title: Investigating receptor enzyme activity using time-scale analysis.
abstract: At early drug discovery, purified protein-based assays are often used to characterise compound potency. In the context of dose response, it is often perceived that a time-independent inhibitor is reversible and a time-dependent inhibitor is irreversible. The legitimacy of this argument is investigated using a simple kinetics model, where it is revealed by model-based analytical analysis and numerical studies that dose response of an irreversible inhibitor may appear time-independent under certain parametric conditions. Hence, the observation of time-independence cannot be used as sole evidence for identification of inhibitor reversibility. It has also been discussed how the synthesis and degradation of a target receptor affect drug inhibition in an in vitro cell-based assay setting. These processes may also influence dose response of an irreversible inhibitor in such a way that it appears time-independent under certain conditions. Furthermore, model-based steady-state analysis reveals the complexity nature of the drug-receptor process.
authors.affiliation: Computational Biology, Discovery Sciences, Innovative Medicines & Early Development, AstraZeneca, Alderley Park, Cheshire, SK10 4TG, UK.
authors.forename: Tao
authors.initials: T
authors.lastname: You
authors.affiliation: Department of Electronic and Electrical Engineering, University of Strathclyde, Glasgow, G1 1XW, UK. hong.yue@strath.ac.uk.
authors.forename: Hong
authors.initials: H
authors.lastname: Yue
mesh_terms: D000818:Animals; D004791:Enzyme Inhibitors / Q000737:chemistry*; D004798:Enzymes / Q000737:chemistry*; D006801:Humans; D008956:Models, Chemical; D011956:Receptors, Cell Surface / Q000737:chemistry*
chemical_list: D004791:Enzyme Inhibitors; D004798:Enzymes; D011956:Receptors, Cell Surface