title: Investigation of imatinib and other approved drugs as starting points for antidiabetic drug discovery with FXR modulating activity.
abstract: A self-organizing map (SOM) is a virtual screening method used for correlation of molecular structure and potential biological activity on a certain target and offers a way to represent multi-dimensional data of large databases in a two-dimensional space. Large databases, for example the DrugBank database, provide information about biological activity and chemical structure of small molecules and are widely used in drug development for identification of new lead structures. The farnesoid X receptor (FXR) is a ligand activated transcription factor involved in key regulation mechanisms within glucose and lipid homeostasis. Although FXR became an established target in drug development for diseases associated with lipid, glucose or hepatic disorders during the last decade, none of the developed compounds have reached later phases of clinical development so far. We used a SOM trained with known FXR ligands to screen the DrugBank database for potential ligands for FXR. In this article, we report the successful identification of six approved drugs out of the Drugbank as FXR modulators (ketoconazole, pentamidine, dobutamine, imatinib, papaverine and montelukast) by using a SOM for screening of the DrugBank database. We show FXR modulation by selected compounds in a full length FXR transactivation assay and modulation of a FXR target gene by imatinib.
authors.affiliation: Institute of Pharmaceutical Chemistry, ZAFES/LiFF/Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt/Main, Germany.
authors.forename: Ramona
authors.initials: R
authors.lastname: Steri
authors.forename: Janosch
authors.initials: J
authors.lastname: Achenbach
authors.forename: Dieter
authors.initials: D
authors.lastname: Steinhilber
authors.forename: Manfred
authors.initials: M
authors.lastname: Schubert-Zsilavecz
authors.forename: Ewgenij
authors.initials: E
authors.lastname: Proschak
mesh_terms: D001483:Base Sequence; D001549:Benzamides; D045744:Cell Line, Tumor; D017931:DNA Primers; D055808:Drug Discovery; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology*; D000068877:Imatinib Mesylate; D050356:Lipid Metabolism; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects* / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001549:Benzamides; D017931:DNA Primers; D005947:Glucose; D007004:Hypoglycemic Agents; D000068877:Imatinib Mesylate; D010879:Piperazines; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated