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Updated: Mar 8, 2026
Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists
Published on: November 15, 2013
Virtual screening and experimental validation identify novel modulators of nuclear receptor RXRα from Drugbank
Dan Xu1, Lijun Cai1, Shangjie Guo1
1School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361005, China.
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.
Insights
Retinoid X receptor alpha (RXRα) drug discovery identified statins Pitavastatin and Fluvastatin as antagonists. Other compounds acted as agonists, offering new therapeutic avenues for RXRα-related diseases.
Area of Science:
- Medicinal Chemistry
- Molecular Pharmacology
- Drug Discovery
Background:
- Retinoid X receptor alpha (RXRα) is a crucial transcription factor implicated in cancer, metabolic, and neurodegenerative diseases.
- RXRα is a significant target for developing novel therapeutic agents.
Purpose of the Study:
- To virtually screen existing drugs for potential RXRα ligands.
- To identify and characterize novel RXRα modulators for therapeutic applications.
Main Methods:
- Virtual screening of 1280 drugs using Glide docking against RXRα ligand-binding domain (LBP).
- Experimental validation of 15 selected compounds using Biacore for binding affinity and reporter gene assays for transcriptional activity.
- Chemical optimization of identified lead compounds.
Main Results:
- Pitavastatin and Fluvastatin were identified as RXRα ligands, binding to the LBP with KD values of 13.30μM and 11.04μM, respectively.
- Pitavastatin and Fluvastatin function as RXRα transcriptional antagonists.
- Domperidone and rosiglitazone maleate also bound to RXRα LBP (KD=8.80μM and 15.01μM) but acted as transcriptional agonists.
Conclusions:
- Statin compounds Pitavastatin and Fluvastatin are effective RXRα antagonists.
- Domperidone and rosiglitazone maleate are identified as RXRα agonists.
- These findings provide novel scaffolds for developing targeted therapies for RXRα-mediated conditions.
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