國家衛生研究院 NHRI:Item 3990099045/5011

NHRI > Institute of Biotechnology and Pharmaceutical Research > Yu-Sheng Chao(2002-2013) > Periodical Articles > Item 3990099045/5011

Please use this identifier to cite or link to this item: http://ir.nhri.org.tw/handle/3990099045/5011

Title:	Structural basis for the improved potency of peroxisome proliferator-activated receptor (PPAR) agonists
Authors:	Peng, YH;Coumar, MS;Leou, JS;Wu, JS;Shiao, HY;Lin, CH;Lin, WH;Lien, TW;Chen, X;Hsu, JT;Chao, YS;Huang, CF;Lyu, PC;Hsieh, HP;Wu, SY
Contributors:	Division of Biotechnology and Pharmaceutical Research
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 PPARgamma 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 PPARgamma EC(50) of 10 nM. Compound 15 showed the most potent PPARgamma 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 PPARgamma; this could be due to the presence of the novel tail part 4-phenylbenzophenone, which could enhance the binding efficiency of 15 to PPARgamma.
Date:	2010-10
Relation:	ChemMedChem. 2010 Oct;5(10):1707-1716.
Link to:	http://dx.doi.org/10.1002/cmdc.201000194
JIF/Ranking 2023:	http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=1860-7179&DestApp=IC2JCR
Cited Times(WOS):	https://www.webofscience.com/wos/woscc/full-record/WOS:000283670200012
Cited Times(Scopus):	http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=77957687159
Appears in Collections:	[Yu-Sheng Chao(2002-2013)] Periodical Articles [John Tsu-An Hsu] Periodical Articles [Xin Chen(2002-2015)] Periodical Articles [Hsing-Pang Hsieh] Periodical Articles [Su-Ying Wu] Periodical Articles

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