目的 基于网络药理学和分子对接技术探究小白菊内酯治疗肺癌的分子机制。方法 从Swiss Target Prediction、SuperPred和HERB数据库筛选小白菊内酯的作用靶基因。通过GeneCards、OMIM、PharmGkb、TTD、DrugBank和DisGeNET数据库收集肺癌的疾病靶基因。使用Cytoscape软件构建“药物–靶基因–疾病”网络，利用STRING数据库构建蛋白互作网络（PPI）；通过Bioconductor平台进行基因本体（GO）功能和京都基因与基因组百科全书（KEGG）富集分析，利用分子对接技术确定小白菊内酯与核心靶基因结合作用。结果 小白菊内酯靶基因共88个，肺癌相关基因8 814个，取交集得到小白菊内酯–肺癌共同靶基因68个。在PPI网络中，组蛋白去乙酰化酶2（HDAC2）、细胞色素P450（CYP）2D6、CYP3A4、CYP2A6、前列腺素内过氧化物酶2（PTGS2）、Toll样受体4（TLR4）、溴结构域包含蛋白（BRD）2、BRD4、单胺氧化酶A（MAOA）、无嘌呤/无嘧啶核酸内切酶-1（APEX1）是小白菊内酯作用于肺癌的10个核心基因。共同靶基因的GO分子功能主要涉及对外源性刺激的反应、花生四烯酸代谢过程、质膜外侧、氧化还原酶活性加入分子氧的掺入或还原，作用于成对供体、p53结合和G蛋白偶联胺受体活性等623个生物学过程。KEGG信号通路主要富集在化学致癌作用–DNA加合物、药物代谢–细胞色素P450、细胞色素P450对异种物质的代谢等11个信号通路。分子对接分析表明，小白菊内酯与10核心基因之间均有良好的结合活性，氢键和π-π堆叠是相互作用的主要形式。结论 小白菊内酯能通过多个靶点和多条信号通路治疗肺癌。

Objective To study the molecular mechanism of parthenolide in treatment of lung cancer based on network pharmacology and molecular docking methods. Methods The potential targets of parthenolide were obtained from the Swiss Target Prediction, SuperPred, and HERB databases, and the relevant targets of lung cancer were screened from the DisGeNET, GeneCards, PharmGkb, TTD, DrugBank, and OMIM databases. The drug-target-disease network was constructed by Cytoscape software. The protein-protein interaction (PPI) network was drawn through the STRING database. Gene Ontology (GO) and pathway enrichment analyses of Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed by the Bioconductor platform. Molecular docking was used to determine the binding of parthenolide to core target genes. Results A total of 88 potential targets of parthenolide were chosen, 8 814 lung cancer-related targets were identified, and 68 overlapping targets were obtained. In the PPI network, HDAC2, CYP2D6, CYP3A4, CYP2A6, PTGS2, TLR4, BRD2, BRD4, MAOA, and APEX1 were the core targets. GO molecular functions of common target genes mainly involve 623 biological processes, such as the response to exogenous stimuli, arachidonic acid metabolism, outer plasma membrane, the addition or reduction of REDOX enzyme activity with molecular oxygen, the action of paired donor, p53 binding and G protein-coupled amine receptor activity. KEGG signaling pathway is mainly concentrated in 11 signaling pathways, including chemical carcinogenation-DNA adducts, drug metabolity-cytochrome P450, and cytochrome P450 metabolism of heterogeneous substances. Molecular docking analysis showed that there was good binding activity between parthenolide and 10 core genes, and hydrogen bond and π-π stacking were the main forms of interaction. Conclusion Parthenolide can treat lung cancer through multi-target and multi-pathway.

R965

国家自然科学基金资助项目（8207091525，81872236）