Virtual Screening of GPX4 Agonists in the Active Ingredients of Artemisia Annua
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摘要: 谷胱甘肽过氧化物酶4(GPX4)是一种能够特异性催化谷胱甘肽将脂质过氧化物转化为类脂醇的硒蛋白，其表达量上调在抑制细胞铁死亡以及相关炎症反应中发挥着重要的作用。为了在青蒿成分中筛选出激动GPX4的潜在活性小分子，首先在“中药系统药理学数据库与分析平台(TCMSP)”检索得到126个青蒿活性小分子；然后，通过类药性筛选出50个青蒿活性小分子；其次，采用GPX4-配体对接模拟和GPX4-配体互作模式对比筛选出8个青蒿活性小分子；继而通过GPX4-配体结合自由能计算分析筛选，发现artemisinin(ARS)、patuletin、kaempferol与阳性对照物1d4(PKUMDL-LC-101-D03)的作用方式相似；最后，进行分子动力学模拟。结果显示：ARS、patuletin、kaempferol、阳性对照物1d4可与GPX4形成稳定性较强的复合物。Abstract: Glutathione peroxidase 4(GPX4) is a selenoprotein that can specifically catalyze the conversion of glutathione from lipid peroxides to lipid alcohols. Up-regulation of GPX4 expression plays an important role in inhibiting ferroptosis and related inflammation. In order to screen out the potential active small molecules that can activate glutathione peroxidase 4(GPX4) from Artemisia annua, 126 active small molecules of Artemisia annua were firstly retrieved from the Traditional Chinese Medicine System Pharmacology Database and Analysis Platform and 50 active small molecules of Artemisia annua were screened out according to drug-like properties. Further, 8 active small molecules of Artemisia annua were screened out through GPX4-ligand docking simulation and GPX4-ligand inte-raction pattern. Analysis and screening with GPX4-ligand free binding energy calculation found that artemisinin, patuletin and kaempferol acted similarly to the positive control 1d4(PKUMDL-LC-101-D03). Finally, molecular dynamics simulation was performed. The results showed that artemisinin, patuletin, kaempferol and the positive control 1d4 can form a stable complex with GPX4.
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Keywords:
- GPX4 /
- Ferroptosis /
- Artemisia annua /
- virtual screening /
- agonist
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图 2 GPX4的SiteMap分析
注：图中连贯条状为GPX4二级结构，而无规则曲面为其活性口袋，其中红色区域代表氢键受体结构，紫色区域代表氢键供体结构，黄色区域为疏水结构。
Figure 2. The SiteMap analysis of GPX4
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图 3 阳性对照物1d4、patuletin、kaempferol、ARS在活性口袋的作用方式
Figure 3. The mode of action of the positive control 1d4, patuletin, kaempferol and ARS in the active pocket of GPX4
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图 5 分子动力模拟蛋白-配体作用方式
注：作用方式持续时间占比=作用方式持续时间/50 ns。
Figure 5. The molecular dynamics simulating protein-ligand interaction
表 1 配体在GPX4活性口袋内的作用方式
Table 1 The mode of action of the ligand in the active pocket of GPX4
化合物 结构式 Docking score/(kcal/mol) 经典氢键 碳氢键 范德华力 盐桥 疏水作用 1d4 
-5.140 PHE100、LYS31、
ASP21、ASP23HIS25 ILE22、VAL27、LYS99、
MET102ASP21、
ASP23HIS25、LYS90、
ALA93、ALA94、
VAL98、ASP101ARS 
-4.896 MET102 LYS90、
PHE100ASP21、ILE22、ALA93、
LYS99、ASP101— ALA94、VAL98 patuletin 
-5.858 ASP21、ASP23、
LYS31、VAL98、
ASP101— ILE22、HIS25、VAL27、
LYS90、ALA93、ALA94、
LYS99、MET102— — kaempferol 
-6.384 ASP21、ASP23、
LYS31、VAL98、
ASP101— ILE22、HIS25、LYS90、
LYS99、PHE100、MET102— — isofraxidin 
-5.201 ASP101、MET102 LYS99 ASP21、ILE22、ASP23、
LYS90、ALA93、ALA94、
VAL98、LYS99、PHE100— — naringenin 
-5.661 ASP21、LYS90 — ILE22、ASP23、VAL27、
LYS31、ALA93、ALA94、
VAL98、LYS99、PHE100、
ASP101、MET102— LYS90 naringenin 
-5.269 ASP31、LYS90 — ILE22、ASP23、HIS25、
VAL27、LYS31、ALA93、
ALA94、VAL98、LYS99、
PHE100、ASP101、MET102— LYS90 apigenin 
-5.272 LYS31、VAL98 — ASP21、ILE22、ASP23、
HIS25、VAL27、LYS90、
LYS99、PHE100、ASP101、— LYS31、MET102、
PHE103quercetin 
-5.767 ASP21、LYS90、
ASP101— ILE22、ASP23、HIS25、
VAL27、LYS31、TYR32、
ALA93、ALA94、VAL98、
LYS99、MET102— LYS90 注：“—”表示该化合物不存在此作用方式。 
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表 2 配体在GPX4复合物体系的结合自由能
Table 2 The MM-GBSA free energy of ligands bound to GPX4
kcal/mol 化合物 ΔGbinda ΔGbindvdWb ΔGbind Coulombc ΔGbind Lipod ΔGbind Covalente ΔGbind Hbondf ΔGbind solvGBg 1d4 -42.655 -36.868 -17.917 -9.142 1.615 -3.000 22.657 ARS -33.703 -31.396 -5.863 -5.122 0.368 0.519 7.791 patuletin -38.922 -25.133 -31.058 -7.826 2.540 -4.441 26.996 kaempferol -36.081 -25.176 -22.284 -8.290 1.472 -3.424 21.621 isofraxidin -25.993 -28.539 -4.734 -6.832 2.139 -0.951 12.924 naringenin -30.814 -24.539 -28.194 -4.372 5.761 -2.333 22.863 naringenin -29.521 -22.923 -27.887 -4.152 5.712 -2.067 21.796 apigenin -20.291 -32.466 -8.470 -6.174 4.839 -0.934 22.914 quercetin -30.952 -28.077 -20.063 -6.383 3.591 -2.597 22.577 注：表中化合物的结构顺序与表 1一致。a表示自由结合能；b表示范德华力对自由结合能的影响；c表示共价键能对自由结合能的影响；d表示亲脂性结合能对自由结合能的影响；e表示库伦能对自由结合能的影响；f表示氢键键能对自由结合能的影响；g表示静电溶剂化能对自由结合能的影响。
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