可电离内分泌干扰物与运甲状腺素蛋白相互作用的计算模拟与验证

项目名称： 可电离内分泌干扰物与运甲状腺素蛋白相互作用的计算模拟与验证

项目编号： No.21507038

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 化学工业

项目作者： 杨先海

作者单位： 生态环境部南京环境科学研究所

项目金额： 22万元

中文摘要： -OH, -COOH等可电离基团是许多内分泌干扰物(EDCs)的重要分子结构特征，然而以往的研究，忽视了含这些基团的化合物在生物体液或实验pH条件下可能发生电离的事实。最近，申请人研究了酚类化合物与运甲状腺素蛋白(TTR)的作用机制，发现该体系具有形态依赖性，且阴离子形态的酚类化合物与TTR的作用强于其对应的分子形态。而含-COOH, -SO3H, -SO2H, -SH等基团的EDCs与内分泌系统生物大分子的作用机制是否也存在形态依赖性是有待进一步揭示的重要科学问题。因此，本项目拟选择含-COOH, -SO3H, -SO2H, -SH等官能团的苯基EDCs为模型化合物及TTR为模型体系，运用体外试验和分子模拟技术相结合的方法，系统研究不同形态EDCs与TTR的相互作用，揭示不同形态EDCs与TTR的分子作用机制，构建运甲状腺素蛋白干扰物的筛选方法，为进一步筛查潜在运甲状腺素蛋白提供技术。

中文关键词： 内分泌干扰物；计算毒理学；虚拟筛选方法；可电离化合物；运甲状腺素蛋白

英文摘要： The ionizable groups e.g.-OH, -COOH in endocrine disrupting chemicals (EDCs) are key structure alert for tight binding to macromolecule in endocrine system. However, all of the previous studies lose sight of the fact that the ionizable groups can ionize under physiological or experimental pH conditions. Recently, we probed the mechanisms between phenolic compounds and TTR. The results indicated that the binding potency between phenolic compounds and TTR depends on the chemical forms, and the anionic forms of phenolic compounds bind stronger with TTR than that of the neutral forms. It is unclear whether the binding potency between the EDCs with -COOH, -SO3H, -SO2H, -SH groups and macromolecular targets also depends on the chemical forms. In this study, ionizable EDCs with -COOH, -SO3H, -SO2H, -SH groups and TTR were selected as a model system and the in vitro assay integrated with molecular modeling methods were employed to reveal the different binding mechanisms for the neutral and anionic forms of selected ionizable EDCs with TTR, and to develop mechanism-based screening methods for virtual screening potential TTR disruptors.

英文关键词： Endocrine disrupting chemicals;Computational toxicology;Virtual screening methods;Ionizable Compounds;Transthyretin