title: Antidiabetic sulfonylureas modulate farnesoid X receptor activation and target gene transcription.
abstract: BACKGROUND
  The sulfonylureas glibenclamide and glimepiride are oral antidiabetic drugs that stimulate insulin secretion by closing pancreatic ATP-dependent potassium channels. The farnesoid X receptor (FXR) is a ligand-activated transcription factor that regulates the expression of several target genes involved in bile acid metabolism and lipid and glucose homeostasis.
  
  
  METHODS
  In this study we investigated the potential effects of sulfonylureas on the signaling of FXR using a reporter-gene assay, real-time qPCR and computational methods such as molecular docking and molecular dynamic simulations.
  
  
  RESULTS
  We demonstrate that glibenclamide and glimepiride modulate FXR activation in a reporter-gene assay and induce FXR target genes in HepG2 cells. Within the docking experiments and molecular dynamics simulation, we found glibenclamide interacting with the ligand-binding domain of FXR and with helix 12.
  
  
  CONCLUSIONS
  Glibenclamide and glimepiride are potential ligands of FXR and modulate activation and signaling.
authors.affiliation: Institute of Pharmaceutical Chemistry/ZAFES/LiFF, Goethe-University Frankfurt Max-von-Laue-Str. 9, D-60438 Frankfurt, Germany.
authors.forename: Ramona
authors.initials: R
authors.lastname: Steri
authors.forename: Mahmut
authors.initials: M
authors.lastname: Kara
authors.forename: Ewgenij
authors.initials: E
authors.lastname: Proschak
authors.forename: Dieter
authors.initials: D
authors.lastname: Steinhilber
authors.forename: Gisbert
authors.initials: G
authors.lastname: Schneider
authors.forename: Manfred
authors.initials: M
authors.lastname: Schubert-Zsilavecz
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D017930:Genes, Reporter; D005905:Glyburide / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D056945:Hep G2 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013453:Sulfonylurea Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D005905:Glyburide; D007004:Hypoglycemic Agents; D018160:Receptors, Cytoplasmic and Nuclear; D013453:Sulfonylurea Compounds; D000099150:Receptor, Farnesoid X-Activated; C057619:glimepiride