目的 基于網(wǎng)絡(luò)藥理及分子對接探討遠志治療認知功能障礙的成分與機制。方法 采用數(shù)據(jù)庫TCMSP、OMIM、Disgenet、GeneCards檢索遠志的活性成分、作用靶點與認知功能障礙靶點；獲取遠志活性成分靶點與認知功能障礙靶點的共同靶點，采用STRING數(shù)據(jù)庫、Cytoscape 3.9.1軟件構(gòu)建遠志活性成分–認知功能障礙共同靶點網(wǎng)絡(luò)圖、蛋白相互作用（PPI）網(wǎng)絡(luò)圖，篩選關(guān)鍵化合物與關(guān)鍵靶點；通過生物信息注釋數(shù)據(jù)庫（DAVID）進行基因本體（GO）、基因組百科全書（KEGG）信號通路的富集分析，運用Cytoscape 3.9.1軟件繪制成分–靶點–通路網(wǎng)絡(luò)圖，預(yù)測關(guān)鍵成分與靶點作用；分別從數(shù)據(jù)庫PubChem、PDB獲取活性成分、靶點蛋白結(jié)構(gòu)，導(dǎo)入Autodock 4.2.軟件進行對接驗證。結(jié)果 共獲遠志活性成分24個、作用靶點544個、認知功能障礙相關(guān)基因1 904個、遠志活性成分與認知功能障礙疾病共同靶點189個、遠志治療認知功能障礙關(guān)鍵靶點26個，蛋白激酶B1(Akt1)、白蛋白（ALB）、信號轉(zhuǎn)導(dǎo)和轉(zhuǎn)錄激活因子3(STAT3)、雌激素受體1(ESR1)、胱天蛋白酶3(CASP3)、V-Jun肉瘤病毒癌基因同源物（JUN）、表皮生長因子受體（EGFR）、過氧化物酶體增殖物激活受體γ(PPARG)、糖原合酶激酶3β(GSK3B)、哺乳動物雷帕霉素靶蛋白（MTOR）居前10位；GO分析顯示，遠志治療認知功能障礙的作用機制涉及細胞對外源性刺激的增殖反應(yīng)、磷酸化、炎性反應(yīng)、蛋白質(zhì)磷酸化等過程；KEGG通路主要富集在癌癥、內(nèi)分泌、病毒感染3類疾病相關(guān)通路；靶點Akt1、JUN、PPARG與成分胡椒內(nèi)酰胺A、1-甲乙氧基-β-咔啉、降賽法拉二酮B的結(jié)合能≤-5.0 kcal/mol。結(jié)論 遠志治療認知功能障礙可能與胡椒內(nèi)酰胺A、1-甲乙氧基-β-咔啉、降賽法拉二酮B調(diào)控作用于Akt1/PPARG/JUN通路的多個靶點發(fā)生代謝/炎癥/凋亡級聯(lián)反應(yīng)有關(guān)。

Objective To analyze the potential components and mechanism of action underlying the therapeutic action of Polygalae Radix against cognitive dysfunction. Methods Using the database of TCMSP, OMIM, Disgenet, and GeneCards, we identified the main active components of Polygalae Radix, and the targets of Polygalae Radix and cognitive dysfunction were obtained. Then, Venn diagrams were used to obtain the common targets of both Polygalae Radix and cognitive dysfunction. The database of STRING and Cytoscape 3.9.1 was used to construct “component–target” network diagrams of the targets. The protein-protein interaction（PPI） network diagrams, gene ontology（GO）, and Kyoto Encyclopedia of Genes and Genomes（KEGG） signaling pathways of the targets were analyzed. Using Cytoscape 3.9.1 software to draw a “component–target–pathway” network diagram. The molecular docking of key components and targets was performed using AutoDock 4.2, and the docking results were visualized using Pymol. Results Twenty-four main active components of Polygalae Radix were predicted. A total of 544 action targets, 1 904 cognitive dysfunction-related genes, 189 common targets of both Polygalae Radix and cognitive dysfunction, including 26 key targets related to cognitive dysfunction treatment. The grade values of Akt1, ALB, STAT3, ESR1, CASP3, JUN, EGFR, PPARG, GSK3B, and MTOR are in the top 10. GO analysis showed that the mechanism of action of Polygalae Radix in treatment of cognitive dysfunction involved cell proliferation response, phosphorylation, inflammatory response and protein phosphorylation to exogenous stimuli. The KEGG pathway is mainly concentrated in the pathways related to cancer, endocrine and viral infection. Molecular docking revealed that the three core components of Polygalae Radix, including piperolactam A, 1-carboethoxy-beta-carboline, and norcepharadione B, exhibited strong binding（≤-5.0 kcal/mol） with the core targets of Akt1, JUN, and PPARG. Conclusion Polygalae Radix is likely to exert its therapeutic effect on cognitive dysfunction by regulating the metabolic/inflammatory/apoptotic cascade reactions that occur at multiple targets of the Akt1/PPARG/JUN pathway via piperonolactam A, 1-methoxy-β-carbaline, and norfaradione B.

R285.5

國家中醫(yī)藥管理局創(chuàng)新團隊和人才培養(yǎng)計劃項目(國中醫(yī)藥人教函<2022>222號); 廣東省重點領(lǐng)域研發(fā)計劃(第五批)項目(163-2018-XMZC-0001-165-0272)