ABSTRACT:

Flavones, natural compounds found in plant, are one of emerging endocrine disrupting chemicals, but little is known about potential inhibition of structurally diverse flavones towards human aldose reductase (hALR2). In the present study, three-dimensional quantitative structure-activity relationships (3D-QSARs) models, comparative molecular similarity indices analysis (CoMSIA) and comparative molecular field analysis (CoMFA) were established to explore the structural specificity and predicted inhibitory activity of 56 selected flavones to hALR2. Then the molecular similarity technique, based similarity on a molecule's shape, hydrogen bonding, and electrostatic properties, was used to distinguish these flavones into two classes. Forty-nine flavones in type Ⅰ had the same binding mode with the close-stated active binding site. But six flavones with bulky substituent in type Ⅱ were proved to interact with open-stated active binding site of the aldose reductase by flexible docking and molecular dynamic analysis. It also confirms that lack of hydrophobic contact with the active site may lead to significant activity decrease in spite of the strong hydrogen bond linkage between flavones and hALR2. Moreover, the conformation adaption of LEU300 leading to the opening of the second pocket of hALR2 resulted from the induced-fit effect of bulky substituent in flavones.

KEYWORDS: 3D-QSARs, flexible docking, two active sites, toxic mechanism, dynamic simulation

摘要: 黄酮类物质是天植物源化合物，也是一种新兴的内分泌干扰物。由于其结构多样，对人醛糖还原酶（hALR2）的抑制作用尚不清楚。本研究通过建立三维定量结构-活性相关（3D-QSARs）模型、比较分子相似性指数分析（CoMSIA）和比较分子场分析（CoMFA）模型，探索56种黄酮类物质对hALR2的诱导契合作用，进而定量预测其抑制活性。基于柔性分子对接和分子动力学模拟发现，Ⅰ型黄酮（49种）与闭合态（close-stated）的活性位点具有相同的结合模式；含有大空间位阻取代基的Ⅱ型黄酮（6种）与开放态（open-stated）的活性位点有较强的结合作用。这也证实了尽管黄酮类化合物和hALR2之间有很强的氢键连接，但与活性位点缺乏疏水接触可能会导致活性显著下降。此外，黄酮中大空间位阻取代基通过诱导关键氨基酸LEU300的构象改变引发hALR2第二活性位点的开启。

关键词: 三维QSAR，柔性对接，双活性位点，毒理机制，动力学模拟

原载于

Journal of Biomolecular Structure and Dynamics（2019 Impact Factor = 3.31）

原文链接：https://www.tandfonline.com/doi/full/10.1080/07391102.2019.1592023