基于网络药理学研究萘哌地尔衍生物YM Ⅲ降压作用及机制初探  

STUDY ON THE ANTIHYPERTENSIVE EFFECT AND MECHANISM OF YMIII DERIVATIVE OF NAPHTHOPIDIL BASED ON NETWORK PHARMACOLOGY

作　　者：李冬梅[1] 边梦霓 侯毅杰 董永和[1] 马俊兵[1] 邱敏[1] 杨征 LI Dongmei;BIAN Mengni;HOU Yijie;DONG Yonghe;MA Junbing;QIU Min;YANG Zheng(Baotou Medical College,Baotou 014040,China)

机构地区：[1]包头医学院,内蒙古包头014040

出　　处：《内蒙古医科大学学报》2023年第1期1-6,9,共7页Journal of Inner Mongolia Medical University

摘　　要：目的 本文旨在通过网络药理学方法阐述萘哌地尔衍生物YM Ⅲ对高血压的治疗作用,分析涉及的生物过程和信号通路,探讨其潜在的降压机制。方法 通过Swiss Target Prediction、Gene Cards数据库分别筛选YM Ⅲ、高血压靶点。通过PPI、GO、KEGG获得YM Ⅲ治疗高血压可能涉及的重要靶点、生物过程和信号通路,Cytoscape用于构建PPI和多个相关网络图以直观展现药物-疾病的复杂联系,随后进行分子对接,预测活性化合物与核心靶点的结合。最后,通过动物实验进一步验证研究结果。结果 通过数据库查询获得104个YM Ⅲ药理靶点和2 614个高血压靶点,确定了46个化合物-疾病交叉靶点。神经活性受体配体相互作用、钙信号通路、缝隙连接、TRP通道的炎症介质调节、多巴胺能突触可能是YM Ⅲ干预高血压的主要通路,它与腺苷酸环化酶激活肾上腺素能受体信号通路、胞浆钙离子浓度、血管收缩调节等多种生物过程相关。分子对接证实YM Ⅲ与关键靶点紧密结合。动物实验表明,YM Ⅲ对去甲肾上腺素(NA)在无Ca^(2+)及复Ca^(2+)条件下所致家兔胸主动脉血管条的收缩呈浓度依赖性抑制作用,而YM Ⅲ10^(-5)mol·L^(-1)在无Ca^(2+)液中对咖啡因所致血管条收缩没有抑制作用。结论 YM Ⅲ可能主要通过对肾上腺素受体-配体结合的抑制,调节细胞内Ca^(2+)稳态,从而扩张血管,发挥降压作用。Objective The purpose of this study is to elucidate the therapeutic effect of naftopidil derivative YMⅢon hypertension by network pharmacological methods,analyze the biological processes and related signaling pathways,explore its potential antihypertensive mechanisms.Methods Select YMⅢand hypertension targets through the Swiss Target Prediction and Gene Cards databases,respectively.By using PPI,GO,and KEGG,important targets,biological processes,and signaling pathways that may be involved in the treatment of hypertension with YMⅢwere obtained.Cytoscape was used to construct PPI and multiple related network diagrams to intuitively display the complex relationship between drugs and diseases.Subsequently,molecular docking was performed to predict the binding of active compounds to core targets.Finally,the research results were further validated through animal experiments.Results The 104 pharmacological targets of YMⅢand 2614 targets of hyperten-sion were obtained by database search targets,and 46 overlapping targets were identifed.Neuroactive ligand-receptor interaction,calcium signaling pathway,gap junction,inflammatory mediator regulation of TRP channels,and dopaminergic synapse may be the main pathways for YMⅢintervention in hypertension,which were related to various biological processes such as adenylate cyclase-activating adrenergic receptor signaling pathway,cellular calcium ion homeostasis,and positive regulation of vasoconstriction.Molecular docking confirmed that YMⅢhad closely binding activities to the key targets.Animal experiments showed that YMⅢhad a concentration dependent inhibitory effect on the contraction of rabbit thoracic aorta strips induced by norepinephrine(NA)in the absence of Ca^(2+)and compound Ca^(2+),while YMⅢ10^(-5)mol·L^(-1) had no inhibitory effect on the contraction of caffeine induced vascular strips in the absence of Ca^(2+)solution.Conclusions YMⅢmay mainly regulate the binding of adrenergic receptors and ligands through inhibition intracellular Ca^(2+)homeostasis

关 键 词：网络药理学 分子对接 高血压 萘哌地尔 萘哌地尔衍生物YMⅢ 

分 类 号：R453[医药卫生—治疗学]