Molecular dynamics study-guided identification of cyclic amine structures as novel hydrophobic tail components of hPPARγ agonists.
Molecular dynamics study-guided identification of cyclic amine structures as novel hydrophobic tail components of hPPARγ agonists.
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分子动力学研究引导鉴定环胺结构作为 hPPARγ 激动剂的新型疏水尾部成分。
DOI：
10.1016/j.bmcl.2014.06.023
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发表时间：
2014
影响因子：
2.7
通讯作者：
H. Miyachi.
中科院分区：
文献类型：
--
作者：
Y. Tanaka;K. Gamo;T. Oyama;M. Ohashi;M. Waki;K. Matsuno;N. Matsuura;H. Tokiwa;H. Miyachi.
我们之前报道过，以哌啶环作为疏水性尾部的α-苄基苯丙酸型hPPARγ选择性激动剂（3）表现出亚微摩尔级的hPPARγ激动活性。为了增强活性，我们计划基于从与3复合的hPPARγ配体结合结构域（LBD）的X射线晶体结构获得的信息进行结构开发。然而，由于LBD的Ω环结构不清楚，因此不能精确描述3哌啶环周围结合口袋的形状和/或性质。因此，我们通过分子动力学模拟构建并插入了一个合理的omega环。然后，我们使用重建的LBD结构来设计新的单环、双环和三环的含胺化合物，这些化合物可能预期对LBD显示出更大的结合亲和力。在这里，我们描述了α-苄基苯丙酸衍生物的合成和评价8。与预期的一样，大多数新合成的化合物显示出更强的hPPARγ激动活性和更大的hPPARγ结合亲和力。这些化合物中的一些也显示出与3相当的水溶性。
We previously reported that a α-benzylphenylpropanoic acid-type hPPARγ-selective agonist with a piperidine ring as the hydrophobic tail part (3) exhibited sub-micromolar-order hPPARγ agonistic activity. In order to enhance the activity, we planned to carry out structural development based on information obtained from the X-ray crystal structure of hPPARγ ligand binding domain (LBD) complexed with3. However, the shape and/or nature of the binding pocket surrounding the piperidine ring of3could not be precisely delineated because the structure of the omega loop of the LBD was poorly defined. Therefore, we constructed and inserted a plausible omega loop by means of molecular dynamics simulation. We then used the reconstructed LBD structure to design new mono-, bi- and tricyclic amine-bearing compounds that might be expected to show greater binding affinity for the LBD. Here, we describe synthesis and evaluation of α-benzylphenylpropanoic acid derivatives8. As expected, most of the newly synthesized compounds exhibited more potent hPPARγ agonistic activity and greater hPPARγ binding affinity than3. Some of these compounds also showed comparable aqueous solubility to3.