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羟基多溴代二苯醚与甲状腺素运载蛋白相互作用的3D-QSAR研究
引用本文:梁峰,穆云松,李会仙,冯承莲.羟基多溴代二苯醚与甲状腺素运载蛋白相互作用的3D-QSAR研究[J].生态毒理学报,2017,12(3):251-260.
作者姓名:梁峰  穆云松  李会仙  冯承莲
作者单位:1. 河南城建学院市政与环境工程学院,平顶山,467036;2. 中国环境科学研究院环境基准与风险评估国家重点实验室,北京,100012
基金项目:国家自然科学基金面上项目(41673087);河南省科技攻关计划项目(162102310389) ;河南省教育厅科学技术研究重点项目(14A610012)
摘    要:近年来,羟基多溴代二苯醚(OH-PBDEs)的类甲状腺素效应逐渐引起人们的关注,然而其结构效应关系和致毒机制尚不清楚。甲状腺激素结合球蛋白(TBG)和运甲状腺素蛋白(TTR)是人体转运甲状腺素的重要蛋白,通过计算毒理学手段可以揭示OH-PBDEs的微观毒理机制。利用分子对接技术研究OH-PBDEs与TBG、TTR的结合模式和构象特征,识别关键氢键氨基酸为赖氨酸Lys270(TBG),亮氨酸Leu110(TTR)和丝氨酸Ser117(TTR)。基于活性构象特征,构建14种典型OH-PBDEs的3D-QSAR模型,定量预测OH-PBDEs与TBG、TTR的结合亲和力。最佳预测模型的相关系数r2分别为0.966(TBG)和0.961(TTR),抽一法交叉验证相关系数q2分别为0.560(TBG)和0.525(TTR)。研究发现,OH-PBDEs的静电和氢键作用可增强结合亲和力,分别贡献65.4%(TBG)和68.7%(TTR)。研究结果为揭示OH-PBDEs与甲状腺素转运蛋白的相互作用提供新视角,有助于全面评价OH-PBDEs对人体甲状腺素调节功能的损伤。

关 键 词:羟基多溴代二苯醚  甲状腺素结合球蛋白  运甲状腺素蛋白  竞争抑制  比较分子场分析  比较相似性指数分析
收稿时间:2016/12/5 0:00:00
修稿时间:2017/1/23 0:00:00

3D-QSAR Study on Interactions between Hydroxylated PBDEs and Thyroid Hormones Transport Proteins
Liang Feng,Mu Yunsong,Li Huixian,Feng Chenglian.3D-QSAR Study on Interactions between Hydroxylated PBDEs and Thyroid Hormones Transport Proteins[J].Asian Journal of Ecotoxicology,2017,12(3):251-260.
Authors:Liang Feng  Mu Yunsong  Li Huixian  Feng Chenglian
Institution:1. School of Municipal and Environmental Engineering, Henan University of Urban Construction, Pingdingshan 467036, China 2. State Key Laboratory of Environmental Criteria and Risk Assessment, Chinese Research Academy of Environmental Sciences, Beijing 100012, China
Abstract:Hydroxylated polybrominated diphenyl ethers (OH-PBDEs) is a kind of emerging persistent organic pollutants that may interfere with regulating function of human thyroid hormone; however, the molecular mechanism behind remains unknown. In the present study, molecular docking was performed to explore the possible inhibition activity of OH-PBDEs to thyroxine-binding globulin (TBG) and transthyretin (TTR). Hydrogen bonding interaction was found to enhance the binding affinity of OH-PBDEs to these proteins through critical hydrogen bond amino acids of Lys270 (TBG), Leu110 (TTR) and Ser117 (TTR). Based on stimulated binding modes, the 3D-QSAR model on 14 OH-PBDEs, triiodothyronine (T3) and tyroxine (T4) was developed to predict binding affinities of OH-PBDEs to TBG and TTR. The optimal models from comparative molecular similarity index analysis (CoMSIA) were developed with r2 value of 0.966 (TBG) and 0.961 (TTR), and q2 value of 0.560 (TBG) and 0.525 (TTR). Electrostatic and hydrophobic field of OH-PBDEs account for 72% (TBG) and 68% (TTR) of binding affinities, respectively. These findings provide new insight into OH-PBDEs-TBG/TTR interactions, and will be conducive to evaluating damage of this type of chemicals to human health.
Keywords:OH-PBDEs  thyroxine-binding globulin  transthyretin  competitive inhibition  comparative molecular field analysis  comparative molecular similarity index analysis
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