期刊
ANNUAL REVIEW OF PHYSIOLOGY
卷 72, 期 -, 页码 247-272出版社
ANNUAL REVIEWS
DOI: 10.1146/annurev-physiol-021909-135917
关键词
nuclear receptor; drug discovery; protein-ligand interactions
类别
资金
- NIDDK NIH HHS [P30 DK067629] Funding Source: Medline
- NIGMS NIH HHS [R01 GM055217] Funding Source: Medline
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [P30DK067629] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM055217] Funding Source: NIH RePORTER
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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