Structural basis for the improved potency of Peroxisome Proliferator-Activated Receptor (PPAR) agonists

Yi Hui Peng, Mohane Selvaraj Coumar, Jiun Shyang Leou, Jian Sung Wu, Hui Yi Shiao, Chia Hui Lin, Wen Hsing Lin, Tzu Wen Lien, Xin Chen, John T.A. Hsu, Yu Sheng Chao, Chien Fu Huang, Ping Chiang Lyu, Hsing Pang Hsieh, Su Ying Wu

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)


The need to develop safer and more effective antidiabetic drugs is essential owing to the growth worldwide of the diabetic population. Targeting the PPAR receptor is one strategy for the treatment of diabetes; the PPAR agonists rosiglitazone and pioglitazone are already on the market. Here we report the identification of a potent PPAR agonist, 15, whose PPARγ activation was more than 20 times better than that of rosiglitazone. Compound 15 was designed to incorporate an indole head with a carboxylic acid group, and 4-phenylbenzophenone tail to achieve a PPARγ EC50 of 10 nm. Compound 15 showed the most potent PPARγ agonist activity among the compounds we investigated. To gain molecular insight into the improved potency of 15, a structural biology study and binding energy calculations were carried out. Superimposition of the X-ray structures of 15 and agonist 10 revealed that, even though they have the same indole head part, they adopt different conformations. The head part of 15 showed stronger interactions toward PPARγ; this could be due to the presence of the novel tail part 4-phenylbenzophenone, which could enhance the binding efficiency of 15 to PPARγ.

Original languageEnglish
Pages (from-to)1707-1716
Number of pages10
Issue number10
Publication statusPublished - 2010 Oct 4

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

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