The Role of Water in the Thermodynamics of Drug Binding to Cyclodextrin
Niya Tordorova, Frederick P. Schwarz
The thermodynamic parameters, DBGo, DBHo, and DBSo, of the drugs flurbiprofen (FLP), nabumetone (NAB), and naproxen (NPX) binding to b-cyclodextrin (bCD) and to g-cyclodextrin (gCD) in 0.10 M sodium phosphate buffer were determined from isothermal titration calorimetry (ITC) measurements over the temperature range from 293.15 K to 313.15 K and at 298.15 K, over a pH range from pH = 6.4 to pH = 7.8 and up to 0.30 M sodium chloride concentration. An in situ assay was employed for the determination of the cyclodextrin concentration in solution. The equilibrium constant for FLP binding to bCD was also determined by an independent drug fluorescence method and was within two standard deviations of the ITC determined value. Values for DBGo ranged from ranged from 9520+120 M-1 for FLP binding to bCD at 293.15 K to 330+109 M-1 for NPX binding to gCD at 308.15 K, a range of values which are amenable for validating DBGo drug docking algorithms. Values for DBGo were the same over the pH range and the sodium chloride concentration range. The binding reactions of FLP and NAB to bCD exhibited almost complete enthalpy-entropy compensation, of NPX to bCD and to gCD exhibited only partial enthalpy-entropy compensation, and of FLP to gCD did not exhibit any enthalpy-entropy compensation. The amount of enthalpy-entropy compensation in each binding reaction correlated with the magnitude of the heat capacity change ranging from 0 for FLP binding to gCD to -362+48 J mol-1K-1 for FLP binding to bCD. This correlation results from changes of the water structure in enthalpy-entropy compensation and in the heat capacity change.