目的 基于网络药理学和分子对接探讨活络效灵丹治疗骨关节炎的作用机制。方法 利用TCMSP数据分析平台和文献检索获取活络效灵丹的活性成分,筛选出口服生物利用度(OB)≥30%且类药性(DL)≥0.18的成分作为潜在活性成分。通过Uniprot数据库预测潜在活性成分对应的基因。查询GeneCards、OMIM、TTD、DrugBank、Pharmgkb等数据库获得骨关节炎的相关靶点且进行去重合并。应用Cytoscape 3.8.2软件建立可视化网络图,根据度值选定核心药物潜在活性成分。借助String数据库分析获取药物与疾病的蛋白相互作用(PPI)网络,凭借Cytoscape3.8.2软件对该网络采取拓扑学分析,对潜在靶点进行GO富集分析和KEGG富集分析。使用SYBYL-X2.0软件进行分子对接验证。结果 活络效灵丹有效活性成分共120种、作用靶点201个,骨关节炎相关靶点1675个;经PPI网络及拓扑结构分析得到184个节点和282条边;木犀草素、槲皮素等为活络效灵丹的主要活性成分。在生物学进程中,靶点主要通过细胞对化学应激的反应等路径发挥作用;在分子功能上,靶点主要影响核受体活性等方面。分子对接结果显示, MAPK1、MAPK14、RELA、JUN作为靶点可与木犀草素、槲皮素等稳定对接。结论 活络效灵丹可能通过调控多个靶点及相关信号通路,影响细胞凋亡、软骨基质降解、抑制关节炎及骨损伤,从而延缓骨关节炎的发展进程。

Objective Based on network pharmacology and molecular docking, to study the mechanism of Huoluo Xiaoling Pills in treatment of osteoarthritis.Methods The active ingredients of Huoluo Xiaoling Pills were obtained from TCMSP database and literature. The compounds were selected by oral bioavailability (OB) value ≥ 30% and drug-like property (DL) value ≥ 0.18 as potential active ingredients. The genes corresponding to the potential actively ingredients were predicted through the Uniprot database. The related targets of osteoarthritis were obtained by querying GeneCards, OMIM, TTD, DrugBank, Pharmgkb and other databases and deduplicated. Cytoscape 3.8.2 software was used to establish a visual network diagram and select the core drug active ingredients according to the degree value. The PPI interaction network of drugs and diseases was obtained with the help of String database analysis, and the network was topologically analyzed by Cytoscape 3.8.2 software. GO enrichment analysis and KEGG enrichment analysis were performed on potential targets. SYBYL-X2.0 software was used for molecular docking verification.Results There are 120 active ingredients, and 201 action targets in Huoluo Xiaoling Pills, and 1 675 osteoarthritis related targets. 184 nodes and 282 edges were obtained by PPI interaction network and topological structure analysis. Luteolin, quercetin, etc. are the mainly active ingredients of Huoluo Xiaoling Pills. In the biological process, the target mainly involved through the cell's response to chemical stress and other pathways. In terms of molecular function, the target mainly affects nuclear receptor activity and other aspects. The results of molecular docking showed that MAPK1, MAPK14, RELA, and JUN can be stably docked with luteolin and quercetin as targets.Conclusion Huoluo Xiaoling Pills may affect cell apoptosis, cartilage matrix degradation, inhibit arthritis and bone damage by regulating multiple targets and related signal pathways, thereby delaying the development of osteoarthritis.

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天津市中医药重点领域科研项目(2017007);天津市教委科研项目(2018KJ029);天津市中医药研究院附属医院科研基金资助项目(2020004)