Kar Supratik, Sepúlveda Maria S, Roy Kunal, Leszczynski Jerzy
Interdisciplinary Center for Nanotoxicity, Department of Chemistry and Biochemistry, Jackson State University, Jackson, MS, 39217, USA.
Department of Forestry and Natural Resources, Purdue University, West Lafayette, IN, 47907, USA.
Chemosphere. 2017 Oct;184:514-523. doi: 10.1016/j.chemosphere.2017.06.024. Epub 2017 Jun 9.
Exposure to perfluorinated and polyfluoroalkyl substances (PFCs/PFASs), endocrine disrupting halogenated pollutants, has been linked to various diseases including thyroid toxicity in human populations across the globe. PFASs can compete with thyroxine (T4) for binding to the human thyroid hormone transport protein transthyretin (TTR) which may lead to reduce thyroid hormone levels leading to endocrine disrupting adverse effects. Environmental fate and endocrine-disrupting activity of PFASs has initiated several research projects, but the amount of experimental data available for these pollutants is limited. In this study, experimental data for T4-TTR competing potency of 24 PFASs obtained in a radioligand-binding assay were modeled using classification- and regression-based quantitative structure-activity relationship (QSAR) tools with simple molecular descriptors obtained from chemical structure of these compounds in order to identify the responsible structural features and fragments of the studied PFASs for endocrine disruption activity. Additionally, docking studies were performed employing the crystal structure complex of TTR with bound 2', 6'-difluorobiphenyl-4-carboxylic acid (PDB: 2F7I) in order to constitute the receptor model for human TTR. The results corroborate evidence for these binding interactions and indicate multiple high-affinity modes of binding. The developed in silico models therefore advance our understanding of important structural attributes of these chemicals and may provide important information for the design of future synthesis of PFASs as well as may serve as an efficient query tool for virtual screening of large PFAS databases to check their endocrine toxicity profile.
接触全氟和多氟烷基物质（PFCs/PFASs）这种具有内分泌干扰作用的卤代污染物，已与包括全球人群甲状腺毒性在内的各种疾病相关联。PFASs可与甲状腺素（T4）竞争结合人类甲状腺激素转运蛋白甲状腺素运载蛋白（TTR），这可能导致甲状腺激素水平降低，从而产生内分泌干扰的不良影响。PFASs的环境归宿和内分泌干扰活性引发了多个研究项目，但这些污染物的实验数据量有限。在本研究中，利用基于分类和回归的定量构效关系（QSAR）工具，结合从这些化合物化学结构中获得的简单分子描述符，对在放射性配体结合试验中获得的24种PFASs的T4 - TTR竞争能力的实验数据进行建模，以确定所研究PFASs内分泌干扰活性的相关结构特征和片段。此外，利用TTR与结合的2', 6'-二氟联苯-4-羧酸的晶体结构复合物（PDB：2F7I）进行对接研究，以构建人类TTR的受体模型。结果证实了这些结合相互作用的证据，并表明存在多种高亲和力的结合模式。因此，所开发的计算机模型增进了我们对这些化学物质重要结构属性的理解，可能为未来PFASs的合成设计提供重要信息，也可作为一个有效的查询工具，用于对大型PFAS数据库进行虚拟筛选，以检查它们的内分泌毒性特征。
