基于网络药理学和分子对接揭示熊果酸治疗肺动脉高压的分子机制

Revealing the Mechanism of Ursolic Acid in Treating Pulmonary Hypertension Based on Network Pharmacology and Molecular Docking

摘要: 目的：采用网络药理学和分子对接探究熊果酸治疗肺动脉高压的潜在作用靶点及信号通路。方法：检索PubChem数据库获得熊果酸的作用靶点，利用GeneCards数据库得到肺动脉高压相关疾病靶点，绘制韦恩图获取两者的交集靶点，String数据库构建交集靶点蛋白相互作用网络图，并导入Cytoscape3.10.1软件使网络可视化，然后筛选关键靶点。利用DAVID数据库和在线工具对熊果酸和肺动脉高压的交集靶点进行GO功能和KEGG通路富集分析。最后利用AutoDock和Pymol软件对熊果酸与核心靶点进行分子对接并对结果进行可视化分析。结果：获得熊果酸作用靶点75个，通过PPI图得到过氧化物酶体增殖物激活受体γ基因(peroxisome proliferator-activated receptor gamma, PPARG)、前列腺素内过氧化物合酶2 (prostaglandin-endoperoxide synthase-2, PTGS2)、雌激素受体1基因(estrogen receptor 1, ESR1)、丝裂原活化蛋白激酶3 (mitogen-activated protein kinase 3, MAPK3)、核受体亚家族3组成员1 (nuclear receptor subfamily 3 group C member 1, NR3C1)等关键蛋白。富集分析显示，参与的通路主要集中在花生四烯酸代谢通路、肿瘤相关通路、5-羟色胺能突触信号通路、PPAR信号通路等。分子对接验证亦显示熊果酸与核心靶点的结合活性较好。结论：熊果酸治疗肺动脉高压通过多靶点、多通路发挥作用，但具体作用机制尚需要动物实验与临床试验的进一步验证。

Abstract: Objective: To explore the potential targets and signal pathway of ursolic acid in treating pulmonary hypertension with network pharmacology and molecular docking technology. Methods: Pubchem was used to retrieve the potential targets of ursolic acid. The related targets of PH were collected by GeneCards. The intersection targets of ursolic acid and pulmonary hypertension were determined by the Wayne diagram. The protein interaction network of intersection targets was constructed by using the String database, and the network was visualized by Cytoscape3.10.1 software to screen key targets. The enrichment analysis of GO function and KEGG pathway was analyzed by the DAVID database and online tools. The molecular docking of ursolic acid and the core targets was performed by AutoDock and Pymol software, and the results were visualized. Results: Seventy-five ursolic acid action targets were obtained, and key proteins such as peroxisome proliferator-activated receptor gamma (PPARG), prostaglandin-endoperoxide synthase-2 (PTGS2), estrogen receptor 1 (ESR1), mitogen-activated protein kinase 3 (MAPK3) and nuclear receptor subfamily 3 group C member 1 (NR3C1) were obtained by PPI map. Enrichment analysis showed that the pathways of ursolic acid treatment for pulmonary hypertension mainly focused on arachidonic acid metabolism pathways, pathways in cancer, serotonergic synaptic signaling pathway, PPAR signalling pathway and so on. The molecular docking validation also showed that ursolic acid had better binding activity with the core targets. Conclusion: ursolic acid plays a role in the treatment of pulmonary hypertension through multiple targets and multiple pathways, but the specific mechanism needs further verification by animal experiments and clinical trials.