目的 基于網(wǎng)絡(luò)藥理學(xué)和分子對接探討活絡(luò)效靈丹治療骨關(guān)節(jié)炎的作用機(jī)制。方法 利用TCMSP數(shù)據(jù)分析平臺(tái)和文獻(xiàn)檢索獲取活絡(luò)效靈丹的活性成分,篩選出口服生物利用度(OB)≥30%且類藥性(DL)≥0.18的成分作為潛在活性成分。通過Uniprot數(shù)據(jù)庫預(yù)測潛在活性成分對應(yīng)的基因。查詢GeneCards、OMIM、TTD、DrugBank、Pharmgkb等數(shù)據(jù)庫獲得骨關(guān)節(jié)炎的相關(guān)靶點(diǎn)且進(jìn)行去重合并。應(yīng)用Cytoscape 3.8.2軟件建立可視化網(wǎng)絡(luò)圖,根據(jù)度值選定核心藥物潛在活性成分。借助String數(shù)據(jù)庫分析獲取藥物與疾病的蛋白相互作用(PPI)網(wǎng)絡(luò),憑借Cytoscape3.8.2軟件對該網(wǎng)絡(luò)采取拓?fù)鋵W(xué)分析,對潛在靶點(diǎn)進(jìn)行GO富集分析和KEGG富集分析。使用SYBYL-X2.0軟件進(jìn)行分子對接驗(yàn)證。結(jié)果 活絡(luò)效靈丹有效活性成分共120種、作用靶點(diǎn)201個(gè),骨關(guān)節(jié)炎相關(guān)靶點(diǎn)1675個(gè);經(jīng)PPI網(wǎng)絡(luò)及拓?fù)浣Y(jié)構(gòu)分析得到184個(gè)節(jié)點(diǎn)和282條邊;木犀草素、槲皮素等為活絡(luò)效靈丹的主要活性成分。在生物學(xué)進(jìn)程中,靶點(diǎn)主要通過細(xì)胞對化學(xué)應(yīng)激的反應(yīng)等路徑發(fā)揮作用;在分子功能上,靶點(diǎn)主要影響核受體活性等方面。分子對接結(jié)果顯示, MAPK1、MAPK14、RELA、JUN作為靶點(diǎn)可與木犀草素、槲皮素等穩(wěn)定對接。結(jié)論 活絡(luò)效靈丹可能通過調(diào)控多個(gè)靶點(diǎn)及相關(guān)信號(hào)通路,影響細(xì)胞凋亡、軟骨基質(zhì)降解、抑制關(guān)節(jié)炎及骨損傷,從而延緩骨關(guān)節(jié)炎的發(fā)展進(jìn)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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天津市中醫(yī)藥重點(diǎn)領(lǐng)域科研項(xiàng)目(2017007);天津市教委科研項(xiàng)目(2018KJ029);天津市中醫(yī)藥研究院附屬醫(yī)院科研基金資助項(xiàng)目(2020004)