Hoare Samuel R J, Pierre Nicolas, Moya Arturo Gonzalez, Larson Brad
Pharmechanics, LLC, 14 Sunnyside Drive South, Owego NY 13827, USA.
Cisbio US, 135 South Road, Bedford, MA 01730, USA.
J Theor Biol. 2018 Jun 7;446:168-204. doi: 10.1016/j.jtbi.2018.02.014. Epub 2018 Feb 25.
The application of kinetics to research and therapeutic development of G-protein-coupled receptors has become increasingly valuable. Pharmacological models provide the foundation of pharmacology, providing concepts and measurable parameters such as efficacy and potency that have underlain decades of successful drug discovery. Currently there are few pharmacological models that incorporate kinetic activity in such a way as to yield experimentally-accessible drug parameters. In this study, a kinetic model of pharmacological response was developed that provides a kinetic descriptor of efficacy (the transduction rate constant, k) and allows measurement of receptor-ligand binding kinetics from functional data. The model assumes: (1) receptor interacts with a precursor of the response ("Transduction potential") and converts it to the response. (2) The response can decay. Familiar response vs time plots emerge, depending on whether transduction potential is depleted and/or response decays. These are the straight line, the "association" exponential curve, and the rise-and-fall curve. Convenient, familiar methods are described for measuring the model parameters and files are provided for the curve-fitting program Prism (GraphPad Software) that can be used as a guide. The efficacy parameter k is straightforward to measure and accounts for receptor reserve; all that is required is measurement of response over time at a maximally-stimulating concentration of agonist. The modular nature of the model framework allows it to be extended. Here this is done to incorporate antagonist-receptor binding kinetics and slow agonist-receptor equilibration. In principle, the modular framework can incorporate other cellular processes, such as receptor desensitization. The kinetic response model described here can be applied to measure kinetic pharmacological parameters than can be used to advance the understanding of GPCR pharmacology and optimize new and improved therapeutics.
将动力学应用于G蛋白偶联受体的研究和治疗开发变得越来越有价值。药理学模型为药理学奠定了基础，提供了诸如效能和效价等概念以及可测量的参数，这些参数是数十年来成功药物发现的基础。目前，很少有药理学模型以能够产生实验可获取的药物参数的方式纳入动力学活性。在本研究中，开发了一种药理学反应动力学模型，该模型提供了效能的动力学描述符（转导速率常数，k），并允许从功能数据测量受体-配体结合动力学。该模型假设：（1）受体与反应的前体（“转导电位”）相互作用并将其转化为反应。（2）反应可以衰减。根据转导电位是否耗尽和/或反应是否衰减，会出现熟悉的反应与时间关系图。这些是直线、“关联”指数曲线和升降曲线。描述了测量模型参数的便捷、熟悉的方法，并提供了可用于曲线拟合程序Prism（GraphPad软件）的文件作为指导。效能参数k易于测量且考虑了受体储备；所需要的只是在最大刺激浓度的激动剂下随时间测量反应。模型框架的模块化性质使其能够扩展。在此，通过纳入拮抗剂-受体结合动力学和缓慢的激动剂-受体平衡来实现这一点。原则上，模块化框架可以纳入其他细胞过程，如受体脱敏。这里描述的动力学反应模型可用于测量动力学药理学参数，这些参数可用于增进对GPCR药理学的理解并优化新的和改进的治疗方法。
