基于网络药理学和分子对接研究丹参治疗浆细胞性乳腺炎的作用机制

Exploring the mechanism of Salviae Miltiorrhizae Radix Et Rhizoma in treating plasma cell mastitis based on network pharmacology and molecular docking

利用网络药理学初步分析丹参治疗浆细胞性乳腺炎的作用机制,应用分子对接辅助研究丹参中活性化合物与浆细胞性乳腺炎主要靶点的亲和力,以证明筛选出的活性物质确实可与疾病靶点结合。基于中药系统药理学数据库与分析平台筛选丹参中的有效活性成分及这些成分的相关作用靶点,构建中药-成分-靶点网络,利用GeneCard数据库和DisGeNET数据库筛选浆细胞性乳腺炎的高相关性基因靶点,将药物成分靶点与疾病基因靶点相互映射,得到药物-成分-靶点-疾病网络,分析网络得到潜在药物活性化合物及潜在作用基因靶点,将此潜在作用靶点导入STRING数据库构建蛋白质-蛋白质相互作用网络。利用DAVID数据库对潜在作用靶点进行生物功能及代谢通路分析。对筛选到的高相关性活性成分和靶点进行分子对接,选择浆细胞性乳腺炎相关度最高的靶点IL-6、ICAM1和PGR,在PDB数据库中找到其三维蛋白结构,后在Zinc数据库中找寻丹参活性成分的分子结构,利用autodock4.0软件将蛋白与分子相对接。得到中药有效活性物质59个及其相关作用靶点132个,疾病相关靶点125个,映射后得到BCL2L1、EDNRA、ERBB2、ICAM1、IFNG、IL-4、IL-6、NR3C1、PGR、STAT3等10个潜在作用靶点,基因本体富集分析后找到潜在作用靶点共14个生物过程,京都基因与基因组百科全书分析后筛选得到16条信号转导通路,以乳腺癌通路、癌症信号通路、库欣综合征通路、NF-κB信号通路等通路为主。分子对接表明筛选出的药物活性成分与潜在作用靶点确有较大的亲和力。该研究初步筛选出了丹参治疗浆细胞性乳腺炎的物质基础,并揭示了丹参治疗该病症是通过多成分、多靶点、多途径共同调控。

This study aimed to preliminarily analyze the mechanism of action of Salviae Miltiorrhizae Radix Et Rhizoma in the treatment of plasma cell mastitis using network pharmacology and study the affinity of active ingredients in Salviae Miltiorrhizae Radix Et Rhizoma to the main targets of plasma cell mastitis using molecular docking technology, so as to prove that the selected active ingredients can indeed bind to the disease targets. We used traditional Chinese medicine’s pharmacology database and analysis platforms to screen for the effective active ingredients in Salviae Miltiorrhizae Radix Et Rhizomaand and the related targets of these ingredients to construct a traditional Chinese medicine-ingredient-target network. Using the GeneCard and DisGeNET databases to screen for the highly correlated gene targets of plasma cell mastitis, the drug ingredient targets were mapped to disease gene targets. The drug-ingredient-target-disease network was obtained, and the potential active ingredients of the drug and gene targets were obtained by analyzing the network. The potential targets were imported into the STRING database to construct a protein-protein interaction network. Biological functions and metabolic pathways of potential targets were analyzed using the DAVID database. The highly correlated active ingredients were screened, and their targets underwent molecular docking, where IL-6, ICAM1, and PGR having the highest correlation with plasma cell mastitis were selected, and their three-dimensional protein structure was found in the PDB database. Next, the molecular structure of the active ingredients of Salviae Miltiorrhizae Radix Et Rhizoma was found in the Zinc database. The proteins were docked to the molecules using Autodock 4.0 software, and 59 effective active ingredients of traditional Chinese medicine and 132 of its related targets as well as 125 disease-related targets were obtained. A total of 10 potential targets of action, BCL2 L1, EDNRA, ERBB2, ICAM1, IFNG, IL-4, IL-6, NR3 C1, PGR, and STAT3, were obtained after mapping;14 biological processes were found after Gene Ontology enrichment analysis;and 16 signaling pathways were screened after Kyoto Encyclopedia of Genes and Genomes analysis, which mainly included breast cancer, cancer signaling, Cushing’s syndrome, and NF-κB signaling pathways, among others. Molecular docking showed that the screened active ingredients of the drug did have a greater affinity to the potential targets of action. This study has preliminarily identified the material basis of Salviae Miltiorrhizae Radix Et Rhizoma miltiorrhiza in the treatment of plasma cell mastitis and revealed that the treatment of this disease using Salviae Miltiorrhizae Radix Et Rhizoma is regulated by multiple ingredients, targets, and pathways.