Theoretical Aspects of GPCR–Ligand Complex Pharmacology

Over the past 50 years in pharmacology, an understanding of seven transmembrane (7TMR) function has been gained from the comparison of experimental data to receptor models. These models have been constructed from building blocks composed of systems consisting of series and parallel mass action binding reactions. Basic functions such as the the isomerization of receptors upon ligand binding, the sequential binding of receptors to membrane coupling proteins, and the selection of multiple receptor conformations have been combined in various ways to build receptor systems such as the ternary complex, extended ternary complex, and cubic ternary complex models for 7TMR function. Separately, the Black/Leff operational model has furnished an extremely valuable method of quantifying drug agonism. In the past few years, incorporation of the basic allosteric nature of 7TMRs has led to additional useful models of functional receptor allosteric mechanisms; these models yield valuable methods for quantifying allosteric effects. Finally, molecular dynamics has provided yet another new set of models describing the probability of formation of multiple receptor states; these radically new models are extremely useful in the prediction of functionally selective drug effects.