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
↵ The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.
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].
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
doi:10.1124/mol.109.062141.
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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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