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Molecular Pharmacology

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Research ArticleArticle

Computer-Aided Discovery, Validation, and Mechanistic Characterization of Novel Neolignan Activators of Peroxisome Proliferator-Activated Receptor γ

Nanang Fakhrudin, Angela Ladurner, Atanas G. Atanasov, Elke H. Heiss, Lisa Baumgartner, Patrick Markt, Daniela Schuster, Ernst P. Ellmerer, Gerhard Wolber, Judith M. Rollinger, Hermann Stuppner and Verena M. Dirsch
Molecular Pharmacology April 2010, 77 (4) 559-566; DOI: https://doi.org/10.1124/mol.109.062141
Nanang Fakhrudin
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Angela Ladurner
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Atanas G. Atanasov
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Elke H. Heiss
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Lisa Baumgartner
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Patrick Markt
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Daniela Schuster
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Ernst P. Ellmerer
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Gerhard Wolber
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Judith M. Rollinger
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Hermann Stuppner
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Verena M. Dirsch
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Abstract

Peroxisome proliferator-activated receptor gamma (PPARγ) agonists are used for the treatment of type 2 diabetes and metabolic syndrome. However, the currently used PPARγ agonists display serious side effects, which has led to a great interest in the discovery of novel ligands with favorable properties. The aim of our study was to identify new PPARγ agonists by a PPARγ pharmacophore–based virtual screening of 3D natural product libraries. This in silico approach led to the identification of several neolignans predicted to bind the receptor ligand binding domain (LBD). To confirm this prediction, the neolignans dieugenol, tetrahydrodieugenol, and magnolol were isolated from the respective natural source or synthesized and subsequently tested for PPARγ receptor binding. The neolignans bound to the PPARγ LBD with EC50 values in the nanomolar range, exhibiting a binding pattern highly similar to the clinically used agonist pioglitazone. In intact cells, dieugenol and tetrahydrodieugenol selectively activated human PPARγ-mediated, but not human PPARα- or -β/δ-mediated luciferase reporter expression, with a pattern suggesting partial PPARγ agonism. The coactivator recruitment study also demonstrated partial agonism of the tested neolignans. Dieugenol, tetrahydrodieugenol, and magnolol but not the structurally related eugenol induced 3T3-L1 preadipocyte differentiation, confirming effectiveness in a cell model with endogenous PPARγ expression. In conclusion, we identified neolignans as novel ligands for PPARγ, which exhibited interesting activation profiles, recommending them as potential pharmaceutical leads or dietary supplements.

Footnotes

    fn-4
  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • fn-5
  • This work was supported by the Austrian Science Fund (FWF) [Grants NFN S10704-B03, S10702-B03, S10703-B03] and the Austrian Federal Ministry for Science and Research [Grants ACM-2007-00178, ACM-2008-00857, and ACM-2009-01206].

  • fn-6
  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.109.062141.

  • fn-7
  • ABBREVIATIONS:

    PPAR
    peroxisome proliferator-activated receptor
    RXR
    retinoid X receptor
    PPRE
    PPAR response element
    TZD
    thiazolidinedione
    LBD
    ligand binding domain
    h
    human
    3D
    three-dimensional
    DMEM
    Dulbecco's modified Eagle's medium
    GW7647
    2-(4-(2-(1-cyclohexanebutyl)-3-cyclohexylureido)ethyl)phenylthio)-2-methylpropionic acid
    GW0742
    4-[2-(3-fluoro-4-trifluoromethyl-phenyl)-4-methyl-thiazol-5-ylmethylsulfanyl]- 2-methyl-phenoxy}-acetic acid
    BADGE
    bisphenol A diglycidyl ether
    DMSO
    dimethyl sulfoxide
    TR-FRET
    time-resolved fluorescence resonance energy transfer
    EGFP
    enhanced green fluorescent protein
    PDB
    Protein Data Bank
    HEK
    human embryonic kidney
    MBX-102
    metaglidasen
    GST
    glutathione transferase.

    • Received November 6, 2009.
    • Accepted January 8, 2010.
  • Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 77 (4)
Molecular Pharmacology
Vol. 77, Issue 4
1 Apr 2010
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Research ArticleArticle

Computer-Aided Discovery, Validation, and Mechanistic Characterization of Novel Neolignan Activators of Peroxisome Proliferator-Activated Receptor γ

Nanang Fakhrudin, Angela Ladurner, Atanas G. Atanasov, Elke H. Heiss, Lisa Baumgartner, Patrick Markt, Daniela Schuster, Ernst P. Ellmerer, Gerhard Wolber, Judith M. Rollinger, Hermann Stuppner and Verena M. Dirsch
Molecular Pharmacology April 1, 2010, 77 (4) 559-566; DOI: https://doi.org/10.1124/mol.109.062141

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Research ArticleArticle

Computer-Aided Discovery, Validation, and Mechanistic Characterization of Novel Neolignan Activators of Peroxisome Proliferator-Activated Receptor γ

Nanang Fakhrudin, Angela Ladurner, Atanas G. Atanasov, Elke H. Heiss, Lisa Baumgartner, Patrick Markt, Daniela Schuster, Ernst P. Ellmerer, Gerhard Wolber, Judith M. Rollinger, Hermann Stuppner and Verena M. Dirsch
Molecular Pharmacology April 1, 2010, 77 (4) 559-566; DOI: https://doi.org/10.1124/mol.109.062141
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