Making cool drugs hot: Isothermal titration calorimetry as a tool to studybinding energetics

Characterization of the thermodynamaics of binding interactions is importan t in improving our understanding of bimolecular recognition and forms an es sential part of the rational drug design process. Isothermal titration calo rimetry (ITC) is rapidly becoming established as the method of choice for u ndertaking such studies. The power of ITC lies in ifs unique ability to mea sure binding reactions by the detection of the heat change during the bindi ng interaction Since heal changes occur. during many physicochemical proces ses, ITC has a broad application, ranging from chemical and biochemical bin ding studies to more complex processes involving enthalpy changes, such as enzyme kinetics. Several features of ITC have facilitated ifs preferential use compared to other. techniques that estimate affinity. IT is a sensitive , rapid, and direct method with no requirement for chemical modification or immobilization. It is the only technique that directly measures enthalpy o f binding and so eliminates the need for van't Hoff analysis, which cart be time consuming and prone to uncertainty in parameter values. Although ITC has facilitated the measurement of the thermodynamics governing binding rea ctions, interpretation of these parameters in structural terms is still a m ajor challenge.