基于网络药理学和分子对接探讨骆驼蓬种子抗肝癌作用机制

doi:10.5246/jcps.2022.07.045

摘要/Abstract

摘要：

骆驼蓬(Peganum harmala L.)是一种药用植物, 其种子在中国西北地区长期被用于治疗胃肠道癌症和疟疾。本研究拟采用网络药理学和分子对接的方法, 探讨骆驼蓬种子(Peganum harmala L. seeds, PHS)对肝癌(hepatocellular carcinoma, HCC)的潜在分子靶点和药理机制。首先, 从TCMID和BATMAN-TCM数据库中获取PHS的化学成分, 并通过SwissADME数据库筛选有效成分。此外, 从PharmMapper和SwissTargetPrediction数据库中获取有效成分的靶点信息。其次, 从Liverome、DisGeNET和GeneCards等数据库中获取HCC相关靶点, 并与PHS取交集。使用Cytoscape软件绘制"化合物-靶点"网络图, 并用它们的共有靶点绘制PPI网络图, 采用DAVID数据库进行GO分析和KEGG富集分析。最后, 利用AutoDockTools进行蛋白受体与活性成分的分子对接验证。结果显示, PHS与HCC有105个共有靶点, 其中的10个核心靶点分别是ALB、AKT1、EGFR、CASP3、SRC、ESR1、MAPK3、MMP9、ANXA5和MAPK1。此外, 获得404个GO功能注释, 包括287个生物过程(biological processes, BP), 37个细胞组成(cell compositions, CC), 80个分子功能(molecular functions, MF), 还获得化学致癌基因受体、PI3K-Akt通路、HCC和乙型肝炎等110个信号分子和通路。分子对接结果表明, 10个核心靶点和12个活性组分的结合能均小于–5 kcal/mol。综上所述, 本研究阐述了PHS治疗HCC的"成分-靶点-通路"相互作用机制, 也为其临床应用提供了科学依据。

关键词: 骆驼蓬种子, 肝细胞癌, 网络药理学, 分子对接, 机制

Abstract:

Peganum harmala L. is a medicinal plant, and its seeds have been used to treat gastrointestinal cancer and malaria for a long time in North-Western China. In the present study, we aimed to probe the potential molecular targets and pharmacological mechanisms of Peganum harmala L. seeds (PHS) on hepatocellular carcinoma (HCC) using network analysis and molecular docking. First, the chemical ingredients of PHS were obtained from TCMID and BATMAN-TCM databases, and the effective ingredients were screened by SwissADME. Furthermore, the target information of the effective ingredients was acquired from PharmMapper and SwissTargetPrediction databases. Secondly, HCC-related targets were obtained from Liverome, DisGeNET, and GeneCards databases. The intersection with the PHS was obtained. The "compounds-targets" was drawn using Cytoscape software, and PPI network diagrams were drawn using their intersection targets. GO analysis and KEGG enrichment analysis were carried out using the DAVID database. Finally, molecular docking was conducted between protein receptors and the active components using AutoDockTools. Our results showed 105 intersection targets of PHS with HCC. Moreover, 10 core targets included ALB, AKT1, EGFR, CASP3, SRC, ESR1, MAPK3, MMP9, ANXA5, and MAPK1. Besides, 404 GO functional annotations were obtained, including 287 biological processes, 37 cell compositions, and 80 molecular functions. In addition, 110 signaling molecules and pathways, including chemical oncogene receptors, PI3K-Akt pathway, HCC, and hepatitis B, were identified. The molecular docking results showed that the binding energies of the 10 core targets and the 12 active components were all less than –5 kcal/mol. In conclusion, this study expounded on the "component-target-pathway" interaction mechanism of PHS for the treatment of HCC, and it also provided a scientific basis for the clinical application of PHS.

Key words: Peganum harmala L. seeds, Hepatocellular carcinoma, Network pharmacology, Molecular docking, Mechanism

Supporting:

伊帕尔古丽·阿皮孜, 王昭志, 贺宏吉, 李喆喆, 王梅. 基于网络药理学和分子对接探讨骆驼蓬种子抗肝癌作用机制[J]. 中国药学(英文版), 2022, 31(7): 517-529.

Ipargul Hafiz, Zhaozhi Wang, Hongji He, Zhezhe Li, Mei Wang. Exploring the mechanism of Peganum harmala L. seeds on hepatocellular carcinoma based on network pharmacology and molecular docking[J]. Journal of Chinese Pharmaceutical Sciences, 2022, 31(7): 517-529.

图/表 11

Figure 1. Flowchart of the current study.

Table 1. ADME information of active ingredients of PHS and the number of targets.

Figure 2. Venn diagram of the common targets.

Figure 3. Component-targets network map of PHS for the treatment of HCC. Note: The more edges, the more HCC targets interact with the active ingredients.

Figure 4. PPI network of interaction target genes.

Figure 5. Screening of core targets in the PPI network. Note: the larger the degree value, the darker the color.

Table 2. Topological parameters of the core target genes.

Figure 6. GO function annotation analysis. Note: The X-axis in the figure represents the count of genes, the Y-axis represents the function, and the color represents the size of the P-value.

Figure 7. KEGG pathway enrichment analysis. Note: The X-axis in the figure represents the ratio of genes, the Y-axis represents the signaling pathway, the bubble area represents the number of pathway-enriched genes, and the color represents the size of the P-value.

Figure 8. Thermal diagram analysis of molecular docking.

Figure 9. Molecular docking visualization. (A, E) Harmaline can form hydrogen bonds with Leu-156 residue on AKT1 and Tyr-138 on ALB; (B, F) harmolol can form hydrogen bonds with Ala-230 residue on AKT1 and Tyr-138 residue on ALB; (C, G) harmine can form hydrogen bonds with Ala-230 residue on AKT1 and Tyr-138 residue on ALB; (D, H) harmol can form hydrogen bonds with Glu-191 and THR-195 residues on AKT1 and Tyr-138 residues on ALB.

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