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http://ir.nhri.org.tw/handle/3990099045/1109
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| Title: | 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 |
| Authors: | 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 |
| Contributors: | Division of Biotechnology and Pharmaceutical Research |
| Abstract: | 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. |
| Keywords: | Chemistry, Medicinal |
| Date: | 2006-05-04 |
| Relation: | 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 |
| Appears in Collections: | [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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| 000237343700006.pdf | | 612Kb | Adobe PDF | 1045 | View/Open |
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