Lab of Physical Chemistry, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, People's Republic of China.
School of Pharmacy, Shandong University, Jinan, 250012, People's Republic of China.
Food Funct. 2020 Apr 30;11(4):3043-3052. doi: 10.1039/c9fo03018b.
Two novel effective antioxidative tripeptides GWY and QWY were designed based on 3D-QSAR models. Their activities were confirmed by an improved TEAC assay. The experimental results showed that GWY and QWY possessed good antioxidant activity, equaling 3.32 mM TE and 2.97 mM TE respectively. This indicated that 3D-QSAR models possessed significant predictive capacity for drug design. In addition, molecular docking and molecular dynamics simulation were applied to reveal the potential molecular mechanism of antioxidant peptides. The result showed that GWY and QWY could enhance the stability of Keap1 by interacting with the key residues Arg415, Arg483, Arg380 and Ser555 in the active sites. Interestingly, the key residues were exactly the binding site of Nrf2 in the active pocket of Keap1. Thus, GWY and QWY could compete with Nrf2 for binding to Keap1. This demonstrated that the new tripeptides might have the ability to activate the signaling pathway Keap1-Nrf2-ARE and improve the antioxidant defense system of the body as well.
基于 3D-QSAR 模型设计了两种新型有效的抗氧化三肽 GWY 和 QWY。它们的活性通过改进的 TEAC 测定法得到证实。实验结果表明，GWY 和 QWY 具有良好的抗氧化活性，分别相当于 3.32 mM TE 和 2.97 mM TE。这表明 3D-QSAR 模型对药物设计具有重要的预测能力。此外，还应用分子对接和分子动力学模拟来揭示抗氧化肽的潜在分子机制。结果表明，GWY 和 QWY 可以通过与活性位点中的关键残基 Arg415、Arg483、Arg380 和 Ser555 相互作用来增强 Keap1 的稳定性。有趣的是，关键残基正是 Keap1 活性口袋中 Nrf2 的结合位点。因此，GWY 和 QWY 可以与 Nrf2 竞争与 Keap1 的结合。这表明新的三肽可能具有激活 Keap1-Nrf2-ARE 信号通路的能力，并改善身体的抗氧化防御系统。
