School of Environmental Engineering, University of Seoul, 163 Seoulsiripdae-ro, Dongdaemun-gu, Seoul 02504, Korea.
Int J Mol Sci. 2019 Mar 10;20(5):1209. doi: 10.3390/ijms20051209.
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 (NHR-14 and NHR-69, respectively). In vivo validation was conducted on the selected EDCs with reproductive toxicity assay using wildtype N2, , and 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 as useful in the in vivo model for validating the in silico approach.
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。该方法有可能应用于发现不良结局途径框架中的分子起始事件（MIEs）。在这项研究中，我们旨在开发一种计算-体内联合方法作为识别潜在 MIEs 的工具。我们使用 Tox21 数据库中的环境化学品，通过分子对接模拟，分别使用线虫中的雌激素受体（ER）、雄激素受体（AR）及其同源模型（NHR-14 和 NHR-69）来识别潜在的内分泌干扰化学品（EDCs）。对于具有生殖毒性的选定 EDCs，我们使用野生型 N2、和功能丧失突变株进行了体内验证。这些化学品与测试受体具有高结合亲和力，并表现出高体内生殖毒性，使用突变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-体内联合方法有可能应用于识别 MIEs。本研究还表明，在体内模型中，作为验证计算方法的有用工具，具有潜力。
