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发布时间：2019-03-09

论文类型：期刊论文

发表时间：2010-05-01

发表刊物：ENVIRONMENTAL HEALTH PERSPECTIVES

收录刊物：Scopus、PubMed、SCIE

卷号：118

期号：5

页面范围：602-606

ISSN号：0091-6765

关键字：application domain; density functional theory; docking; HO-PBDEs; hydroxylated polybrominated diphenyl ethers; PBDEs; quantitative structure-activity relationship; thyroid hormone receptor

摘要：BACKGROUND: Hydroxylated polybrominated diphenyl ethers (HO-PBDEs) may disrupt thyroid hormone status because of their structural similarity to thyroid hormone. However, the molecular mechanisms of interactions with thyroid hormone receptors (TRs) are not fully understood.
   OBJECTIVES: We investigated the interactions between HO-PBDEs and TR beta to identify critical structural features and physico-chemical properties of HO-PBDEs related to their hormone activity, and to develop quantitative structure-activity relationship ( QSAR) models for the thyroid hormone activity of HO-PBDEs.
   METHODS: We used the recombinant two-hybrid yeast assay to determine the hormone activities to TR beta and molecular docking to model the ligand-receptor interaction in the binding site. Based on the mechanism of action, molecular structural descriptors were computed, selected, and employed to characterize the interactions, and finally a QSAR model was constructed. The applicability domain ( AD) of the model was assessed by Williams plot.
   RESULTS: The 18 HO-PBDEs tested exhibited significantly higher thyroid hormone activities than did PBDEs (p < 0.05). Hydrogen bonding was the characteristic interaction between HO-PBDE molecules and TR beta, and aromaticity had a negative effect on the thyroid hormone activity of HO-PBDEs. The developed QSAR model had good robustness, predictive ability, and mechanism interpretability.
   CONCLUSIONS: Hydrogen bonding and electrostatic interactions between HO-PBDEs and TR beta are important factors governing thyroid hormone activities. The HO- PBDEs with higher ability to accept electrons tend to have weak hydrogen bonding with TR beta and lower thyroid hormone activities.