Isothermal titration calorimetry: Controlling binding forces in lead optimization

The completion of the human genome has resulted in the identification of large numbers of novel targets for drug development. Many of these targets belong to protein families with homologous structures and similar active sites. Against these targets, successful drugs must display high affinity and high selectivity, goals that have been difficult to accomplish and that emphasize the need for better optimization strategies. Those strategies require control over the forces that maximize affinity towards the intended target and minimize affinity towards other proteins. Because isothermal titration calorimetry (ITC) is the only experimental technique that provides a partition of the binding energy into its enthalpic and entropic components, it is rapidly becoming a key technology in lead optimization.