基于网络药理学和分子对接分析连翘治疗下肢静脉性溃疡的作用机制

Mechanism of Lianqiao treatment of venous leg ulcers base on network pharmacology and molecular docking

目的:通过网络药理学方法探讨连翘治疗下肢静脉性溃疡(Venous Leg Ulcers,VLU)的机制。方法:从中药系统药理学分析平台(Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform,TCMSP)查找连翘的所有成分和潜在靶点,并构建药物有效成分-靶点网络;通过Dis Ge NET、人类在线孟德尔遗传(Online Mendelian Inheritance in Man,OMIM)数据库筛选VLU的相关靶标,利用Cytoscape3.2.1软件中Bisogenet插件对连翘与VLU共同靶点进行网络拓扑分析,利用人类基因组注释数据库(DAVID)对核心靶点蛋白进行基因本体(Gene Ontology,GO)、京都基因与基因组百科全书(Kyoto Encyclopedia of Gene and Genomes,KEGG)通路富集分析。利用Auto Dock Tools 1.5.6软件对主要靶点及对应的活性成分进行分子对接验证结合强度。结果:获得到具有作用靶点的有效成分20个,药物的潜在靶点129个。2个疾病数据库收集疾病靶点242个,药物疾病共同靶点14个。网络拓扑分析获得连翘治疗VLU核心靶点155个,GO富集分析结果包括无义介导的m RNA降解、信号识别粒子(Signal Recognition Particle,SRP)依赖性共翻译蛋白靶向膜、翻译起始、病毒转录、rRNA加工、蛋白翻译、RNA聚合酶II启动子转录的负调控、通过剪接体进行m RNA剪接、病毒过程、凋亡过程的负调控等生物分析过程。KEGG富集结果显示有44条通路,主要涉及磷脂酰肌醇3-激酶/蛋白激酶B(PI3K/Akt)信号通路、丝裂原活化蛋白激酶(Mitogen-Activated Protein Kinase,MAPK)信号通路、缺氧诱导因子1(Hypoxia Inducible Factor-1,HIF-1)信号通路等。结论:连翘治疗VLU是多成分、多靶点、多途径相互作用的结果,通过干预细胞凋亡、调控炎症反应、促进血管生成、优化胶原蛋白沉积等途径达到促进溃疡愈合的目的。

Objective: To explore the mechanism of Lianqiao(Forsythia suspensa) treat VLU by network pharmacology. Methods: To find all components and potential targets of Lianqiao from the TCMSP, and to construct a drug active ingredient-target network;The related targets of Venous Leg Ulcers were screened through the DisGeNET and OMIM databases. The Bisogenet plug-in in the software performs network topology analysis on common targets of Lianqiao and VLU, using the DAVID database to analyze GO and KEGG pathway of core target proteins. Using AutoDock Tools 1.5.6 to perform molecular docking on the core target and corresponding active ingredients to verify the binding strength. Results: 20 active ingredients with effective targets and 129 potential drug targets were obtained. Two disease databases collected 242 disease targets and 14 drug disease common targets. Network topology analysis obtained 155 core targets of Lianqiao treatment of VLU. GO enrichment analysis results included nuclear-transcribed mRNA catabolic process, nonsensemediated decay, SRP-dependent cotranslational protein targeting to membrane, translational initiation, viral transcription, rRNA processing, translation, negative regulation of transcription from RNA polymerase II promoter, mRNA splicing, via spliceosome, viral process, negative regulation of apoptotic process and other biological analysis processes. The KEGG enrichment results show that there are 44 pathways, mainly related to the PI3 K/Akt signal pathway, the MAPK signal pathway, and the HIF-1 signal pathway. Conclusion: Lianqiao treatment of Venous Leg Ulcers is the result of multi-component, multi-target, multi-path interactions. It can promote the healing of ulcers by intervening cell apoptosis, regulating inflammatory response, promoting angiogenesis, and optimizing collagen deposition.