Investigating receptor enzyme activity using time-scale analysis

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.

Source: IET Systems Biology - November 20, 2015 Category: Biology Source Type: research