title: Virtual screening and experimental validation identify novel modulators of nuclear receptor RXRα from Drugbank database.
abstract: 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=13.30μM 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 (KD=8.80μM and 15.01μM, respectively) but serve as transcriptional agonists of RXRα.
authors.affiliation: School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361005, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Xu
authors.affiliation: School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361005, China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Cai
authors.affiliation: School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361005, China.
authors.forename: Shangjie
authors.initials: S
authors.lastname: Guo
authors.affiliation: School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361005, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Xie
authors.affiliation: School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361005, China.
authors.forename: Meimei
authors.initials: M
authors.lastname: Yin
authors.affiliation: School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361005, China.
authors.forename: Ziwen
authors.initials: Z
authors.lastname: Chen
authors.affiliation: School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361005, China.
authors.forename: Hu
authors.initials: H
authors.lastname: Zhou
authors.affiliation: 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.
authors.forename: Ying
authors.initials: Y
authors.lastname: Su
authors.affiliation: School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361005, China. Electronic address: zengzhiping@xmu.edu.cn.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Zeng
authors.affiliation: 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. Electronic address: xkzhang@xmu.edu.cn.
authors.forename: Xiaokun
authors.initials: X
authors.lastname: Zhang
mesh_terms: D018360:Crystallography, X-Ray; D016208:Databases, Factual; D004353:Drug Evaluation, Preclinical; D005229:Fatty Acids, Monounsaturated / Q000737:chemistry / Q000494:pharmacology; D000077340:Fluvastatin; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology; D047490:Retinoid X Receptor alpha / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D005229:Fatty Acids, Monounsaturated; D007211:Indoles; D008024:Ligands; D011804:Quinolines; D047490:Retinoid X Receptor alpha; D000077340:Fluvastatin; C108475:pitavastatin
keywords: Agonist; Antagonist; Old drug; RXRα; Virtual screening