Dept. of Chemistry and Biochemistry, Auburn University, Auburn, AL 36849, USA.
Bioorg Med Chem Lett. 2013 Feb 1;23(3):873-9. doi: 10.1016/j.bmcl.2012.11.060. Epub 2012 Dec 3.
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 PPARγ/δ agonists without the deleterious side effects associated with full PPARγ agonists. Docking simulations of 23 novel compounds within the ligand binding domain of PPARγ/δ 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 PPARγ/δ 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 PPARγ/δ agonist which did not display the deleterious side effects associated with full PPARγ agonists.
2 型糖尿病呈流行态势，因此开发新型药物疗法以提高胰岛素敏感性变得至关重要。本研究的目的是开发新型双重 PPARγ/δ 激动剂，而不具有与全 PPARγ 激动剂相关的有害副作用。使用 AutoDock Vina 在 PPARγ/δ 的配体结合域中对 23 种新型化合物进行了对接模拟，该模拟一致再现了已知 PPAR 激动剂的实验结合构象。使用其他对接程序 AutoDock 和 Surflex-Dock（来自 SYBYL-X）进行了比较和描述。通过转录启动子活性测定、已知 PPARγ/δ 靶基因的定量 PCR 基因分析以及与已知 PPAR 激动剂相比的脂质积累和线粒体生物发生的体外测定来完成化合物的生物学评估。我们发现在所评估的 23 种化合物中，有一种（化合物 9）是最有效和选择性的双重 PPARγ/δ 激动剂，它没有表现出与全 PPARγ 激动剂相关的有害副作用。
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