for complexes with human carbonic anhydrase II).