Xu Dan, Cai Lijun, Guo Shangjie, Xie Lei, Yin Meimei, Chen Ziwen, Zhou Hu, Su Ying, Zeng Zhiping, Zhang Xiaokun
School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361005, China.
School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361005, China; Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
Bioorg Med Chem Lett. 2017 Feb 15;27(4):1055-1061. doi: 10.1016/j.bmcl.2016.12.058. Epub 2016 Dec 26.
Retinoid X receptor alpha (RXRα), an important ligand-dependent transcription factor, plays a critical role in the development of various cancers and metabolic and neurodegenerative diseases. Therefore, RXRα represents one of the most important targets in modern drug discovery. In this study, Drugbank 2.0 with 1280 old drugs were virtually screened by Glide according to the crystal structure of ligand-binding domain (LBP) of RXRα. 15 compounds selected were tested for their binding and transcriptional activity toward RXRα by Biacore and reporter gene assay, respectively. The identified new scafford ligand of RXRα, Pitavastatin (1), was chemically optimized. Our results demonstrated that statin compounds Pitavastatin (1) and Fluvastatin (4) could bind to the LBP of RXRα (K=13.30μM and 11.04μM, respectively) and serve as transcriptional antagonists of RXRα. On the contrary, compound (12) (domperidone) and (13) (rosiglitazone maleate) could bind to the LBP of RXRα (K=8.80μM and 15.01μM, respectively) but serve as transcriptional agonists of RXRα.
维甲酸X受体α（RXRα）是一种重要的配体依赖性转录因子，在多种癌症以及代谢和神经退行性疾病的发展过程中发挥着关键作用。因此，RXRα是现代药物研发中最重要的靶点之一。在本研究中，依据RXRα配体结合域（LBP）的晶体结构，利用Glide软件对包含1280种旧药的DrugBank 2.0数据库进行了虚拟筛选。分别通过Biacore和报告基因检测法对筛选出的15种化合物针对RXRα的结合能力和转录活性进行了测试。对所鉴定出的RXRα新型骨架配体匹伐他汀（1）进行了化学优化。我们的研究结果表明，他汀类化合物匹伐他汀（1）和氟伐他汀（4）能够与RXRα的LBP结合（K值分别为13.30μM和11.04μM），并作为RXRα的转录拮抗剂。相反，化合物（12）（多潘立酮）和（13）（马来酸罗格列酮）能够与RXRα的LBP结合（K值分别为8.80μM和15.01μM），但作为RXRα的转录激动剂。
