Identification of PPARγ ligands with one-dimensional drug profile matching

Diána Kovács, Zoltán Simon, Péter Hári, A. Málnási-Csizmadia, Csaba Hegedus, László Drimba, J. Németh, Réka Sári, Z. Szilvássy, Barna Peitl

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Introduction: 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. Materials and 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. Conclusion: 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.

Original languageEnglish
Pages (from-to)917-928
Number of pages12
JournalDrug Design, Development and Therapy
Volume7
DOIs
Publication statusPublished - Aug 30 2013

Fingerprint

nitazoxanide
PPAR gamma
Generic Drugs
Ligands
Pharmaceutical Preparations
Fatty Acid-Binding Proteins
Glucose Clamp Technique
Adipocytes
Computer Simulation
Chemical Databases
Pharmaceutical Databases
Insulin
Gene Expression
Cell Line
Proteins
Patents
Therapeutic Uses
United States Food and Drug Administration
Insulin Resistance
Blood Glucose

Keywords

  • Computer-aided prediction of receptor-ligand interaction
  • In silico lead selection
  • Insulin sensitizers
  • One-dimensional drug profle matching
  • Peroxisome proliferator activated receptor gamma
  • PPARγ
  • Type two diabetes

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Pharmacology
  • Drug Discovery

Cite this

Identification of PPARγ ligands with one-dimensional drug profile matching. / Kovács, Diána; Simon, Zoltán; Hári, Péter; Málnási-Csizmadia, A.; Hegedus, Csaba; Drimba, László; Németh, J.; Sári, Réka; Szilvássy, Z.; Peitl, Barna.

In: Drug Design, Development and Therapy, Vol. 7, 30.08.2013, p. 917-928.

Research output: Contribution to journalArticle

Kovács, Diána ; Simon, Zoltán ; Hári, Péter ; Málnási-Csizmadia, A. ; Hegedus, Csaba ; Drimba, László ; Németh, J. ; Sári, Réka ; Szilvássy, Z. ; Peitl, Barna. / Identification of PPARγ ligands with one-dimensional drug profile matching. In: Drug Design, Development and Therapy. 2013 ; Vol. 7. pp. 917-928.
@article{9706069f29f14c5a87cf22bf3a74134f,
title = "Identification of PPARγ ligands with one-dimensional drug profile matching",
abstract = "Introduction: 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. Materials and 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. Conclusion: 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.",
keywords = "Computer-aided prediction of receptor-ligand interaction, In silico lead selection, Insulin sensitizers, One-dimensional drug profle matching, Peroxisome proliferator activated receptor gamma, PPARγ, Type two diabetes",
author = "Di{\'a}na Kov{\'a}cs and Zolt{\'a}n Simon and P{\'e}ter H{\'a}ri and A. M{\'a}ln{\'a}si-Csizmadia and Csaba Hegedus and L{\'a}szl{\'o} Drimba and J. N{\'e}meth and R{\'e}ka S{\'a}ri and Z. Szilv{\'a}ssy and Barna Peitl",
year = "2013",
month = "8",
day = "30",
doi = "10.2147/DDDT.S47173",
language = "English",
volume = "7",
pages = "917--928",
journal = "Drug Design, Development and Therapy",
issn = "1177-8881",
publisher = "Dove Medical Press Ltd.",

}

TY - JOUR

T1 - Identification of PPARγ ligands with one-dimensional drug profile matching

AU - Kovács, Diána

AU - Simon, Zoltán

AU - Hári, Péter

AU - Málnási-Csizmadia, A.

AU - Hegedus, Csaba

AU - Drimba, László

AU - Németh, J.

AU - Sári, Réka

AU - Szilvássy, Z.

AU - Peitl, Barna

PY - 2013/8/30

Y1 - 2013/8/30

N2 - Introduction: 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. Materials and 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. Conclusion: 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.

AB - Introduction: 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. Materials and 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. Conclusion: 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.

KW - Computer-aided prediction of receptor-ligand interaction

KW - In silico lead selection

KW - Insulin sensitizers

KW - One-dimensional drug profle matching

KW - Peroxisome proliferator activated receptor gamma

KW - PPARγ

KW - Type two diabetes

UR - http://www.scopus.com/inward/record.url?scp=84884537448&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84884537448&partnerID=8YFLogxK

U2 - 10.2147/DDDT.S47173

DO - 10.2147/DDDT.S47173

M3 - Article

C2 - 24039401

AN - SCOPUS:84884537448

VL - 7

SP - 917

EP - 928

JO - Drug Design, Development and Therapy

JF - Drug Design, Development and Therapy

SN - 1177-8881

ER -