Binding of Ligands to GPCRs – How Valid is a Thermodynamic Discrimination of Antagonists and Agonists?

Andrea Strasser and Hans-Jo

Abstract

In 1979, a thermodynamic discrimination between antagonists and agonists at GPCRs was discussed in literature for the first time. Subsequently a small number of experimental studies, addressing not only Gibbs energy but also enthalpy and entropy of ligand binding were performed within the last 30 years at different GPCRs. Some of these studies support the suggested “thermodynamic discrimination”, but this concept does not hold for all GPCRs analyzed by thermodynamic methods so far. This review presents an overview in this field of research. Furthermore, the data presented in literature are critically discussed and related to each other. As experimental methods provide information about the final and the starting state of the ligand-receptor binding, specific sub-processes are not accessible. But in the framework of an interpretation on a molecular level, quantitative insights in these processes are essential. A workaround of this problem is given by the development of molecular modelling methods, during the last decade. Taking into account all data so far, the concept of “thermodynamic discrimination” between antagonists and agonists may be extended to “thermodynamic and kinetic discrimination” of antagonists, partial agonists and full agonists. However, to\r\nobtain a deeper insight on molecular level, more systematic studies, including a large number of compounds with high structural variety have to be performed.