Kinetic operational models of agonism for G-protein-coupled receptors

Journal of Theoretical Biology
Samuel R J HoareBrad Larson

Abstract

The application of kinetics to research and therapeutic development of G-protein-coupled receptors has become increasingly valuable. Pharmacological models provide the foundation of pharmacology, providing concepts and measurable parameters such as efficacy and potency that have underlain decades of successful drug discovery. Currently there are few pharmacological models that incorporate kinetic activity in such a way as to yield experimentally-accessible drug parameters. In this study, a kinetic model of pharmacological response was developed that provides a kinetic descriptor of efficacy (the transduction rate constant, kτ) and allows measurement of receptor-ligand binding kinetics from functional data. The model assumes: (1) receptor interacts with a precursor of the response ("Transduction potential") and converts it to the response. (2) The response can decay. Familiar response vs time plots emerge, depending on whether transduction potential is depleted and/or response decays. These are the straight line, the "association" exponential curve, and the rise-and-fall curve. Convenient, familiar methods are described for measuring the model parameters and files are provided for the curve-fitting program Prism (GraphPad Softwa...Continue Reading

Citations

Jan 25, 2020·British Journal of Pharmacology·David B FinlayMichelle Glass
Jul 25, 2020·Scientific Reports·Sam R J HoareLloyd J Bridge
Apr 2, 2019·Frontiers in Endocrinology·Flavie LandomielEric Reiter
Sep 17, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Wolfgang SadeeZaijie Wang
Aug 10, 2019·Journal of Pharmacokinetics and Pharmacodynamics·Carrie GermanAndrzej Przekwas
Oct 5, 2019·Biochemical Pharmacology·Peishen Zhao, Sebastian G B Furness
May 26, 2021·British Journal of Pharmacology·Liang YangStephen B Duffull

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