核受体
计算生物学
生物
转录因子
基因
细胞生物学
药物设计
药物发现
受体
生物信息学
遗传学
作者
Peiying Huang,Vikas Chandra,Fraydoon Rastinejad
出处
期刊:Annual Review of Physiology
[Annual Reviews]
日期:2010-03-17
卷期号:72 (1): 247-272
被引量:460
标识
DOI:10.1146/annurev-physiol-021909-135917
摘要
As ligand-regulated transcription factors, the nuclear hormone receptors are nearly ideal drug targets, with internal pockets that bind to hydrophobic, drug-like molecules and well-characterized ligand-induced conformational changes that recruit transcriptional coregulators to promoter elements. Yet, due to the multitude of genes under the control of a single receptor, the major challenge has been the identification of ligands with gene-selective actions, impacting disease outcomes through a narrow subset of target genes and not across their entire gene-regulatory repertoire. Here, we summarize the concepts and work to date underlying the development of steroidal and nonsteroidal receptor ligands, including the use of crystal structures, high-throughput screens, and rational design approaches for finding useful therapeutic molecules. Difficulties in finding selective receptor modulators require a more complete understanding of receptor interdomain communications, posttranslational modifications, and receptor-protein interactions that could be exploited for target gene selectivity.
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