Influence of the cellular environment on ligand binding kinetics at membrane-bound targets.

While historically 'in vitro' binding data were obtained by analyzing equilibrium experiments, kinetic data are increasingly appreciated to provide information on the time a particular compound remains bound to its target. This information is of biological importance to understand the molecular mechanism of a drug not only to evaluate the time a particular receptor/enzyme is blocked in the case of antagonists/inhibitors but also to investigate its contribution to the efficacy to mediate signaling in the case of agonists. There is accumulating evidence that many drugs binding to either membrane-bound receptors or enzymes are found to display long duration of action which can be ascribed to slow dissociation from their target proteins. In the present review three such examples are discussed which encompass ligands that bind to membrane-bound proteins and from which it appears that the tight binding kinetics is influenced by the cellular/membrane environment of the target protein.