Virtual Screening of Nrf2 Dietary-Derived Agonists and Safety by a New Deep-Learning Model and Verified In Vitro and In Vivo.
Virtual Screening of Nrf2 Dietary-Derived Agonists and Safety by a New Deep-Learning Model and Verified In Vitro and In Vivo.
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DOI：
10.1021/acs.jafc.3c00867
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发表时间：
2023-05
影响因子：
6.1
通讯作者：
Song Liu;Huanlong Qin;Xin-Ran Ji;Jian-Wen Gan;Meng-Jia Sun;Jin Tao;Zhuo-Qi Tao;Guang-Nian Zhao;Bing-Xin Ma
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文献类型：
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作者：
Song Liu;Huanlong Qin;Xin-Ran Ji;Jian-Wen Gan;Meng-Jia Sun;Jin Tao;Zhuo-Qi Tao;Guang-Nian Zhao;Bing-Xin Ma
核因子(红系2)样蛋白2(Nrf2)是抗氧化剂的重要调控靶点，但缺乏Nrf2活性部位的信息阻碍了通过大规模虚拟筛选从食品衍生化合物中发现新的Nrf2激动剂。两个深度学习模型分别接受了筛选Nrf2激动剂和安全性的培训。经过训练的模型在5分钟内从大约70,000种饮食化合物中筛选出潜在的活性化学物质。在通过深度学习筛选确定的169种潜在的Nrf2激动剂中，137种以前从未报道过。从新的NRF2激动剂中筛选出的6个化合物显著提高了NRF2在四氯化碳(CCl4)中毒的HepG2细胞中的活性(尼古丁(99.44±18.5%)、青蒿素(97.91±8.22%)、大豆苷(87.73±3.77%)、亚麻素(74.27±5.73%)、青蒿素(72.74±10.41%)和山茶素(77.78±4.80%)。尼古丁、青蒿素和大豆苷的安全性和Nrf2激动剂活性也通过单剂量急性经口毒性研究和CCl4中毒大鼠实验得到证实。
Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is an essential regulatory target of antioxidants, but the lack of Nrf2 active site information has hindered discovery of new Nrf2 agonists from food-derived compounds by large-scale virtual screening. Two deep-learning models were separately trained to screen for Nrf2-agonists and safety. The trained models screened potentially active chemicals from approximately 70,000 dietary compounds within 5 min. Of the 169 potential Nrf2 agonists identified via deep-learning screening, 137 had not been reported before. Six compounds selected from the new Nrf2 agonists significantly increased (p < 0.05) the activity of Nrf2 on carbon tetrachloride (CCl4)-intoxicated HepG2 cells (nicotiflorin (99.44 ± 18.5%), artemetin (97.91 ± 8.22%), daidzin (87.73 ± 3.77%), linonin (74.27 ± 5.73%), sinensetin (72.74 ± 10.41%), and tectoridin (77.78 ± 4.80%)), and their safety were demonstrated by an MTT assay. The safety and Nrf2 agonistic activity of nicotiflorin, artemetin, and daidzin were also reconfirm by a single-dose acute oral toxicity study and CCl4-intoxicated rat assay.