ArticleThe Journal of biological chemistry2015
Structural Basis for Small Molecule NDB (N-Benzyl-N-(3-(tert-butyl)-4-hydroxyphenyl)-2,6-dichloro-4-(dimethylamino) Benzamide) as a Selective Antagonist of Farnesoid X Receptor α (FXRα) in Stabilizing the Homodimerization of the Receptor.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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25 citing papers in PubMed, 52 citations in OpenAlex.
- Discovery of sulfonyl benzoic acid derivatives with joint TGR5-agonist and FXR-antagonist activity for myocardial ischemia/reperfusion injury protection.Acta pharmaceutica Sinica. B · 2026Article
- Tailoring obeticholic acid activity by iridium(III) complex conjugation to develop a farnesoid X receptor probe.Journal of advanced research · 2025Article
- Development of cyclopeptide inhibitors specifically disrupting FXR-coactivator interaction in the intestine as a novel therapeutic strategy for MASH.Life metabolism · 2025Article
- The roles of nuclear receptors in cholesterol metabolism and reverse cholesterol transport in nonalcoholic fatty liver disease.Hepatology communications · 2024Review
- Expanding the Library of 1,2,4-Oxadiazole Derivatives: Discovery of New Farnesoid X Receptor (FXR) Antagonists/Pregnane X Receptor (PXR) Agonists.Molecules (Basel, Switzerland) · 2023Article
- The Farnesoid X Receptor as a Master Regulator of Hepatotoxicity.International journal of molecular sciences · 2022Review
- FX5, a non-steroidal glucocorticoid receptor antagonist, ameliorates diabetic cognitive impairment in mice.Acta pharmacologica Sinica · 2022Article
- Article
- FXR: structures, biology, and drug development for NASH and fibrosis diseases.Acta pharmacologica Sinica · 2022Review
- wSDTNBI: a novel network-based inference method for virtual screening.Chemical science · 2022Article
- Discovery of Orally Active and Nonsteroidal Farnesoid X Receptor (FXR) Antagonist with Propensity for Accumulation and Responsiveness in Ileum.ACS medicinal chemistry letters · 2021Article
- Farnesoid X receptor (FXR): Structures and ligands.Computational and structural biotechnology journal · 2021Review
- Article
- Investigation around the Oxadiazole Core in the Discovery of a New Chemotype of Potent and Selective FXR Antagonists.ACS medicinal chemistry letters · 2019Article
- Synthesis and biological evaluation of novel SIPI-7623 derivatives as farnesoid X receptor (FXR) antagonists.Molecular diversity · 2019Article
- Data on biosynthesis of BPAF glucuronide, enzyme kinetics of BPAF glucuronidation, and molecular modeling.Data in brief · 2019Article
- Irisin Is Controlled by Farnesoid X Receptor and Regulates Cholesterol Homeostasis.Frontiers in pharmacology · 2019Article
- Discovery of Novel Molecular Frameworks of Farnesoid X Receptor Modulators by Ensemble Machine Learning.ChemistryOpen · 2019Article
- 18β-Glycyrrhetinic acid protects against alpha-naphthylisothiocyanate-induced cholestasis through activation of the Sirt1/FXR signaling pathway.Acta pharmacologica Sinica · 2018Article
- Ranking docking poses by graph matching of protein-ligand interactions: lessons learned from the D3R Grand Challenge 2.Journal of computer-aided molecular design · 2018Article
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Farnesoid X receptor α (FXRα) as a bile acid sensor plays potent roles in multiple metabolic processes, and its antagonist has recently revealed special interests in the treatment of metabolic disorders, although the underlying mechanisms still remain unclear. Here, we identified that the small molecule N-benzyl-N-(3-(tert-butyl)-4-hydroxyphenyl)-2,6-dichloro-4-(dimethylamino) benzamide (NDB) functioned as a selective antagonist of human FXRα (hFXRα), and the crystal structure of hFXRα ligand binding domain (hFXRα-LBD) in complex with NDB was analyzed. It was unexpectedly discovered that NDB induced rearrangements of helix 11 (H11) and helix 12 (H12, AF-2) by forming a homodimer of hFXRα-LBD, totally different from the active conformation in monomer state, and the binding details were further supported by the mutation analysis. Moreover, functional studies demonstrated that NDB effectively antagonized the GW4064-stimulated FXR/RXR interaction and FXRα target gene expression in primary mouse hepatocytes, including the small heterodimer partner (SHP) and bile-salt export pump (BSEP); meanwhile, administration of NDB to db/db mice efficiently decreased the gene expressions of phosphoenolpyruvate carboxykinase (PEPCK), glucose 6-phosphatase (G6-pase), small heterodimer partner, and BSEP. It is expected that our first analyzed crystal structure of hFXRα-LBD·NDB will help expound the antagonistic mechanism of the receptor, and NDB may find its potential as a lead compound in anti-diabetes research.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.