| 罗连响,廖颖琳,王渠,等.基于计算机虚拟筛选发现具有抑制GPx4活性的海洋化合物[J].中国海洋药物,2022,41(5):1-12. |
| 基于计算机虚拟筛选发现具有抑制GPx4活性的海洋化合物 |
| Discovery of marine compounds with GPx4 inhibition based on computer virtual screening |
| 投稿时间：2021-07-27 修订日期：2021-11-04 |
| DOI： |
| 中文关键词: 铁死亡 GPx4 海洋化合物 虚拟筛选 分子动力学 |
| English Keywords:Ferroptosis, GPx4, molecular docking, marine compounds, Lipinski"s rule, virtual screening |
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| 中文摘要: |
| 目的：铁死亡是近年新发现的一种区别于凋亡、坏死、自噬和焦亡的细胞程序性死亡。其原理是诱发胞内铁离子积累，由此引发膜不饱和脂质过氧化并最终导致细胞死亡。谷胱甘肽过氧化物酶GPX4是一种能够清除过氧化物并降低细胞内ROS水平的蛋白酶，抑制GPX4的活性导致细胞铁死亡的发生，从而以更有效率地杀伤肿瘤细胞。 方法：使用Libdock软件对现有GPX4结构进行了虚拟筛选，对于Libdock得分最好的前100个海洋化合物，进一步根据利平斯基五规则（Lipinski"s Rule of Five）中的分子量限制条件进行筛选，得到了6个符合条件的海洋分子。然后借助CovDock功能对得分最佳的两个活性海洋分子进行了与蛋白的共价对接，并对这两个配体进行基于复合物药效团的药效特征分析以验证化合物与受体结合所需的关键性质。最后预测了全部六个海洋化合物的ADMET（吸收、分布、代谢、排泄和毒性）特性，以确定其成药特性。结果：海洋库中的两个分子被预测为具有最佳类药性质，因此被我们选作后续研究对象。对这两个化合物与GPx4形成复合物的分子动力学计算表明，它们与靶标的结合效果稳定。结论：本研究筛选出的两种海洋化合物可能是有效的GPx4抑制剂，为肿瘤的治疗提供新的候选化合物。 |
| English Summary: |
| OBJECTIVE:Ferroptosis is a newly discovered cell death mechanism in recent years, and the accumulation of intracellular iron triggers peroxidation of membrane unsaturated lipids, which induces an increase in intracellular ROS levels and eventually leads to cell death. This new mode of cell mortality has innovative and positive implications for the treatment of tumors. GPX4 is a protease capable of scavenging intracellular peroxides and decreasing intracellular ROS levels, and inhibition of GPX4 activity is beneficial to the occurrence of cellular ferroptosis. METHODS: A virtual screening of the available GPX4 structures was performed using Libdock software. For the top 100 marine compounds with the best Libdock scores, six eligible marine molecules were further screened according to the molecular weight restrictions in Lipinski"s Rule of Five (LRF). Then the two best scoring active marine molecules were covalently docked to proteins with the help of CovDock function and the two ligands were characterized for complex-based pharmacophore potency. Finally, the ADMET (absorption, distribution, metabolism, excretion and toxicity) properties of all six marine compounds were predicted to determine their drug-forming properties. RESULTS: Two molecules from the marine library were predicted to have the best drug-like properties and were therefore selected for our follow-up study. Molecular dynamics calculations for the formation of complexes of these two compounds with GPx4 showed that their binding to the targets was stable. CONCLUSION: The two newly identified marine compounds in this study exhibited better GPX4 binding activity, which may provide a reference for further development of ferroptosis inducers，and results in more efficient tumor targeting and killing. |
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