Wilson S, Bergsma D J, Chambers J K, Muir A I, Fantom K G, Ellis C, Murdock P R, Herrity N C, Stadel J M
SmithKline Beecham Pharmaceuticals, Harlow, Essex.
Br J Pharmacol. 1998 Dec;125(7):1387-92. doi: 10.1038/sj.bjp.0702238.
The pharmaceutical industry has readily embraced genomics to provide it with new targets for drug discovery. Large scale DNA sequencing has allowed the identification of a plethora of DNA sequences distantly related to known G protein-coupled receptors (GPCRs), a superfamily of receptors that have a proven history of being excellent therapeutic targets. In most cases the extent of sequence homology is insufficient to assign these 'orphan' receptors to a particular receptor subfamily. Consequently, reverse molecular pharmacological and functional genomic strategies are being employed to identify the activating ligands of the cloned receptors. Briefly, the reverse molecular pharmacological methodology includes cloning and expression of orphan GPCRs in mammalian cells and screening these cells for a functional response to cognate or surrogate agonists present in biological extract preparations, peptide libraries, and complex compound collections. The functional genomics approach involves the use of 'humanized yeast cells, where the yeast GPCR transduction system is engineered to permit functional expression and coupling of human GPCRs to the endogenous signalling machinery. Both systems provide an excellent platform for identifying novel receptor ligands. Once activating ligands are identified they can be used as pharmacological tools to explore receptor function and relationship to disease.
制药行业欣然接受了基因组学，以便为药物研发提供新的靶点。大规模DNA测序已使人们能够识别出大量与已知G蛋白偶联受体（GPCRs）远缘相关的DNA序列，GPCRs是一类受体超家族，其作为出色治疗靶点的历史已得到证实。在大多数情况下，序列同源性程度不足以将这些“孤儿”受体归为特定的受体亚家族。因此，正在采用反向分子药理学和功能基因组学策略来识别克隆受体的激活配体。简而言之，反向分子药理学方法包括在哺乳动物细胞中克隆和表达孤儿GPCRs，并针对生物提取物制剂、肽库和复合化合物库中存在的同源或替代激动剂的功能反应对这些细胞进行筛选。功能基因组学方法涉及使用“人源化酵母细胞”，其中对酵母GPCR转导系统进行工程改造，以允许人GPCRs进行功能表达并与内源性信号传导机制偶联。这两种系统都为识别新型受体配体提供了出色的平台。一旦识别出激活配体，就可以将其用作药理学工具来探索受体功能及其与疾病的关系。
