Virtual screening and experimental validation identify novel modulators of nuclear receptor RXRα from Drugbank database

详细信息    查看全文

• 作者：Dan Xu¹ ; ^a ; Lijun Cai¹ ; ^a ; Shangjie Guo^a ; Lei Xie^a ; Meimei Yin^a ; Ziwen Chen^a ; Hu Zhou^a ; Ying Su^a ; ^b ; Zhiping Zeng^a ; ^{zengzhiping@xmu.edu.cn} ; Xiaokun Zhang^a ; ^b ; ^{xkzhang@xmu.edu.cn}
• 关键词：RXRα ; Old drug ; Agonist ; Antagonist ; Virtual screening
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2017
• 出版时间：15 February 2017
• 年：2017
• 卷：27
• 期：4
• 页码：1055-1061
• 全文大小：1663 K
• 卷排序：27

文摘

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 (KD = 13.30 μM and 11.04 μM, 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 (KD = 8.80 μM and 15.01 μM, respectively) but serve as transcriptional agonists of RXRα.