目的 利用網(wǎng)絡(luò)藥理學(xué)、分子對(duì)接技術(shù)，篩選并分析丹參治療缺血性腦卒中（CIS）的關(guān)鍵化合物、作用靶點(diǎn)、生物學(xué)功能及信號(hào)通路，闡述其可能的作用機(jī)制。方法 使用TCMSP數(shù)據(jù)庫(kù)檢索丹參的活性成分及作用靶點(diǎn)，在GeneCards、NCBI和OMIM數(shù)據(jù)庫(kù)中獲取CIS的靶點(diǎn)，并將藥物和疾病交集后的靶點(diǎn)輸入STRING數(shù)據(jù)庫(kù)，構(gòu)建蛋白質(zhì)相互作用網(wǎng)絡(luò)，利用Cytoscape 3.7.2軟件構(gòu)建藥物-化合物-作用靶點(diǎn)-疾病網(wǎng)絡(luò)。通過Bioconductor進(jìn)行GO功能富集和KEGG通路分析。采用AutoDock Tools 1.5.6、AutoDock vina 1.1.2將得到的關(guān)鍵活性成分和核心靶點(diǎn)進(jìn)行分子對(duì)接，運(yùn)用Pymol和Ligplot軟件對(duì)結(jié)果進(jìn)行可視化。結(jié)果 從丹參中共篩選出65個(gè)活性成分和108個(gè)對(duì)應(yīng)靶點(diǎn)，以及CIS交集后獲得靶點(diǎn)87個(gè)，其中度值大于50的靶點(diǎn)有6個(gè)，包括AKT1、IL6、FOS、VEGFA、MAPK1、EGFR，即本研究的核心靶點(diǎn)。GO功能富集分析得到GO條目124個(gè)（P<0.05），KEGG通路富集分析篩出134條信號(hào)通路（P<0.05），以PI3K-AKT信號(hào)通路所占靶點(diǎn)數(shù)目最多。構(gòu)建的藥物-化合物-作用靶點(diǎn)-疾病網(wǎng)絡(luò)顯示，木犀草素、丹參酮Ⅱ_A等活性化合物在整個(gè)網(wǎng)絡(luò)中發(fā)揮著關(guān)鍵作用；分子對(duì)接結(jié)果顯示，木犀草素、丹參酮Ⅱ_A與6個(gè)核心靶蛋白均具有較好的親和力（結(jié)合能遠(yuǎn)小于-5 kJ/mol）。結(jié)論 丹參的主要活性化合物，包括木犀草素、丹參酮Ⅱ_A等，可作用于AKT1、IL6、FOS、VEGFA、MAPK1、EGFR等核心靶點(diǎn)，共同參與調(diào)節(jié)PI3K-AKT等多條信號(hào)通路，發(fā)揮抑制細(xì)胞凋亡、抗炎、神經(jīng)保護(hù)等作用，可能是丹參治療CIS的潛在機(jī)制。

Objective To screen the key compounds, targets, biological functions and signal pathways of Salviae miltiorrhizae in treatment of cerebral ischemic stroke by using network pharmacology and molecular docking techniques, and to analyze the possible mechanism of action. Methods TCMSP database was emaployed to search for the active ingredients and targets of Salviae miltiorrhizae, as well as the targets of CIS were obtained in GeneCards, NCBI and OMIM database. Then drug targets and disease targets were overlapped, and put into STRING database to establish a protein interaction network. Moreover, drug-compound-targetdisease network was constructed and GO function and KEGG pathway enrichment analysis were carried out in Bioconductor. With the aid of AutoDock Tools 1.5.6 and AutoDock vina 1.1.2, the key active ingredients and core targets were docked at molecular level, and the results were visualized by using Pymol and Ligplot software. Results A total of 65 active ingredients and 108 targets were selected out from Salviae miltiorrhizae, and 2 558 targets were collected related to CIS. After intersection, 87 targets were obtained, among which the degree value of 6 targets was greater than 50, including AKT1, IL6, FOS, VEGFA, MAPK1, EGFR, as the core targets of this study. A total of 124 GO entries and 134 signal pathways were identified, with the PI3K/AKT signal pathway occupying the largest number of targets. The results showed that luteolin and tanshinone Ⅱ_A played a key role in the drug-compoundtarget-disease network and well connected to six core targets (binding energy is much less than -5 kJ/mol). Conclusion The main active compounds of Salviae miltiorrhizae, such as luteolin, tanshinone Ⅱ_A, could target for AKT1, IL6, FOS, VEGFA, MAPK1, EGFR, and participated in the regulation of PI3K/AKT signaling pathway and many other pathways, responsible for anti-apoptosis, antiinflammatory, neuroprotection and other biological functions, that may be potential mechanisms of Salvia miltiorrhiza in treatment of CIS.

R284.3

北京市雙一流高層次人才科研經(jīng)費(fèi)項(xiàng)目（1000041510053）