Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 21, Issue 14, Pages 4266-4278Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2013.04.069
Keywords
FXR, farnesoid X receptor; NRs, nuclear receptors; HTS, high-throughput screen; LBD, ligand-binding domain; TR-FRET, time resolved fluorescence resonance energy transfer
Funding
- American Lebanese Syrian Associated Charities (ALSAC)
- St. Jude Children's Research Hospital (St. Jude)
- National Institutes of Health National Institute of General Medical Sciences [GM086415]
- National Institutes of Health National Cancer Institute [P30-CA21765]
Ask authors/readers for more resources
FXR (farnesoid X receptor, NRIH4), a nuclear receptor, plays a major role in the control of cholesterol metabolism. FXR ligands have been investigated in preclinical studies for targeted therapy against metabolic diseases, but have shown limitations. Therefore, there is a need for new agonist or antagonist ligands of FXR, both for potential clinical applications, as well as to further elucidate its biological functions. Here we describe the use of the X-ray crystal structure of FXR complexed with the potent small molecule agonist GW4064 to design and synthesize a novel fluorescent, high-affinity probe (DY246) for time resolved fluorescence resonance energy transfer (TR-FRET) assays. We then used the TR-FRET assay for high throughput screening of a library of over 5000 bioactive compounds. From this library, we identified 13 compounds that act as putative FXR transcriptional antagonists. (C) 2013 Elsevier Ltd. All rights reserved.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available