Energetics of ligand binding to receptors.

The primary events in the biological signals elicited by hormonal ligands are the initial binding of the ligands to their receptors and the consequent changes in the receptors that this induces. Although the effects of chemical modifications of ligands on their affinity for receptors have been intensively studied in several systems, the influence of such changes upon the ability of ligands to induce the conformational changes in receptors that are necessary for the expression of agonism has been largely ignored. This paper considers some theoretical and experimental approaches to the problem of the relationships between ligand structure, binding energy and the induction of conformational change in receptors. The significance of the concept of productive and non-productive ligand binding to proteins previously applied with considerable success by Jencks to the understanding of enzyme catalysis, is highlighted. Given a series of closely related ligands it is possible to estimate the energetic contributions of substituent groups not only to the binding affinity to the receptor but also to the induction of conformational change in the receptor provided that the rate of conformational change, can be monitored.