Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland, Australia.
Nat Chem Biol. 2017 Aug 18;13(9):929-937. doi: 10.1038/nchembio.2431.
G-protein-coupled receptors (GPCRs) are one of the most tractable classes of drug targets. These dynamic proteins can adopt multiple active states that are linked to distinct functional outcomes. Such states can be differentially stabilized by ligands interacting with the endogenous agonist-binding orthosteric site and/or by ligands acting via spatially distinct allosteric sites, leading to the phenomena of 'biased agonism' or 'biased modulation'. These paradigms are having a major impact on modern drug discovery, but it is becoming increasingly apparent that 'kinetic context', at the level of both ligand-receptor and receptor-signal pathway kinetics, can have a profound impact on the observation and quantification of these phenomena. The concept of kinetic context thus represents an important new consideration that should be routinely incorporated into contemporary chemical biology and drug discovery studies of GPCR bias and allostery.
G 蛋白偶联受体（GPCR）是最具可操作性的药物靶点之一。这些动态蛋白可以采用多种与不同功能结果相关的活性状态。通过与内源性激动剂结合的正位点相互作用的配体和/或通过通过空间上不同的变构位点起作用的配体，这些状态可以被不同程度地稳定，从而产生“偏向激动剂”或“偏向调节”现象。这些范例正在对现代药物发现产生重大影响，但越来越明显的是，在配体-受体和受体信号通路动力学的水平上，“动力学背景”会对这些现象的观察和量化产生深远影响。因此，动力学背景的概念代表了一个重要的新考虑因素，应该在当代化学生物学和 GPCR 偏向性和变构的药物发现研究中经常纳入。
