Andrews Stephen P, Brown Giles A, Christopher John A
Heptares Therapeutics Ltd., BioPark, Welwyn Garden City, Hertfordshire, AL7 3AX (UK).
ChemMedChem. 2014 Feb;9(2):256-75. doi: 10.1002/cmdc.201300382. Epub 2013 Dec 18.
G protein-coupled receptors (GPCRs) are an important family of membrane proteins; historically, drug discovery in this target class has been fruitful, with many of the world's top-selling drugs being GPCR modulators. Until recently, the modern techniques of structure- and fragment-based drug discovery had not been fully applied to GPCRs, primarily because of the instability of these proteins when isolated from their cell membrane environments. Recent advances in receptor stabilisation have facilitated major advances in GPCR structural biology over the past six years, with 21 new receptor targets successfully crystallised with one or more ligands. The dramatic increase in GPCR structural information has yielded an increased use of structure-based methods for hit identification and progression, which are reviewed herein. Additionally, a number of fragment-based drug discovery techniques have been validated for use with GPCRs in recent years; these approaches and their use in hit identification are reviewed.
G蛋白偶联受体(GPCRs)是一类重要的膜蛋白;从历史上看,针对这类靶点的药物研发成果丰硕,许多全球畅销药物都是GPCR调节剂。直到最近,基于结构和片段的现代药物研发技术尚未完全应用于GPCRs,主要原因是这些蛋白质从细胞膜环境中分离出来时不稳定。受体稳定化方面的最新进展在过去六年推动了GPCR结构生物学的重大进步,已有21个新的受体靶点与一种或多种配体成功结晶。GPCR结构信息的大幅增加使得基于结构的方法在命中物识别和研发过程中的使用有所增加,本文对此进行综述。此外,近年来一些基于片段的药物研发技术已被验证可用于GPCRs;本文将对这些方法及其在命中物识别中的应用进行综述。