分子对接用于分析靶标与其配体的结构复合物,以了解靶标特异性的化学和结构基础。该方法有可能用于在不良结果途径框架中发现分子启动事件(MIE)。在这项研究中,我们的目标是开发计算机体内联合方法,作为识别潜在MIE的工具。我们使用来自Tox21数据库的环境化学物质通过分子对接模拟来识别潜在的内分泌干扰化学物质(EDCs)。使用雌激素受体(ER),线虫秀丽隐杆线虫中的雄激素受体(AR)及其同源性模型(分别为NHR-14和NHR-69)。使用野生型N2、nhr-14和nhr-69功能丧失突变菌株,用秀丽隐杆线虫生殖毒性测定对选择的EDC进行体内验证。这些化学物质对测试的受体显示出高的结合亲和力,并显示出高的体内生殖毒性,使用突变菌株进一步证实了这一点。本研究表明,分子对接的结合亲和力可能与体内毒性相关。这些结果证明,我们的计算机体内结合方法具有用于识别MIE的潜力。该研究还表明秀丽隐杆线虫在体内模型中用于验证计算机模拟方法的潜力。
Molecular docking is used to analyze structural complexes of a target with its ligand for understanding the chemical and structural basis of target specificity. This method has the potential to be applied for discovering molecular initiating events (MIEs) in the Adverse Outcome Pathway framework. In this study, we aimed to develop in silico⁻in vivo combined approach as a tool for identifying potential MIEs. We used environmental chemicals from Tox21 database to identify potential endocrine-disrupting chemicals (EDCs) through molecular docking simulation, using estrogen receptor (ER), androgen receptor (AR) and their homology models in the nematode Caenorhabditis elegans (NHR-14 and NHR-69, respectively). In vivo validation was conducted on the selected EDCs with C. elegans reproductive toxicity assay using wildtype N2, nhr-14, and nhr-69 loss-of-function mutant strains. The chemicals showed high binding affinity to tested receptors and showed the high in vivo reproductive toxicity, and this was further confirmed using the mutant strains. The present study demonstrates that the binding affinity from the molecular docking potentially correlates with in vivo toxicity. These results prove that our in silico⁻in vivo combined approach has the potential to be applied for identifying MIEs. This study also suggests the potential of C. elegans as useful in the in vivo model for validating the in silico approach.