標題: Structural Basis for the Improved Potency of Peroxisome Proliferator-Activated Receptor (PPAR) Agonists
作者: Peng, Yi-Hui
Coumar, Mohane Selvaraj
Leou, Jiun-Shyang
Wu, Jian-Sung
Shiao, Hui-Yi
Lin, Chia-Hui
Lin, Wen-Hsing
Lien, Tzu Wen
Chen, Xin
Hsu, John T. -A.
Chao, Yu-Sheng
Huang, Chien-Fu
Lyu, Ping-Chiang
Hsieh, Hsing-Pang
Wu, Su-Ying
生物科技學系
Department of Biological Science and Technology
關鍵字: diabetes;PPAR agonists;structural biology;structure-activity relationships
公開日期: 4-十月-2010
摘要: 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 PPAR gamma 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 PPAR gamma EC(50) of 10 nm. Compound 15 showed the most potent PPAR gamma 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 PPAR gamma; this could be due to the presence of the novel tail part 4-phenylbenzophenone, which could enhance the binding efficiency of 15 to PPAR gamma.
URI: http://dx.doi.org/10.1002/cmdc.201000194
http://hdl.handle.net/11536/32085
ISSN: 1860-7179
DOI: 10.1002/cmdc.201000194
期刊: CHEMMEDCHEM
Volume: 5
Issue: 10
起始頁: 1707
結束頁: 1716
顯示於類別:期刊論文