Department of Pharmacology, University of North Carolina, Chapel Hill, 27599, USA.
Annu Rev Pharmacol Toxicol. 2011;51:117-44. doi: 10.1146/annurev-pharmtox-010510-100553.
G protein-coupled receptors (GPCRs) are an evolutionarily conserved family of signaling molecules comprising approximately 2% of the human genome; this receptor family remains a central focus in basic pharmacology studies and drug discovery efforts. Detailed studies of drug action at GPCRs over the past decade have revealed existing and novel ligands that exhibit polypharmacology-that is, drugs with activity at more than one receptor target for which they were designed. These "off-target" drug actions can be a liability that causes adverse side effects; however, in several cases, drugs with less selectivity demonstrate better clinical efficacy. Here we review physical screening and cheminformatic approaches that define drug activity at the GPCR receptorome. In many cases, such profiling has revealed unexpected targets that explain therapeutic actions as well as off-targets underlying drug side effects. Such drug-receptor profiling has also provided new insights into mechanisms of action of existing drugs and has suggested directions for future drug development.
G 蛋白偶联受体（GPCRs）是一个进化上保守的信号分子家族，约占人类基因组的 2%；这个受体家族仍然是基础药理学研究和药物发现工作的重点。在过去十年中，对 GPCR 药物作用的详细研究揭示了现有的和新的配体，这些配体表现出多药理学——即具有活性的药物超过一个受体靶点，而这些靶点是为它们设计的。这些“非靶点”药物作用可能是导致不良反应的不利因素；然而，在某些情况下，选择性较低的药物表现出更好的临床疗效。在这里，我们回顾了定义 GPCR 受体组中药物活性的物理筛选和化学信息学方法。在许多情况下，这种分析揭示了意想不到的靶点，这些靶点解释了治疗作用以及药物副作用的非靶点。这种药物-受体分析还为现有药物的作用机制提供了新的见解，并为未来的药物开发提供了方向。
