基于网络药理学探讨浙贝母-海螵蛸药对治疗胃食管反流病作用机制

目的：基于网络药理学探讨浙贝母-海螵蛸药对治疗胃食管反流病（GERD） 的作用机制。方法：通过中药系统药理学数据库与分析平台（TCMSP）、BATMAN-TCM、中药与有效成分、本草组鉴-HERB等数据库及相关文献筛选浙贝母-海螵蛸的活性成分，使用Swiss ADME与SwissTargetPrediction平台对活性成分靶点进行预测。利用GeneCards、DisGeNET、Drugbank筛选GERD的作用靶点，通过Jvenn平台取浙贝母-海螵蛸与GERD的交集靶点，将交集靶点上传STRING11.0数据库，运用Cytoscape3.7.1软件构建蛋白互作网络图，获取浙贝母-海螵蛸药对治疗GERD的核心靶点；借助Metascape数据库对核心靶点进行基因本体论（GO） 和京都基因和基因组百科全书（KEGG） 通路富集分析；采用AutoDock工具将药对中的关键成分与核心靶点进行分子对接验证。结果：共筛选出浙贝母-海螵蛸药对活性成分28个，药物靶点536个，GERD靶点1 997个。浙贝母-海螵蛸药对的核心活性成分有贝母素乙、浙贝丙素、苦鬼臼毒素等；浙贝母-海螵蛸药对治疗GERD的核心靶点有丝氨酸/苏氨酸蛋白激酶（AKT1）、丝裂原活化蛋白激酶（MAPK） 1、磷脂酰肌醇3-激酶催化亚基δ（PIK3CD）、表皮生长因子（EGFR）、原癌基因（JUN） 等。浙贝母-海螵蛸药对治疗GERD主要作用于神经活性配体-受体相互作用、磷脂酰肌醇3-激酶（PI3K） /蛋白激酶B（AKT）、MAPK及癌症等信号通路。分子对接发现药物核心活性成分浙贝丙素、贝母素乙与AKT1等靶点结合活性较高。结论：浙贝母-海螵蛸药对中贝母素乙、浙贝丙素、苦鬼臼毒素等成分能作用于AKT1、EGFR等靶点治疗GERD，其作用机制与调节神经活性配体-受体相互作用、PI3K/Akt信号、MAPK信号通路等多条信号通路有关。

Exploration on Action Mechanism of Fritillariae Thunbergii Bulbus-Sepiae EndoconchaDrug Pair for Gastroesophageal Reflux Disease Based on Network Pharmacology

Abstract： Objective： To explore the action mechanism of Fritillariae Thunbergii Bulbus-SepiaeEndoconcha drug pair for gastroesophageal reflux disease (GERD) based on network pharmacology.Methods： The active components of Fritillariae Thunbergii Bulbus-Sepiae Endoconcha were screenedthrough Traditional Chinese Medicines Systems Pharmacology Platform (TCMSP)， BATMAN-TCM，Chinese medicine and active ingredients，Ben Cao Zu Jian-HERB databases and related literature. SWISSADME and SwissTargetPrediction platform were used to predict active ingredient targets. GeneCards，DisGeNET and Drugbank were used to screen the targets of GERD； the intersection targets of FritillariaeThunbergii Bulbus-Sepiae Endoconcha drug pair and GERD were obtained through Jvenn Platform，and theintersection targets were uploaded to STRING11.0 database. Cytoscape3.7.1 software was used toconstruct protein interaction network diagram to obtain the core targets of Fritillariae Thunbergii Bulbus-Sepiae Endoconcha drug pair for GERD treatment； Genetic Ontology (GO) and Kyoto Encyclopedia ofGenes and Genomes (KEGG) pathway enrichment analysis were performed for core targets usingMetascape database；AutoDock tools was used to verify the molecular docking between key componentsin drug pairs and core targets. Results： A total of 28 active ingredients of Fritillariae Thunbergii Bulbus-Sepiae Endoconcha durg pairs，536 medicine targets and 1 997 GERD targets were screened out. The coreactive components of Fritillariae Thunbergii Bulbus-Sepiae Endoconcha drug pairs included Peiminine，Zhebeirine， Picropodophyllin， etc.； the core targets of Fritillariae Thunbergii Bulbus-Sepiae Endoconchadrug pairs in the treatment of GERD included serine/threonine-protein kinase (AKT1)， mitogen-activatedprotein kinase (MAPK) 1， phosphatidylinosiol 3-kinase catalytic domain δ(PIK3CD)， epidermal growthfactor (EGFR)， proto-oncogene (JUN) and so on. Fritillariae Thunbergii Bulbus-Sepiae Endoconchamedicine pairs mainly act on neuroactive ligand-receptor interaction， phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT)， MAPK and cancer signal pathways in the treatment of GERD. Molecular dockingshowed that the core active ingredient Zhebeirine and Peiminine had higher binding activity to AKT1 andother targets. Conclusion： Fritillariae Thunbergii Bulbus-Sepiae Endoconcha drug pairs can act on theAKT1，EGFR and other targets to treat GERD，and its mechanism of action is related to the regulation ofneuroactive ligand-receptor interaction，PI3K/Akt signal，MAPK signal pathway and other signal pathways.