title: Identification of PPARγ ligands with One-dimensional Drug Profile Matching.
abstract: BACKGROUND
  Computational molecular database screening helps to decrease the time and resources needed for drug development. Reintroduction of generic drugs by second medical use patents also contributes to cheaper and faster drug development processes. We screened, in silico, the Food and Drug Administration-approved generic drug database by means of the One-dimensional Drug Profile Matching (oDPM) method in order to find potential peroxisome proliferator-activated receptor gamma (PPARγ) agonists. The PPARγ action of the selected generics was also investigated by in vitro and in vivo experiments.
  
  
  METHODS
  The in silico oDPM method was used to determine the binding potency of 1,255 generics to 149 proteins collected. In vitro PPARγ activation was determined by measuring fatty acid-binding protein 4/adipocyte protein gene expression in a Mono Mac 6 cell line. The in vivo insulin sensitizing effect of the selected compound (nitazoxanide; 50-200 mg/kg/day over 8 days; n = 8) was established in type 2 diabetic rats by hyperinsulinemic euglycemic glucose clamping.
  
  
  RESULTS
  After examining the closest neighbors of each of the reference set's members and counting their most abundant neighbors, ten generic drugs were selected with oDPM. Among them, four enhanced fatty acid-binding protein/adipocyte protein gene expression in the Mono Mac 6 cell line, but only bromfenac and nitazoxanide showed dose-dependent actions. Induction by nitazoxanide was higher than by bromfenac. Nitazoxanide lowered fasting blood glucose levels and improved insulin sensitivity in type 2 diabetic rats.
  
  
  CONCLUSIONS
  We demonstrated that the oDPM method can predict previously unknown therapeutic effects of generic drugs. Nitazoxanide can be the prototype chemical structure of the new generation of insulin sensitizers.
authors.affiliation: Department of Pharmacology and Pharmacotherapy, University of Debrecen, Nagyerdei Boulevard 98, Debrecen, Hungary.
authors.forename: Diána
authors.initials: D
authors.lastname: Kovács
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Simon
authors.forename: Péter
authors.initials: P
authors.lastname: Hári
authors.forename: András
authors.initials: A
authors.lastname: Málnási-Csizmadia
authors.forename: Csaba
authors.initials: C
authors.lastname: Hegedűs
authors.forename: László
authors.initials: L
authors.lastname: Drimba
authors.forename: József
authors.initials: J
authors.lastname: Németh
authors.forename: Réka
authors.initials: R
authors.lastname: Sári
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Szilvássy
authors.forename: Barna
authors.initials: B
authors.lastname: Peitl
mesh_terms: D000818:Animals; D001577:Benzophenones / Q000008:administration & dosage / Q000494:pharmacology; D001786:Blood Glucose / Q000187:drug effects; D001969:Bromobenzenes / Q000008:administration & dosage / Q000494:pharmacology; D045744:Cell Line, Tumor; D003198:Computer Simulation; D062313:Databases, Pharmaceutical; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D016568:Drugs, Generic / Q000008:administration & dosage / Q000494:pharmacology*; D015309:Glucose Clamp Technique; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008024:Ligands; D008297:Male; D009574:Nitro Compounds; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D001577:Benzophenones; D001786:Blood Glucose; D001969:Bromobenzenes; D016568:Drugs, Generic; D007328:Insulin; D008024:Ligands; D009574:Nitro Compounds; D047495:PPAR gamma; D013844:Thiazoles; C053083:bromfenac; C041747:nitazoxanide
keywords: PPARγ; computer-aided prediction of receptor-ligand interaction; in silico lead selection; insulin sensitizers; one-dimensional drug profile matching; peroxisome proliferator activated receptor gamma; type two diabetes
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