Time scale analysis of receptor enzyme activity: Irreversible inhibition sometimes exhibits incubation-time independence

Abstract

At early drug discovery, purified protein-based assays are often used to characterise compound potency. As far as dose response is concerned, it is often thought that a timeindependent inhibitor is reversible and a time-dependent inhibitor is irreversible. Using a simple kinetics model, we investigate the legitimacy of this. Our model-based analytical analysis and numerical studies reveal that dose response of an irreversible inhibitor may appear time-independent under certain parametric conditions. Hence, time-independence cannot be used as evidence for inhibitor reversibility. Furthermore, we also analysed how the synthesis and degradation of a target receptor affect drug inhibition in an in vitro cell-based assay setting. Indeed, these processes may also influence dose response of an irreversible inhibitor in such a way that it appears timeindependent under certain conditions. Hence, time-independent dose response in a cell assay also needs careful considerations. It is necessary to formulate a suitable model for analysis of proteinbased assay and in vitro cell assay data to ensure a consistent understanding. Keywords-irreversible inhibition; model of receptor turnover; fast drug process; slow drug process; timescale analysis I.