A Simple Method for Quantifying Functional Selectivity and Agonist Bias
A Simple Method for Quantifying Functional Selectivity and Agonist Bias
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DOI：
10.1021/cn200111m
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发表时间：
2012-03-01
影响因子：
5
通讯作者：
Novick, Steven
中科院分区：
文献类型：
--
作者：
Kenakin, Terry;Watson, Christian;Novick, Steven
激动剂对七跨膜（7 TM）受体的激活并不总是导致由给定受体介导的所有信号传导途径的均匀激活。相对于其他配体，许多激动剂“偏向”产生受体行为的子集。这种“功能选择性”的标志是细胞类型依赖性;这对从治疗系统中移除的全细胞测试系统中的激动剂的概况分析提出了特别的问题。这种反应特异性的基于细胞的变异性使得难以指导旨在鉴定和优化治疗上有意义的激动剂偏倚的药物化学工作。出于这个原因，我们提出了一个规模，基于Black和Leff操作模型，其中包含描述7 TM激动所需的关键要素，即，受体的亲和力（K-A（-1））和激活特定信号通路的功效（tau）。利用“转导系数”项log（tau/K-A），该标度可以以理论上可以告知结构活性研究和/或候选药物选择矩阵的方式统计地评估选择性激动剂效应。四个趋化因子CCRS介导的磷酸肌醇生产与内化的偏差进行量化，以说明这种方法的实际应用。这种方法相对于受体密度的独立性和差异的置信度的统计估计的计算进行了具体讨论。
Activation of seven-transmembrane (7TM) receptors by agonists does not always lead to uniform activation of all signaling pathways mediated by a given receptor. Relative to other ligands, many agonists are "biased" toward producing subsets of receptor behaviors. A hallmark of such "functional selectivity" is cell type dependence; this poses a particular problem for the profiling of agonists in whole cell test systems removed from the therapeutic one(s). Such response-specific cell-based variability makes it difficult to guide medicinal chemistry efforts aimed at identifying and optimizing therapeutically meaningful agonist bias. For this reason, we present a scale, based on the Black and Leff operational model, that contains the key elements required to describe 7TM agonism, namely, affinity (K-A(-1)) for the receptor and efficacy (tau) in activating a particular signaling pathway. Utilizing a "transduction coefficient" term, log(tau/K-A), this scale can statistically evaluate selective agonist effects in a manner that can theoretically inform structure activity studies and/or drug candidate selection matrices. The bias of four chemokines for CCRS-mediated inositol phosphate production versus internalization is quantified to illustrate the practical application of this method. The independence of this method with respect to receptor density and the calculation of statistical estimates of confidence of differences are specifically discussed.