目的 基于網(wǎng)絡(luò)藥理學(xué)和分子對接技術(shù)探究小白菊內(nèi)酯治療肺癌的分子機(jī)制。方法 從Swiss Target Prediction、SuperPred和HERB數(shù)據(jù)庫篩選小白菊內(nèi)酯的作用靶基因。通過GeneCards、OMIM、PharmGkb、TTD、DrugBank和DisGeNET數(shù)據(jù)庫收集肺癌的疾病靶基因。使用Cytoscape軟件構(gòu)建“藥物–靶基因–疾病”網(wǎng)絡(luò)，利用STRING數(shù)據(jù)庫構(gòu)建蛋白互作網(wǎng)絡(luò)（PPI）；通過Bioconductor平臺進(jìn)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(shù)確定小白菊內(nèi)酯與核心靶基因結(jié)合作用。結(jié)果 小白菊內(nèi)酯靶基因共88個(gè)，肺癌相關(guān)基因8 814個(gè)，取交集得到小白菊內(nèi)酯–肺癌共同靶基因68個(gè)。在PPI網(wǎng)絡(luò)中，組蛋白去乙?；?（HDAC2）、細(xì)胞色素P450（CYP）2D6、CYP3A4、CYP2A6、前列腺素內(nèi)過氧化物酶2（PTGS2）、Toll樣受體4（TLR4）、溴結(jié)構(gòu)域包含蛋白（BRD）2、BRD4、單胺氧化酶A（MAOA）、無嘌呤/無嘧啶核酸內(nèi)切酶-1（APEX1）是小白菊內(nèi)酯作用于肺癌的10個(gè)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(yīng)、花生四烯酸代謝過程、質(zhì)膜外側(cè)、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(jié)合和G蛋白偶聯(lián)胺受體活性等623個(gè)生物學(xué)過程。KEGG信號通路主要富集在化學(xué)致癌作用–DNA加合物、藥物代謝–細(xì)胞色素P450、細(xì)胞色素P450對異種物質(zhì)的代謝等11個(gè)信號通路。分子對接分析表明，小白菊內(nèi)酯與10核心基因之間均有良好的結(jié)合活性，氫鍵和π-π堆疊是相互作用的主要形式。結(jié)論 小白菊內(nèi)酯能通過多個(gè)靶點(diǎn)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(xué)基金資助項(xiàng)目（8207091525，81872236）