G protein-coupled receptors (GPCRs) are targeted by about a third of clinically used drugs. Many GPCRs couple to more than one type of heterotrimeric G proteins, become phosphorylated by any of several different GRKs, and then bind one or more types of arrestin. Thus, classical therapeutically active drugs simultaneously initiate several branches of signaling, some of which are beneficial, whereas others result in unwanted on-target side effects. The development of novel compounds to selectively channel the signaling into the desired direction has the potential to become a breakthrough in health care. However, there are natural and technological hurdles that must be overcome. The fact that most GPCRs are subject to homologous desensitization, where the active receptor couples to G proteins, is phosphorylated by GRKs, and then binds arrestins, suggest that in most cases the GPCR conformations that facilitate their interactions with these three classes of binding partners significantly overlap. Thus, while partner-specific conformations might exist, they are likely low-probability states. GPCRs are inherently flexible, which suggests that complete bias is highly unlikely to be feasible: in the conformational ensemble induced by any ligand, there would be some conformations facilitating receptor coupling to unwanted partners. Things are further complicated by the fact that virtually every cell expresses numerous G proteins, several GRK subtypes, and two non-visual arrestins with distinct signaling capabilities. Finally, novel screening methods for measuring ligand bias must be devised, as the existing methods are not specific for one particular branch of signaling.

G蛋白偶联受体（GPCR）被约三分之一的临床使用药物靶向。许多GPCR与多于一种类型的异三聚体G蛋白偶联，被几种不同的GRK中的任何一种磷酸化，然后结合一种或多种类型的抑制蛋白。因此，经典的治疗活性药物会同时启动多个信号分支，其中一些是有益的，而另一些会导致不希望出现的靶上副作用。选择性将信号传导至所需方向的新型化合物的开发，有可能成为医疗保健领域的突破。但是，必须克服自然和技术上的障碍。大多数GPCR都经过同源脱敏作用，其中活性受体与G蛋白偶联，被GRK磷酸化，然后结合抑制蛋白，提示在大多数情况下，促进它们与这三类结合伴侣相互作用的GPCR构象会显着重叠。因此，尽管可能存在特定于伙伴的构象，但它们可能是低概率状态。GPCR具有内在的灵活性，这表明完全偏倚是极不可能的：在任何配体诱导的构象集合中，会有一些构象促进受体偶联到不需要的伴侣上。几乎每个细胞都表达大量G蛋白，几种GRK亚型和两种具有独特信号传导功能的非视觉抑制蛋白的事实使事情变得更加复杂。最后，由于现有方法并非特定于信号的一个特定分支，因此必须设计出用于测量配体偏倚的新颖筛选方法。