高等学校化学学报 ›› 2018, Vol. 39 ›› Issue (2): 299-309.doi: 10.7503/cjcu20170402

• 物理化学 • 上一篇    下一篇

基于分子对接技术及CoMSIA/HQSAR辅助的二羟基多氯联苯衍生物分子修饰

辛美玲1,2, 褚振华1,2, 李鱼1,2()   

  1. 1. 华北电力大学环境科学与工程学院, 北京 102206
    2. 华北电力大学资源环境系统优化教育部重点实验室, 北京 102206
  • 收稿日期:2017-06-26 出版日期:2018-02-10 发布日期:2017-12-25
  • 作者简介:联系人简介: 李 鱼, 男, 博士, 教授, 博士生导师, 主要从事环境污染控制化学研究. E-mail: liyuxx@jlu.edu.cn
  • 基金资助:
    国家“十一五”科技支撑项目(批准号: 2008BAC43B01)和中央高校基金项目(批准号: JB2013146)资助

Molecular Modification of Polychlorinated Biphenyl Dihydroxy Derivatives Through Molecular Docking Associated with CoMSIA/HQSAR Models

XIN Meiling1,2, CHU Zhenhua1,2, LI Yu1,2,*()   

  1. 1. College of Environmental Science and Engineering,North China Electric Power University, Beijing 102206, China
    2. The Moe Key Laboratory of Resources and Environmental Systems Optimization,North China Electric Power University, Beijing 102206, China
  • Received:2017-06-26 Online:2018-02-10 Published:2017-12-25
  • Contact: LI Yu E-mail:liyuxx@jlu.edu.cn

摘要:

利用类二噁英类多氯联苯(PCBs)大气氧化降解产物二羟基多氯联苯与2,3-二羟基联苯双加氧酶(Bphc, PDB ID: 1KW6)进行分子对接, 构建以分子结构参数为自变量, 对接打分函数(Kd, 代表对接活性)为因变量的分子相似性指数分析(CoMSIA)与分子全息定量结构-活性相关关系(HQSAR)模型, 并对二羟基多氯联苯进行分子修饰, 研究结果表明, Bphc酶对二羟基多氯联苯均有不同程度的降解能力, 影响Bphc酶对接活性的氨基酸残基为His145, Val147, Ile174, His194, His208, His209, His240, Asn242, Tyr249及Thr280, 且二羟基多氯联苯与氨基酸残基对接形成的氢键越多对接活性越高. 建立了CoMSIA和HQSAR模型耦合的二羟基多氯联苯分子取代活性精确定位方法, 以打分函数较低的二羟基多氯联苯5,6-2OH-CB60为目标分子, 设计出8种打分函数显著提升的新型分子, 其对接活性提高65%~185%, 分子毒性(IC50)下降10%~83%, 生物富集性(BCF)下降4%~27%, 迁移性(KOA)与半衰期(t1/2)增降幅基本不变. 所设计新型分子反应路径的推断可以验证二羟基多氯联苯5,6-2OH-CB60在环境中与活性自由基或与活性分子反应生成所设计的新型5,6-2OH-CB60分子, 即类二噁英类PCBs可通过大气氧化降解最终生成酶降解性显著提高的新型二羟基多氯联苯, 达到进一步控制类二噁英类PCBs环境行为的目的.

关键词: 类二噁英类多氯联苯, 二羟基多氯联苯, Bphc酶, 分子对接, 分子相似性指数分数, 分子全息定量结构-活性相关关系

Abstract:

Molecular docking of dihydroxy polychlorinated biphenyls, which are atmospheric degradation products of dioxin-like polychlorinated biphenyls(PCBs), with dihydroxybiphenyl dioxygenase(Bphc, PDB ID: 1KW6) was studied, and the comparative molecular similarity indices analysis(CoMSIA) and the hologram quantitative structure-activity relationship(HQSAR) model were constructed, in which the molecular structure parameters as independent variables and total score(Kd, representing the docking activity) as the dependent variable, meanwhile, molecular modification of dihydroxy polychlorinated biphenyls was carried out. The results showed that Bphc enzymes can degrade all kinds of dihydroxy polychlorinated biphenyls in different degrees; the amino acid residues(His145, Val147, Ile174, His194, His208, His209, His240, Asn242, Tyr249, Thr280) affect the docking activity of Bphc enzyme, and also, more the hydrogen bond formed by the docking of dihydroxy polychlorinated biphenyls with amino acid residues, the higher the docking activity. A method for accurate determination of molecular substitution activity of dihydroxy polychlorinated biphenyls coupled with CoMSIA and HQSAR model was established. Based on the above, the 5,6-2OH-CB60 was as the target molecule, and eight novel molecules with improved scoring function were designed, whose docking activity increased 65%—185%, toxicity(IC50) decreased 10%—83%, bioaccumulation(BCF) decreased 4%—27%, migration(KOA) and half-life(t1/2) remained unchanged. The synthesis of the reaction pathways of novel molecules could confirm that the dihydroxy polychlorinated biphenyls 5,6-2OH-CB60 can react with active radicals and active molecules to form novel 5,6-2OH-CB60 molecules, which means the dioxin-like polychlorinated biphenyls can be degraded by atmospheric oxidation to produce a new type of two dihydroxy polychlorinated biphenyl whose enzyme degradation is remarkably improved, so as to further control the environmental behavior of dioxin-like PCBs.

Key words: Dioxin-like polychlorinated biphenyl(PCB), Dihydroxy polychlorinated biphenyl, Bphc, Molecular docking, Comparative molecular similarity indices analysis(CoMSIA), Hologram quantitative structureactivity relationship(HQSAR)

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