基于网络药理学探讨芪–归药对防治骨髓抑制毒性的作用机制

Potential Mechanisms of Huangqi-Danggui Herb Pairs in the Treatment of Myelosuppression Based on Network Pharmacology

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摘要目的:利用网络药理学研究策略,结合中药对机体代谢的调控作用,探讨黄芪–当归药对防治化疗药物骨髓抑制毒性的直接作用及间接调控机制。方法:通过网络数据库,筛选得到芪–归药对中活性成分可直接作用的病理靶点,构建“活性成分–蛋白靶点–病理机制”直接交互网络;同时,以中药对体内代谢调控及骨髓抑制毒性发病机制为基础,从中药影响内源性物质代谢角度,筛选出芪–归药对可间接调控的作用靶点。利用分子对接模拟实验,验证所筛选关键靶蛋白与黄芪与当归中有效成分的结合活性。结果:从数据库中共筛选得到芪–归药对中154个潜在活性成分和11个核心靶点,主要涉及细胞表面离子通道、胞内蛋白激酶、p53等信号通路;同时,代谢通路富集分析表明,芪–归药对机体酮体代谢具有调控作用,亦可作为防治骨髓抑制毒性的潜在机制。分子对接结果显示,所筛选关键靶蛋白与芪–归药对中有效成分具有良好的结合活性。结论:芪–归药对防治化疗骨髓抑制毒性具有多成分、多靶点、代谢复杂、药效输出广泛、多途径协同增效的作用特点,并可能通过调控机体代谢进而发挥防治功效。该研究为后续道地药材资源的开发、芪–归药对防治骨髓抑制的药效物质基础及作用机制研究提供了理论依据。 Object: Network pharmacology research strategies combined with Traditional Chinese Medicine metabolic regulation theories were used to study direct and indirect mechanisms of Hua-ngqi-Danggui herb pairs (HD) for the prevention and treatment of chemotherapeutic myelosup-pression. Methods: Chemical components and related targets of HD were searched using network database. Combined with myelosuppression related targets, “chemical-targets-disease” network was established. Meanwhile, related targets in metabolism which HD may regulate were also screened out. The molecular docking simulation experiment was used to verify the binding activity of the screened key target proteins to the active components. Results: 154 potential active components and 11 core targets were screened out by topology analysis. Meanwhile, metabolic pathways enrichment analysis showed that HD can regulate ketone body metabolism. The results showed that cell surface channels, cytosol protein kinase activity, p53 class mediator signal transduction pathway and ketone body metabolism may play important roles for the prevention and treatment of myelosuppression by HD. Conclusion: This study indicated that the prevention and treatment of myelosuppression by HD were a synergetic effect with multi-components, multi-targets and ketone body metabolism may also play crucial parts. The direct and indirect mechanisms we revealed may provide the theoretical basis for pharmacodynamic materials and functional mechanisms studies of HD.