目的 基于網絡藥理學和分子對接技術探究小白菊內酯治療肺癌的分子機制。方法 從Swiss Target Prediction、SuperPred和HERB數據庫篩選小白菊內酯的作用靶基因。通過GeneCards、OMIM、PharmGkb、TTD、DrugBank和DisGeNET數據庫收集肺癌的疾病靶基因。使用Cytoscape軟件構建“藥物–靶基因–疾病”網絡，利用STRING數據庫構建蛋白互作網絡（PPI）；通過Bioconductor平臺進行基因本體（GO）功能和京都基因與基因組百科全書（KEGG）富集分析，利用分子對接技術確定小白菊內酯與核心靶基因結合作用。結果 小白菊內酯靶基因共88個，肺癌相關基因8 814個，取交集得到小白菊內酯–肺癌共同靶基因68個。在PPI網絡中，組蛋白去乙?；?（HDAC2）、細胞色素P450（CYP）2D6、CYP3A4、CYP2A6、前列腺素內過氧化物酶2（PTGS2）、Toll樣受體4（TLR4）、溴結構域包含蛋白（BRD）2、BRD4、單胺氧化酶A（MAOA）、無嘌呤/無嘧啶核酸內切酶-1（APEX1）是小白菊內酯作用于肺癌的10個核心基因。共同靶基因的GO分子功能主要涉及對外源性刺激的反應、花生四烯酸代謝過程、質膜外側、氧化還原酶活性加入分子氧的摻入或還原，作用于成對供體、p53結合和G蛋白偶聯胺受體活性等623個生物學過程。KEGG信號通路主要富集在化學致癌作用–DNA加合物、藥物代謝–細胞色素P450、細胞色素P450對異種物質的代謝等11個信號通路。分子對接分析表明，小白菊內酯與10核心基因之間均有良好的結合活性，氫鍵和π-π堆疊是相互作用的主要形式。結論 小白菊內酯能通過多個靶點和多條信號通路治療肺癌。

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

國家自然科學基金資助項目（8207091525，81872236）