國家衛生研究院 NHRI:Item 3990099045/1109
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    題名: Structure-based drug design of a novel family of PPAR gamma partial agonists: Virtual screening, X-ray crystallography, and in vitro/in vivo biological activities
    作者: Lu, IL;Huang, CF;Peng, YH;Lin, YT;Hsieh, HP;Chen, CT;Lien, TW;Lee, HJ;Mahindroo, N;Prakash, E;Yueh, A;Chen, HY;Goparaju, CMV;Chen, X;Liao, CC;Chao, YS;Hsu, JTA;Wu, SY
    貢獻者: Division of Biotechnology and Pharmaceutical Research
    摘要: Peroxisome proliferator-activated receptor gamma ( PPAR gamma) is well-known as the receptor of thiazolidinedione antidiabetic drugs. In this paper, we present a successful example of employing structure-based virtual screening, a method that combines shape-based database search with a docking study and analogue search, to discover a novel family of PPAR gamma agonists based upon pyrazol-5-ylbenzenesulfonamide. Two analogues in the family show high affinity for, and specificity to, PPAR gamma and act as partial agonists. They also demonstrate glucose-lowering efficacy in vivo. A structural biology study reveals that they both adopt a distinct binding mode and have no H-bonding interactions with PPAR gamma. The absence of H-bonding interaction with the protein provides an explanation why both function as partial agonists since most full agonists form conserved H-bonds with the activation function helix (AF-2 helix) which, in turn, enhances the recruitment of coactivators. Moreover, the structural biology and computer docking studies reveal the specificity of the compounds for PPAR gamma could be due to the restricted access to the binding pocket of other PPAR subtypes, i.e., PPAR alpha and PPAR delta, and steric hindrance upon the ligand binding.
    關鍵詞: Chemistry, Medicinal
    日期: 2006-05-04
    關聯: Journal of Medicinal Chemistry. 2006 May;49(9):2703-2712.
    Link to: http://dx.doi.org/10.1021/jm051129s
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0022-2623&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000237343700006
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=33646449916
    顯示於類別:[伍素瑩] 期刊論文
    [岳嶽] 期刊論文
    [徐祖安] 期刊論文
    [謝興邦] 期刊論文
    [趙宇生(2002-2013)] 期刊論文
    [陳新(2002-2015)] 期刊論文
    [陳炯東] 期刊論文

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