1. Structural Basis for the Improved Potency of Peroxisome Proliferator-Activated Receptor (PPAR) Agonists
- Author
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John T.A. Hsu, Tzu Wen Lien, Xin Chen, Jiun Shyang Leou, Chia Hui Lin, Yi Hui Peng, Wen-Hsing Lin, Jian Sung Wu, Chien Fu Huang, Yu-Sheng Chao, Hsing Pang Hsieh, Su Ying Wu, Hui Yi Shiao, Mohane Selvaraj Coumar, and Ping-Chiang Lyu
- Subjects
Agonist ,medicine.medical_specialty ,Indoles ,medicine.drug_class ,Population ,Peroxisome proliferator-activated receptor ,Pharmacology ,Crystallography, X-Ray ,Biochemistry ,PPAR agonist ,Benzophenones ,Structure-Activity Relationship ,Internal medicine ,Drug Discovery ,medicine ,General Pharmacology, Toxicology and Pharmaceutics ,education ,Receptor ,Indole test ,chemistry.chemical_classification ,education.field_of_study ,Binding Sites ,Indoleacetic Acids ,Organic Chemistry ,Hydrogen Bonding ,Protein Structure, Tertiary ,PPAR gamma ,Endocrinology ,chemistry ,Drug Design ,Thermodynamics ,Molecular Medicine ,Thiazolidinediones ,Rosiglitazone ,Pioglitazone ,medicine.drug - Abstract
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 EC(50) 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.
- Published
- 2010