PPARs泛激动剂设计、分子对接及分子动力学模拟研究  

Design, molecular docking and dynamics simulations of PPARs pan agonists

作　　者：张立松[1] 王树青[1] 王润玲[1] 程先超[1] 徐为人[2] 

机构地区：[1]天津医科大学药学院天津市临床药物关键技术重点实验室,天津300070 [2]天津药物研究院天津市新药设计与发现重点实验室,天津300193

出　　处：《天津医科大学学报》2013年第4期282-286,共5页Journal of Tianjin Medical University

基　　金：国家自然科学基金资助项目(81273361)

摘　　要：目的:得到治疗效果好,副作用小的PPAR泛激动剂。方法:用core hopping的方法对LY465608中间链部分和尾链部分进行结构替换。得到新的化合物并与3个蛋白质受体进行分子对接。应用分子动力学模拟先导化合物与PPAR-α、β、γ受体的相互作用情况。基于Lipinski’s rule of five,对得到的先导化合物进行ADME预测。结果:对接结果表明得到的目标化合物能与PPAR-α、β、γ活性位点区域的氨基酸残基形成氢键,使AF-2螺旋稳定于激活构象。分子动力学模拟结果表明模拟过程中受体与激动剂复合物体系是稳定的。ADME预测发现它们体内的吸收、分布、代谢和排泄情况符合作为药物的一般特点。结论:得到的8个化合物可以作为PPAR泛激动剂予以进一步的研究。Objective： To obtain the new PPAR pan agonist with better treatment and minimal side effects. Methods： The replacement of the middle and near parts of LY465608 was carried out by core hopping method, after which the obtained compounds were combined with 3 bags of protein receptor ligands. And then make it carry on molecular docking with the PPAR-α、β、γ receptor. Molecular dynamics was used to simulate of the interaction between target compounds and PPAR-α、β、γ receptor. ADME prediction was made for the new compounds obtained on the basis of Lipinski＇s rule of five. Results： The results of docking showed that target compounds were able to combine in the form of hydrogen bonds with amino acid residues of the PPAR-α、β、γ active site binding region, and that caused the AF-2 helix to stabilize in the activation conformation. Molecular dynamics results indicated that the receptor and the agonist compound＇s system were stable in simulation process. ADME prediction found that they were consistent with the drug characteristics in absorption, distribution, metabolism and excretion. Conclusion： The eight compounds acquired could be used as PPAR pan agonists and might be effective in the treatment of type 2 diabetes and metabolic syndrome.

关 键 词：PPARs泛激动剂 分子对接 分子动力学 ADME预测 

分 类 号：R914.2[医药卫生—药物化学]