网络毒理学和分子对接分析马钱子碱表明 CHRM1 是潜在的神经毒性靶点。
Network toxicology and molecular docking analyses on strychnine indicate CHRM1 is a potential neurotoxic target.
机构信息
School of Forensic Medicine, Guizhou Medical University, Guiyang, Guizhou Province, China.
Department of technology, Zhongshan branch of Liupanshui Public Security Bureau, Liupanshui, Guizhou Province, China.
出版信息
BMC Complement Med Ther. 2022 Oct 17;22(1):273. doi: 10.1186/s12906-022-03753-4.
BACKGROUND
Improper use of strychnine can cause death. The aim of this study was to identify and evaluate toxic mechanisms of action associated with active compounds in strychnine using a network toxicology approach, and explore potential pathogenic targets.
METHODS
In the present study, strychnine target and central nervous system-related gene set were established using the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database and four disease gene databases (Genecards, OMIM, PharmGkb, TTD). An "ingredient-target" interactive active network map was constructed using Cytoscape software (version 3.8.0). Functional enrichment analysis was performed based on the hub genes. A protein-protein interaction network was constructed using STRING database. The pharmacokinetics (ADMET) properties of strychnine were evaluated using SwissADME tool. Molecular docking was performed using Autodock Vina to explore the interactions between the active compounds and the target protein.
RESULTS
Five strychnine toxicity-related components and a gene set of 40 genes were obtained. GO and KEGG analyses showed that Strychnine acts on the central nervous system through G protein-coupled receptor signaling pathway. Analysis of "ADMET" related parameters showed a high gastrointestinal tract absorption of (S)-stylopine and isobrucine and the compounds could cross the blood brain barrier. CHRM1 was selected as a key gene in strychnine toxicity. Molecular docking results showed that the co-crystalized ligands did not form hydrogen bond with CHRM1. (S)-stylopine had the highest binding affinity (binding energy = - 8.5 kcal/mol) compared with the other two compounds.
CONCLUSION
Network toxicology and molecular docking reveal the toxicity mechanisms of strychnine active compounds. The findings showed that CHRM1 is a potential neurotoxic target. (S)-stylopine showed stronger neurotoxic effect compared with the other ligands.
背景
士的宁使用不当可导致死亡。本研究旨在采用网络毒理学方法鉴定和评估士的宁中活性化合物相关的毒性作用机制，并探讨潜在的致病靶点。
方法
本研究采用中药系统药理学（TCMSP）数据库和四个疾病基因数据库（Genecards、OMIM、PharmGkb、TTD），建立了士的宁靶点和中枢神经系统相关基因集。利用 Cytoscape 软件（版本 3.8.0）构建“成分-靶点”互作活性网络图谱。基于枢纽基因进行功能富集分析。利用 STRING 数据库构建蛋白-蛋白相互作用网络。采用 SwissADME 工具评估士的宁的药代动力学（ADMET）性质。利用 Autodock Vina 进行分子对接，以探讨活性化合物与靶蛋白之间的相互作用。
结果
获得了 5 种士的宁毒性相关成分和 40 个基因的基因集。GO 和 KEGG 分析表明，士的宁通过 G 蛋白偶联受体信号通路作用于中枢神经系统。“ADMET”相关参数分析表明，（S）-马钱子碱和异士的宁具有较高的胃肠道吸收能力，且这两种化合物可穿透血脑屏障。CHRM1 被选为士的宁毒性的关键基因。分子对接结果表明，共晶配体未与 CHRM1 形成氢键。与其他两种化合物相比，（S）-马钱子碱具有更高的结合亲和力（结合能=-8.5 kcal/mol）。
结论
网络毒理学和分子对接揭示了士的宁活性化合物的毒性作用机制。研究结果表明，CHRM1 是一个潜在的神经毒性靶点。与其他配体相比，（S）-马钱子碱表现出更强的神经毒性作用。
Zotero 插件