目的 采用網(wǎng)絡(luò)藥理學(xué)結(jié)合GEO數(shù)據(jù)庫多芯片聯(lián)合分析及分子對接的方法研究化橘紅防治動脈型肺動脈高壓的潛在分子作用機制。方法 利用TCMSP、ETCM、Swiss Target Prediction和PharmMapper等數(shù)據(jù)庫結(jié)合文獻報道，獲取化橘紅活性成分的作用靶點。通過GEO數(shù)據(jù)庫多芯片聯(lián)合分析獲得動脈型肺動脈高壓的差異表達基因，聯(lián)合GeneCard、DisGeNET和DiGSeE等數(shù)據(jù)庫篩選出動脈型肺動脈高壓的潛在疾病基因。對疾病基因和活性成分靶點取交集，以Cytoscape 3.7.2軟件構(gòu)建化橘紅活性成分–靶點的可視化網(wǎng)絡(luò)。基于String數(shù)據(jù)庫，構(gòu)建化橘紅防治動脈型肺動脈高壓靶點的蛋白互作（PPI）網(wǎng)絡(luò)，分析篩選出核心靶點，進行基因本體（GO）功能富集分析和京都基因與基因組百科全書（KEGG）信號通路富集分析，構(gòu)建化橘紅活性成分–靶點–信號通路網(wǎng)絡(luò)。將化橘紅主要活性成分與網(wǎng)絡(luò)拓撲分析后所得到的排名前10的核心靶點進行分子對接，Autodock Vina預(yù)測其分子結(jié)合自由能及Pymol作分子對接可視化圖。結(jié)果 篩選出活性成分15個，得到可作用于動脈型肺動脈高壓的靶點150個，核心靶點涉及腫瘤蛋白P53（TP53）、β-肌動蛋白（ACTB）、腫瘤壞死因子（TNF）、血管內(nèi)皮生長因子A（VEGFA）、絲裂原活化蛋白激酶3（MAPK3）、缺氧誘導(dǎo)因子-1α（HIF1A）和胱天蛋白酶3（CASP3）等。GO富集分析得到生物學(xué)過程相關(guān)條目572條、分子功能相關(guān)條目115條及細胞組分相關(guān)條目84條（P<0.01）。KEGG通路富集分析得到173條信號通路（P<0.01），主要涉及癌癥通路、脂質(zhì)與動脈粥樣硬化通路、流體剪切應(yīng)力與動脈粥樣硬化、細胞衰老、缺氧誘導(dǎo)因子-1（HIF-1）信號通路、磷酯酰肌醇-3-激酶（PI3K）-蛋白激酶B（Akt）信號通路、白細胞介素-17（IL-17）信號通路和細胞凋亡等。分子對接結(jié)果表明關(guān)鍵成分和關(guān)鍵靶點間均具有較好的結(jié)合活性。結(jié)論 化橘紅通過多靶點、多通路發(fā)揮治療動脈型肺動脈高壓的作用。

Objective To investigate the potential molecular mechanism of action of Citri Grandis Exocarpium in the prevention and treatment of pulmonary arterial hypertension by using network pharmacology combined with GEO database multi-chip analysis and molecular docking method. Methods TCMSP, ETCM, Swiss Target Prediction, PharmMapper and other databases were used to obtain the targets of the active ingredients of Citri Grandis Exocarpium in combination with literature reports. The differentially expressed genes of arterial pulmonary hypertension were obtained by multi-chip analysis of GEO database, and the potential disease genes of arterial pulmonary hypertension were screened by combining with GeneCard, DisGeNET, and DiGSeE databases. The intersection of the disease genes and the active ingredient targets was taken, and the Cytoscape 3.7.2 software was used to construct the visualization network of the active ingredient-targets of Citri Grandis Exocarpium. Based on the String database, the protein interactions network of the targets of Citri Grandis Exocarpium for the prevention and treatment of arterial pulmonary hypertension was constructed, the core targets were analyzed and screened, GO functional enrichment analysis and KEGG signaling pathway enrichment analysis were performed, and the active ingredient-target-signaling pathway network of Citri Grandis Exocarpium was constructed. The molecular docking was performed between the top ten active ingredients and the core targets obtained from the network topology analysis, and the molecular binding free energy was predicted by Autodock Vina and visualized by Pymol. Results 15 active ingredients were screened, and 150 targets were identified for arterial pulmonary hypertension, including TP53, ACTB, TNF, VEGFA, MAPK3, HIF1A, CASP3, etc. GO enrichment analysis yielded 572 entries related to biological processes, 115 entries related to molecular functions, and 84 entries related to cellular components (P < 0.01). KEGG pathway enrichment analysis yielded 173 signaling pathways (P < 0.01), mainly involving cancer pathway, lipid and atherosclerosis pathway, fluid shear stress and atherosclerosis, cellular senescence, HIF-1 signaling pathway, PI3K-Akt signaling pathway, IL-17 signaling pathway, and apoptosis. The molecular docking results showed good binding activity between key components and key targets. Conclusion Citri Grandis Exocarpium exerts its effect on the treatment of arterial pulmonary hypertension through multi-target and multi-pathway.

R925.5

國家自然科學(xué)基金面上項目（81370242）；廣東醫(yī)科大學(xué)學(xué)科建設(shè)項目（4SG21229GDGFY01）；廣東醫(yī)科大學(xué)校級大學(xué)生創(chuàng)新創(chuàng)業(yè)訓(xùn)練計劃項目（GDMU2021117，GDMU2021156）；湛江市非資助科技攻關(guān)計劃項目（2021B01145）；湛江市科技計劃項目（2022A01183）