國家衛生研究院 NHRI:Item 3990099045/5011
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    题名: Structural basis for the improved potency of peroxisome proliferator-activated receptor (PPAR) agonists
    作者: 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
    贡献者: Division of Biotechnology and Pharmaceutical Research
    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 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.
    日期: 2010-10
    關聯: 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
    显示于类别:[趙宇生(2002-2013)] 期刊論文
    [徐祖安] 期刊論文
    [陳新(2002-2015)] 期刊論文
    [謝興邦] 期刊論文
    [伍素瑩] 期刊論文

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