Shi Yanhong
Division of Neurosciences, Center for Gene Expression and Drug Discovery, Beckman Research Institute of City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA.
Comb Chem High Throughput Screen. 2006 Nov;9(9):683-9. doi: 10.2174/138620706778700125.
To date, the pharmaceutical industry has placed a considerable amount of interest in the discovery of drug targets and diagnostics. One of the most challenging areas of drug discovery today is the search for novel receptor-ligand pairs. Nuclear receptors comprise a large superfamily of ligand-dependent transcription factors that regulate the expression of genes critical for a variety of biological processes, including development, growth, differentiation, and homeostasis. Orphan nuclear receptors, for which the ligands are not yet identified, represent the most ancient component of the nuclear receptor superfamily. Orphan nuclear receptors not only offer a unique system to uncover novel signaling pathways that impact human health, but also provide excellent targets of drug discoveries for a variety of human diseases. This review highlights advances made on ligand identification for orphan nuclear receptors using transgenic mouse models, cell-based screening, direct binding, structure-based assays, and computer-aided virtual screening. With rapid advances in combinatorial chemistry and high throughput screening, along with other modern technologies, this field promises a bountiful harvest.
迄今为止，制药行业对药物靶点和诊断方法的发现投入了大量关注。当今药物研发中最具挑战性的领域之一是寻找新型受体-配体对。核受体构成了一个庞大的配体依赖性转录因子超家族，它们调节着对包括发育、生长、分化和体内平衡在内的各种生物过程至关重要的基因的表达。尚未确定配体的孤儿核受体是核受体超家族中最古老的组成部分。孤儿核受体不仅为揭示影响人类健康的新型信号通路提供了独特的系统，也为多种人类疾病提供了优秀的药物研发靶点。本综述重点介绍了利用转基因小鼠模型、基于细胞的筛选、直接结合、基于结构的分析方法以及计算机辅助虚拟筛选等手段在孤儿核受体配体鉴定方面取得的进展。随着组合化学和高通量筛选以及其他现代技术的迅速发展，该领域有望取得丰硕成果。
