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537882 
Journal Article 
The dipeptide H-Trp-Glu-OH shows highly antagonistic activity against PPAR gamma: Bioassay with molecular modeling simulation 
Ye, F; Zhang, ZS; Luo, HB; Shen, JH; Chen, KX; Shen, X; Jiang, HL 
2006 
Yes 
ChemBiochem
ISSN: 1439-4227
EISSN: 1439-7633 
7 
1 
74-82 
English 
16317783 
WOS:000234701000013 
The peroxisome proliferator-activated receptor gamma (PPAR gamma) is an important therapeutic drug target for several conditions, including diabetes, inflammation, dyslipidemia, hypertension, and cancer. It is shown that on antagonist or partial agonist of PPAR gamma has attractive potential applications in the discovery of novel antidiabetic agents that may retain efficacious insulin-sensitizing properties and minimize potential side effects. In this work, the dipeptide H-Trp-Glu-OH (G3335) was discovered to be a novel PPAR gamma antagonist. Biacore 3000 results based on the surface plasmon resonance (SPR) technique showed that G3335 exhibits a highly specific binding affinity against PPAR gamma (K-D= 8.34 mu M) and is able to block rosiglitazone, a potent PPAR gamma agonist, in the stimulation of the interaction between the PPAR gamma ligand-binding domain (LBD) and RXR alpha-LBD. Yeast two-hybrid assays demonstrated that G3335 exhibits strong antagonistic activity (IC50=8.67 mu M) in perturbing rosiglitazone in the promotion 1 of the PPAR gamma-LBD-CBP interaction. Moreover, in transactivation assays, G3335 was further confirmed as an antagonist of PPAR gamma in that G3335 could competitively bind to PPAR gamma against 0.1,mu M rosiglitazone to repress reporter-gene expression with an IC50 value of 31.9 mu M. In addition, homology modeling and molecular-docking analyses were performed to investigate the binding mode of PPAR gamma-LBD with G3335 at the atomic level. The results suggested that residues Cys285, Arg288, Ser289, and His449 in PPAR gamma ploy vital roles in PPAR gamma-LBD-G3335 binding. The significance of Cys285 for PPAR gamma-LBD-G3335 interaction was further demonstrated by PPAR gamma point mutation (PPAR gamma-LBD-Cys285Ala). It is hoped our current work will provide a powerful approach for the discovery of PPAR gamma antagonists, and that G3335 might be developed as a possible lead compound in diabetes research. 
antagonists; ligand binding; molecular modeling; PPAR; surface plasmon; resonance; yeast two-hybrid assay; activated receptor-gamma; inhibits adipocyte differentiation; ligand-binding; gene-expression; 15-deoxy-delta(12,14)-prostaglandin; j(2); orbital electronegativity; insulin-resistance; alpha; thiazolidinedione; discovery