二噁英及其类似物的雄激素干扰效应的虚拟筛选和分子动力学模拟

Virtual screening and molecular dynamics simulation of androgen disrupting effects of dioxins and dioxin-like compounds

二噁英作为典型的环境污染物引发的内分泌干扰效应威胁着人类的健康,为了快速发现潜在的对人体雄激素有干扰效应的二噁英类似物(Dioxin-like compounds,DLCs)并研究其干扰机制,采用基于分子对接的虚拟筛选研究方法,建立雄激素受体(AR)的3个靶点蛋白2AX6、1T7T和6ULB的分子对接模型,并通过Autodock Vina程序进行虚拟筛选方法学研究.结果表明,2AX6靶点蛋白模型对引起雄激素干扰效应的二噁英类物质具有较强的富集能力,基于该模型对ZINC数据库进行虚拟筛选发现8个DLCs与靶点蛋白结合能值低于阈值-24.27 kJ·moL^(-1),且与毒性最强的二噁英化合物TCDD的结构高度相似,毒性预测发现其均具有潜在的雄激素干扰效应,其中4个与AR受体有强的相互作用;分子动力学模拟(Molecular Dynamics,MD)研究表明,DLCs与2AX6靶点蛋白主要通过与Arg752和Gln711氨基酸残基形成氢键及其他氨基酸残基的疏水作用稳定结合,形成的复合物体系的均方根偏差(Root mean square deviation, RMSD)值最终稳定在0.11~0.13 nm,与TCDD的雄激素干扰效应作用机制相似.研究对快速筛选潜在的环境内分泌干扰物与毒性评估提供了有益的探索.

Dioxin is a typical environmental pollutant which has endocrine disruption effects that threaten human health.In order to rapidly identify dioxin-like compounds(DLCs)with androgen disruption effects on humans and to study their disrupting mechanisms,a virtual screening research method based on molecular docking was used to establish molecular docking models of the three target proteins 2AX6,1T7T,and 6ULB of the androgen receptor(AR).The Autodock Vina program was used to conduct virtual screening methodological studies.The results showed that the 2AX6 target protein model had a strong enrichment ability for dioxins that caused androgen disruption effects.Based on the virtual screening of the ZINC database,it was discovered that 8 DLCs had binding energy values below the threshold value of-24.27 kJ·mol^(-1) and were strikingly structurally similar to the most toxic dioxin compound TCDD.The toxicity prediction found that all of them had androgen-disrupting effects,and 4 of them had powerful interactions with AR.Molecular dynamics studies have shown that DLCs were stably bound to the 2AX6 target protein mainly through hydrogen bonding with Arg752 and Gln711 amino acid residues and hydrophobic interactions with other amino acid residues.The root mean square deviation(RMSD)values of the complex system formed were ultimately stabilized between 0.11 nm and 0.13 nm,similar to the mechanism of action of TCDD’s androgen interference effect.The study provides useful exploration for the rapid screening and toxicity assessment of potential environmental endocrine disruptors.