Quantitative Structure Activity Relationship Studies and Molecular Dynamics Simulations of 2-(Aryloxyacetyl)cyclohexane-1,3-Diones Derivatives as 4-Hydroxyphenylpyruvate Dioxygenase Inhibitors
Quantitative Structure Activity Relationship Studies and Molecular Dynamics Simulations of 2-(Aryloxyacetyl)cyclohexane-1,3-Diones Derivatives as 4-Hydroxyphenylpyruvate Dioxygenase Inhibitors
复制标题
2-(芳氧基乙酰基)环己烷-1,3-二酮衍生物作为4-羟基苯基丙酮酸双加氧酶抑制剂的定量结构活性关系研究和分子动力学模拟
DOI：
10.3389/fchem.2019.00556
复制
发表时间：
2019-08-20
影响因子：
5.5
通讯作者：
Ye, Fei
中科院分区：
文献类型：
--
作者：
Fu, Ying;Liu, Yong-Xuan;Ye, Fei
4-羟基苯基丙酮酸双加氧酶(HPPD)是生物合成植物质酚和生育酚的重要酶。此外，它也是开发新除草剂的潜在目标。计算机辅助药物设计(CADD)技术是高效发现新的HPPD抑制剂的有效工具。以43个已知活性的化合物为研究对象，建立了基于公共框架和分子对接的比较分子场分析(CoMFA)和比较分子相似指数分析(CoMSIA)模型。确定了结构对活性的贡献，为新型抑制剂的设计提供了进一步的信息。用分子对接的方法解释了配体与蛋白质结合方式引起的活性变化。分子动力学结果表明，静电能是配体-蛋白质相互作用的主要驱动力，其中Phe403对配体-蛋白质相互作用的贡献最大。本工作为合理设计具有更高活性的新型HPPD抑制剂提供了有用的信息。
4-Hydroxyphenylpyruvate dioxygenase (HPPD) is a significant enzyme in the biosynthesis of plastoquinone and tocopherol. Moreover, it is also a potential target to develop new herbicide. The technology of computer-aided drug design (CADD) is a useful tool in the efficient discovery of new HPPD inhibitors. Forty-three compounds with known activities were used to generate comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models based on common framework and molecular docking. The structural contribution to the activity was determined, which provided further information for the design of novel inhibitors. Molecular docking was used to explain the changes in activity caused by the binding mode between ligand and protein. The molecular dynamics (MD) results indicated that the electrostatic energy was the major driving force for ligand-protein interaction and the Phe403 made the greatest contribution to the binding. The present work has provided useful information for the rational design of novel HPPD inhibitors with improved activity.