Department of Pharmacology, School of Medicine, University of California, Irvine, CA, United States.
Prog Mol Biol Transl Sci. 2018;160:63-104. doi: 10.1016/bs.pmbts.2018.08.001. Epub 2018 Oct 15.
Agonists and most natural ligands bind to receptors in their inactive state and quickly induce an active receptor conformation that initiates cell signaling. The active receptor state initiates signaling because of its structural complementariness with coupling proteins that activate signaling pathways, such as G proteins and G protein-coupled receptor kinases. Agonist bias refers to the propensity of an agonist to direct receptor signaling through one pathway relative to another. Thus, if the agonist exhibits much higher affinity for active state 1 compared to active state 2, it will cause a robust activation of receptor coupling protein 1 but not 2, and ultimately, a preferential stimulation of signaling pathway 1. Biased agonists are potentially more selective therapeutic agents because there are numerous cases where the therapeutic and adverse effects of an agonist are mediated by distinct pathways involving G proteins and β-arrestin. Given the mechanism for agonist bias, the most straightforward approach for quantifying bias involves the estimation of agonist affinity for the inactive receptor state and the active receptor states involved in signaling through different pathways. The approach provides quantitative estimates of the sensitivities of different signaling pathways, enabling one to determine to what extent the observed selectivity is caused by agonist or system bias. In addition, the approach is a powerful adjunct to in silico docking studies and can be applied to in vivo assays, structure-activity relationships, and the analysis of published agonist concentration-response curves.
激动剂和大多数天然配体与处于非活性状态的受体结合，并迅速诱导产生起始细胞信号转导的活性受体构象。由于其与激活信号通路的偶联蛋白（如 G 蛋白和 G 蛋白偶联受体激酶）的结构互补性，活性受体状态起始信号转导。激动剂偏向是指激动剂相对于另一种途径引导受体信号转导的倾向。因此，如果激动剂对活性状态 1 的亲和力远高于活性状态 2，它将导致受体偶联蛋白 1 的强烈激活，但不会导致受体偶联蛋白 2 的激活，最终，偏向于刺激信号通路 1。偏向激动剂可能是更具选择性的治疗药物，因为在许多情况下，激动剂的治疗和不良反应是由涉及 G 蛋白和β-arrestin 的不同途径介导的。鉴于激动剂偏向的机制，定量评估偏向的最直接方法涉及估计激动剂对非活性受体状态和通过不同途径参与信号转导的活性受体状态的亲和力。该方法提供了不同信号通路敏感性的定量估计，使人们能够确定观察到的选择性在多大程度上是由激动剂或系统偏向引起的。此外，该方法是计算机对接研究的有力辅助手段，可应用于体内测定、构效关系以及对已发表的激动剂浓度-反应曲线的分析。
