The aryl hydrocarbon receptor (AhR), which is a ligand-dependent transcription factor, plays a crucial role in the regulation of xenobiotic metabolism. There are a large number of artificial or natural molecules in the environment that can activate AhR. In this study, we developed a virtual screening procedure to identify potential ligands of AhR. One structure-based method and two ligand-based methods were used for the virtual screening procedure. The results showed that the precision rate (0.96) and recall rate (0.64) of our procedure were significantly higher than those of a procedure used in a previous study, which suggests that supervised machine learning techniques can greatly improve the performance of virtual screening. Moreover, a pesticide dataset including 777 frequently used pesticides was screened. Seventy-seven pesticides were identified as potential AhR ligands by all three screening methods, among which 12 have never been previously reported as AhR agonists. Two non-agonist AhR ligands and 14 of the 77 pesticides were randomly selected for testing by in vitro and in vivo assays. All 14 pesticides showed different degrees of AhR agonistic activity, and none of the two non-agonist AhR ligand pesticides showed AhR agonistic activity, which suggests that our procedure had good robustness. Four of the pesticides were reported as AhR agonists for the first time, suggesting that these pesticides may need further toxicity assessment. In general, our procedure is a rapid, powerful and computationally inexpensive tool for predicting chemicals with AhR agonistic activity, which could be useful for environmental risk prediction and management.

芳烃受体（AhR）是一种依赖配体的转录因子，在异生物代谢的调节中起着至关重要的作用。环境中存在大量可以激活AhR的人工或天然分子。在这项研究中，我们开发了一种虚拟筛选程序来识别AhR的潜在配体。一种基于结构的方法和两种基于配体的方法用于虚拟筛选过程。结果表明，我们的程序的准确率（0.96）和查全率（0.64）明显高于先前研究中使用的程序，这表明有监督的机器学习技术可以大大提高虚拟筛选的性能。此外，筛选了包括777种常用农药的农药数据集。通过所有三种筛选方法，已将77种农药鉴定为潜在的AhR配体，其中12种以前从未被报告为AhR激动剂。随机选择2种非激动剂AhR配体和77种农药中的14种进行测试体外和体内测定。所有14种农药均显示出不同程度的AhR激动活性，而两种非激动剂AhR配体农药均未显示出AhR激动活性，这表明我们的方法具有良好的鲁棒性。首次将四种农药报告为AhR激动剂，这表明这些农药可能需要进一步的毒性评估。总的来说，我们的程序是一种快速，强大且计算上便宜的工具，可预测具有AhR激动活性的化学物质，对环境风险的预测和管理很有用。