Design, development and evaluation of novel dual PPARδ/PPARγ agonists
Design, development and evaluation of novel dual PPARδ/PPARγ agonists
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DOI：
10.1016/j.bmcl.2012.11.060
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发表时间：
2013-02-01
影响因子：
2.7
通讯作者：
Amin, Rajesh H.
中科院分区：
文献类型：
--
作者：
Gathiaka, Symon;Nanayakkara, Gayani;Amin, Rajesh H.
2型糖尿病处于流行比例，因此开发用于改善胰岛素敏感性的新型药物疗法已变得至关重要。本研究的目的是开发新型双重PPAR γ/δ激动剂，而没有与完全PPAR γ激动剂相关的有害副作用。使用AutoDock维纳对23种新型化合物在PPAR γ/δ的配体结合结构域内进行对接模拟，该模拟一致地再现了来自已知PPAR激动剂的实验结合姿势。与其他对接程序AutoDock和Surflex-Dock（来自SYBYL-X）进行比较并进行描述。化合物的生物学评价通过转录启动子活性测定、对已知的PPAR γ/δ靶点的定量PCR基因分析以及对脂质积累和线粒体生物发生与已知的PPAR激动剂的体外测定来完成。我们发现在所评价的23种化合物中有一种（化合物9）是最有效和选择性的双重PPAR γ/δ激动剂，其没有显示出与完全PPAR γ激动剂相关的有害副作用。(c)2012爱思唯尔有限公司版权所有。
Type 2 diabetes is at epidemic proportions and thus development of novel pharmaceutical therapies for improving insulin sensitivity has become of paramount importance. The objectives of the current study were to develop novel dual PPAR gamma/delta agonists without the deleterious side effects associated with full PPAR gamma agonists. Docking simulations of 23 novel compounds within the ligand binding domain of PPAR gamma/delta were performed using AutoDock Vina which consistently reproduced experimental binding poses from known PPAR agonists. Comparisons were made and described with other docking programs AutoDock and Surflex-Dock (from SYBYL-X). Biological evaluation of compounds was accomplished by transcriptional promoter activity assays, quantitative PCR gene analysis for known PPAR gamma/delta targets as well as in vitro assays for lipid accumulation and mitochondrial biogenesis verses known PPAR agonists. We found one (compound 9) out of the 23 compounds evaluated, to be the most potent and selective dual PPAR gamma/delta agonist which did not display the deleterious side effects associated with full PPAR gamma agonists. (c) 2012 Elsevier Ltd. All rights reserved.