National & Local Joint Engineering Research Centre of High-Throughput Drug Screening Technology, Hubei Key Laboratory of Biotechnology of Traditional Chinese Medicine, State Key Laboratory of Biocatalysis and Enzyme Engineering, School of Life Sciences, Hubei University, Wuhan 430062, China.
College of Chemistry and Chemical Engineering, Hubei University, Wuhan 430062, China.
Mar Drugs. 2022 Mar 4;20(3):191. doi: 10.3390/md20030191.
Oxidative stress has been implicated in the etiology of Parkinson's disease (PD). Molecules non-covalently binding to the Keap1-Nrf2 complex could be a promising therapeutic approach for PD. Herein, two novel prenylated indole alkaloids asperpenazine (), and asperpendoline () with a scarce skeleton of pyrimido[1,6-]indole were discovered from the co-cultivated fungi of MCCC 3A00521 and sp. HUBU 0120. Compound exhibited potential neuroprotective activity on SH-SY5Y cells against oxidative stress. Molecular mechanism research demonstrated that inhibited Keap1 expression, resulting in the translocation of Nrf2 from the cytoplasm to the nucleus, activating the downstream genes expression of HO-1 and NQO1, leading to the reduction in reactive oxygen species (ROS) and the augment of glutathione. Molecular docking and dynamic simulation analyses manifested that interacted with Keap1 (PDB ID: 1X2R) via forming typical hydrogen and hydrophobic bonds with residues and presented less fluctuation of RMSD and RMSF during a natural physiological condition.
氧化应激与帕金森病 (PD) 的病因有关。与 Keap1-Nrf2 复合物非共价结合的分子可能是治疗 PD 的一种有前途的方法。本文从 MCCC 3A00521 和 sp. HUBU 0120 的共培养真菌中发现了两种新型的被prenylated 吲哚生物碱asperpenazine () 和 asperpendoline ()，它们具有罕见的嘧啶并[1,6-]吲哚骨架。化合物 对氧化应激的 SH-SY5Y 细胞表现出潜在的神经保护活性。分子机制研究表明， 抑制 Keap1 的表达，导致 Nrf2 从细胞质易位到细胞核，激活 HO-1 和 NQO1 的下游基因表达，从而减少活性氧 (ROS) 和增加谷胱甘肽。分子对接和动态模拟分析表明， 通过与残基形成典型的氢键和疏水键与 Keap1 (PDB ID: 1X2R) 相互作用，并在自然生理条件下表现出较小的 RMSD 和 RMSF 波动。
