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。
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.
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