A kinetic operational model of agonism incorporating receptor desensitization for G-protein-coupled receptors

Abstract

AbstractPharmacological responses are modulated over time by regulation of signaling mechanisms. The canonical short-term regulation mechanisms are receptor desensitization and degradation of the response. Here for the first time a pharmacological model for measuring drug parameters is developed that incorporates short-term mechanisms of regulation of signaling. The model is formulated in a manner that enables measurement of drug parameters using familiar curve fitting methods. The efficacy parameter iskτ, which is simply the initial rate of signaling before it becomes limited by regulation mechanisms. The regulation parameters are rate constants,kDESfor receptor desensitization andkDfor response degradation. Efficacy and regulation are separate parameters, meaning these properties can be optimized independently of one another in drug discovery. The parameters can be applied to translate in vitro findings to in vivo efficacy in terms of the magnitude and duration of drug effect. When the time course data conform to certain shapes, for example the association exponential curve, a mechanism-agnostic approach can be applied to estimate agonist efficacy, without the need to know the underlying regulatory mechanisms. The model was verified by comparison with historical data and by fitting these data to estimate the model parameters. This new model for quantifying drug activity can be broadly applied to the short-term cell signaling assays used routinely in drug discovery and to aid their translation to in vivo efficacy, facilitating the development of new therapeutics.HighlightsRegulation of signaling impacts measurement of drug effectReceptor desensitization is incorporated here into a kinetic model of signalingDrug effect and signaling regulation can now be measured independentlyThe analysis framework is designed for signaling assays used in drug discoveryThese new analysis capabilities will aid development of new therapeutics