You Tao, Yue Hong
Computational Biology, Discovery Sciences, Innovative Medicines & Early Development, AstraZeneca, Alderley Park, Cheshire, SK10 4TG, UK.
Department of Electronic and Electrical Engineering, University of Strathclyde, Glasgow, G1 1XW, UK.
IET Syst Biol. 2015 Dec;9(6):268-76. doi: 10.1049/iet-syb.2015.0037.
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.
在药物发现早期，基于纯化蛋白的检测方法常被用于表征化合物的效力。在剂量反应的背景下，人们通常认为非时间依赖性抑制剂是可逆的，而时间依赖性抑制剂是不可逆的。使用一个简单的动力学模型对这一论点的合理性进行了研究，通过基于模型的分析和数值研究发现，在某些参数条件下，不可逆抑制剂的剂量反应可能表现为非时间依赖性。因此，不能将非时间依赖性的观察结果作为鉴定抑制剂可逆性的唯一证据。还讨论了在基于体外细胞的检测环境中，靶受体的合成和降解如何影响药物抑制作用。这些过程也可能以某种方式影响不可逆抑制剂的剂量反应，使其在某些条件下表现为非时间依赖性。此外，基于模型的稳态分析揭示了药物 - 受体过程的复杂性。
