基于网络药理学和分子对接技术探究连翘抗顺铂肾毒性作用机制

Mechanism Prediction of Forsythia suspensa Against Cisplatin-induced Kidney Toxicity by Network Pharmacology and Molecular Docking

目的:通过运用网络药理学,并结合分子对接技术,探讨连翘抗顺铂肾毒性可能的物质基础,并进一步分析其潜在的分子机制。方法:首先通过筛选连翘活性成分和作用靶点并构建PPI网络,根据网络拓扑参数筛选核心靶点,确定连翘中抗顺铂肾毒性的重要活性成分。对核心靶点进行基因本体(GO)和京都基因与基因组百科全书(KEGG)分析,构建“KEGG通路-关键基因-活性成分关系网络”。然后对筛选后的活性成分和关键靶点进行分子对接验证。结果:药材-化合物-靶点相互作用网络结果显示连翘苷、连翘酯苷A的Degree值分别为20、18,是连翘抗顺铂肾毒性作用的前两位重要活性成分。PPI网络分析发现ALB、EGFR、SRC、HSP90AA1、CASP3、MAPK14、MAPK1、ESR1和KDR的Degree值分别为26、21、20、19、16、15、15、14、13,为PPI网络中的核心靶点基因。GO和KEGG分析发现MAPK信号通路和Rap1信号通路在连翘抗顺铂肾毒性作用中发挥重要作用。分子对接结果显示,连翘酯苷A和连翘苷均与MAPK14及MAPK1有较高的亲和力,二者可能通过作用于MAPK通路来发挥肾脏保护作用。结论:连翘酯苷A和连翘苷可能是连翘治疗顺铂导致的肾脏损伤过程中发挥疗效的关键成分,且可能通过MAPK信号通路来发挥肾脏保护作用。

Objective:To explore the possible material foundation of Forsythia suspensa anti-cisplatin kidney toxicity by using network pharmacology and molecular docking technology,and further analyze the potential molecular mechanism.Methods:First,the active components and targets of Forsythia suspensa were screened and the PPI network was constructed.Then the core targets were screened according to the network topology parameters,and the important active components of Forsythia suspensa anti-cisplatin kidney toxicity were determined.The core target was then analyzed by Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG),and“the KEGG pathway-key gene-active component network”was constructed.Then,molecular docking verifi cation was carried out for the screened active ingredients and key targets.Results:As showed in the results of the medicine-compound-target interaction network,the degree value of phillyrin and forsythoside A were 20 and 18,respectively,which were the two important active components of Forsythia suspensa against cisplatin-induced kidney toxicity.PPI network analysis showed that the degree values of ALB,EGFR,SRC,HSP90AA1,CASP3,MAPK14,MAPK1,ESR1 and KDR were 26,21,20,19,16,15,15,14 and 13,respectively,which were the core target genes in PPI network.GO and KEGG analysis showed that MAPK signaling pathway and Rap1 signaling pathway play important roles in the treatment of cisplatininduced kidney toxicity of Forsythia suspensa.Molecular docking results suggested that both forsythoside A and phillyrin had high affi nity with MAPK14 and MAPK1,which may play a protective role in kidney by acting on MAPK pathway.Conclusion:Forsythoside A and phillyrin may be the key components of Forsythia suspensa in treating kidney injury induced by cisplatin,and may play a protective role in kidney by MAPK signaling pathways.