| 引用本文:米硕，韩舒，刘凯洋，包丽媛，张凤婷，王宏月，李文汇，赵颖，杜红.基于药效团和分子对接探究诃子制草乌通过瞬时受体电位香草酸1介导的减毒机制[J].世界中医药,2023,(12):. |
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| 基于药效团和分子对接探究诃子制草乌通过瞬时受体电位香草酸1介导的减毒机制 |
| Mechanism of Aconitum kusnezoffii Processed with Terminalia chebula in Reducing Toxicity Mediated by TRPV1 Based on Pharmacophore and Molecular Docking |
| 投稿时间：2022-05-29 |
| DOI：10.3969/j.issn.1673-7202.2023.12.001 |
| 中文关键词: 药效团 分子对接 新乌头碱 没食子酸 诃子制草乌 瞬时受体电位香草酸1通道 H9c2心肌细胞 炮制减毒原理 |
| English Keywords:Pharmacophore Molecular docking Mesaconitine Gallic acid Aconitum kusnezoffii processed with Terminalia chebula TRPV1 channel H9c2 cardiomyocytes Principle of toxicity reduction by processing |
| 基金项目:国家自然科学基金项目（82274206）；国家自然科学基金面上项目（81774004）；国家自然科学基金重点项目（82130113) |
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| 中文摘要: |
| 目的：本研究利用药效团、分子对接及实时反转录PCR（RT-PCR)方法探究诃子制草乌通过瞬时受体电位香草酸1（TRPV1）介导的减毒机制。方法：采用Discovery Studio 4.0软件构建基于TRPV1激动剂分子共同特征的TRPV1激活药效团，虚拟筛选出草乌中的潜在活性成分；对草乌成分及诃子制草乌中引入的诃子成分进行Autodock vina分子对接研究；根据结果选出代表性成分，采用实时反转录PCR验证是否可促进心肌细胞中TRPV1 mRNA表达。结果：药效团共筛选出草乌中包括毒性较大的双酯型生物碱乌头碱、新乌头碱及次乌头碱在内的13个成分，分子对接结果表明这13个成分及诃子制草乌引入的诃子成分均有潜力与TRPV1结合。RT-PCR实验中没食子酸和新乌头碱在浓度≥25 μmol/L时，均可明显促进大鼠H9c2心肌细胞中TRPV1 mRNA表达的增加，随着给药浓度的增大表达量增加，新乌头碱促进TRPV1 mRNA表达的作用更强。药效团、分子对接结果表明诃子和草乌中均含有多种具备TRPV1激活潜力的成分。结论：实验证明新乌头碱、没食子酸均可在一定程度上激活TRPV1通道，可作为TRPV1的激动剂。根据结果推测，诃子可能会通过拮抗草乌中的活性成分与TRPV1的结合，从而降低草乌通过TRPV1介导的毒性；也可能是诃子制草乌在引入没食子酸等诃子成分后，可在安全剂量范围内使TRPV1通道快速脱敏从而实现减毒。 |
| English Summary: |
| To explore the mechanism of Aconitum kusnezoffii processed with Terminalia chebula in reducing toxicity mediated by transient receptor potential vanilloid 1(TRPV1) based on pharmacophore，molecular docking，and real-time reverse transcription PCR(RT-PCR).Methods:The Discovery Studio 4.0 software was used to construct a pharmacophore model based on the common features of TRPV1 agonists.Virtual screening was performed to identify potential active compounds in A.kusnezoffii.Molecular docking was conducted using Autodock vina on the components of A.kusnezoffii and the introduced components of T.chebula in A.kusnezoffii processed with T.chebula.Representative compounds were selected based on the results，and real-time RT-PCR was used to verify their ability to promote TRPV1 mRNA expression in cardiomyocytes.Results:The pharmacophore model identified 13 compounds in A.kusnezoffii，including the highly toxic diester alkaloids aconitine，mesaconitine，and hypaconitine.The molecular docking results indicated that these 13 compounds，as well as the introduced components of T.chebula in A.kusnezoffii processed with T.chebula，had the potential to bind to TRPV1.In the RT-PCR experiments，gallic acid and mesaconitine significantly increased TRPV1 mRNA expression in rat H9c2 cardiomyocytes at the concentration of≥25 μmol/L，with increased expression levels observed with higher concentrations.Mesaconitine exhibited a stronger effect on promoting TRPV1 mRNA expression.The pharmacophore modeling and molecular docking results demonstrated the presence of multiple components in T.chebula and A.kusnezoffii with the potential to activate TRPV1.Conclusion:Experimental results confirmed that mesaconitine and gallic acid can activate the TRPV1 channel to a certain extent，indicating their role as TRPV1 agonists.Based on the results，it can be inferred that T.chebula may reduce the toxicity mediated by TRPV1 by antagonizing the binding of active components in A.kusnezoffii to TRPV1.Alternatively，A.kusnezoffii processed with T.chebula may achieve detoxification by rapidly desensitizing the TRPV1 channel within a safe dose range after introducing gallic acid and other components. |
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