Virtual screening and experimental validation identify novel modulators of nuclear receptor RXRα from Drugbank database
Virtual screening and experimental validation identify novel modulators of nuclear receptor RXRα from Drugbank database
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虚拟筛选和实验验证从 Drugbank 数据库中鉴定出核受体 RXR α 的新型调节剂
DOI：
10.1016/j.bmcl.2016.12.058
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发表时间：
2017-02-15
影响因子：
2.7
通讯作者：
Zhang, Xiaokun
中科院分区：
文献类型：
--
作者：
Xu, Dan;Cai, Lijun;Zhang, Xiaokun
视黄酸X受体α（RXRα）是一种重要的依赖配体的转录因子，在多种癌症以及代谢和神经退行性疾病的发展中起着关键作用。因此，RXRα是现代药物研发中最重要的靶点之一。在本研究中，根据RXRα配体结合域（LBP）的晶体结构，利用Glide软件对包含1280种老药的DrugBank 2.0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的结合及转录活性进行了测试。对鉴定出的RXRα新型支架配体匹伐他汀（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（KD分别为13.301 μM和11.04 μM），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（KD分别为8.80 μM和15.01 μM），但作为RXRα的转录激动剂。（C）2016爱思唯尔有限公司。保留所有权利。
Retinoid X receptor alpha (RXR alpha), an important ligand-dependent transcription factor, plays a critical role in the development of various cancers and metabolic and neurodegenerative diseases. Therefore, RXR alpha 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 RXR alpha. 15 compounds selected were tested for their binding and transcriptional activity toward RXR alpha by Biacore and reporter gene assay, respectively. The identified new scafford ligand of RXR alpha, Pitavastatin (1), was chemically optimized. Our results demonstrated that statin compounds Pitavastatin (1) and Fluvastatin (4) could bind to the LBP of RXR alpha (K-D = 13.301 mu M and 11.04 mu M, respectively) and serve as transcriptional antagonists of RXR alpha. On the contrary, compound (12) (domperidone) and (13) (rosiglitazone maleate) could bind to the LBP of RXR alpha(K-D = 8.80 mu M and 15.01 mu M, respectively) but serve as transcriptional agonists of RXR alpha. (C) 2016 Elsevier Ltd. All rights reserved.