Modeling and simulation of inverse agonism dynamics

With the recent discovery and increased recognition of constitutive activity of G-protein coupled receptors (GPCRs) and inverse agonists have come a number of important questions. The signaling mechanisms underlying inverse agonist effects on constitutively active systems need to be elucidated qualitatively. Furthermore, quantitative analysis is needed to support experimental observations, characterize the pharmacology of the ligands and systems of interest, and to provide numerical predictions of dynamic physiological responses to inverse agonists in an effort toward drug design. Here, we review the concept of inverse agonism and describe the application of mathematical and computational techniques to models of inverse agonists in GPCR systems. Numerical simulation results for active G-protein levels demonstrate a variety of dynamic features including inhibition of agonist-induced peak-plateau responses, undershoots, multiple time scales, and both surmountable and insurmountable inverse agonism.