吴茱萸碱衍生物血管舒张活性评价及分子对接模拟研究

Vasodilatory Activity Evaluation and Molecular Docking Simulation of Evodiamine Derivatives

合成了6个吴茱萸碱衍生物5a-5f,并通过血管环实验、CCK-8细胞增殖实验、内皮细胞毒性实验对其血管舒张活性、细胞毒性进行了研究,通过网络药理学方法筛选了吴茱萸碱与高血压的关联靶点,通过分子对接分析了高活性衍生物5a与5个关联靶点的相互作用模式。结果表明,吴茱萸碱衍生物5a-5f均对苯肾上腺素预收缩的大鼠肠系膜动脉血管具有舒张作用,其中衍生物5a的舒张作用最强;吴茱萸碱衍生物5a-5f对肝癌细胞的细胞毒性相比吴茱萸碱有所改变,其中衍生物5a、5c对肝癌细胞的细胞毒性有所下降;衍生物5a对内皮细胞HUVEC的损伤比吴茱萸碱略小;筛选出吴茱萸碱与高血压的关联靶点5个,活性较高的衍生物5a与这5个关联靶点的结合能均较高,可以通过氢键、疏水作用和碳氢相互作用等多种方式进行对接,表明这类吴茱萸碱衍生物很可能通过多靶点共同作用而具有了较高的血管舒张活性。

In this paper,we synthesized six evodiamine derivatives 5a-5f,and studied their vasodilatory activities and cytotoxicities by vascular loop experiment,CCK-8 cell proliferation experiment,and endothelial cytotoxicity experiment.Moreover,we screened the associated targets of evodiamine and hypertension by network pharmacology.Furthermore,we analyzed the interaction mode between the high activity derivative 5a and five associated targets.The results show that the evodiamine derivatives 5a-5f have diastolic effects on the mesenteric artery of rat pre-constricted by phenylephrine,among which derivative 5a has the strongest diastolic effect.The cytotoxicities of evodiamine derivatives 5a-5f to hepatocellular carcinoma cells are changed compared with evodiamine,and the cytotoxicities of derivatives 5a and 5c to hepatocellular carcinoma cells are slightly decreased.Derivative 5a has slightly less damage to endothelial cells HUVEC than the evodiamine.Five associated targets of evodiamine and hypertension are selected.Derivative 5a with high activity has high binding energy with the five associated targets,and can be docked through hydrogen bonds,hydrophobic interaction,and hydrocarbon interaction.The results indicate that this type of evodiamine derivatives are likely to have high vasodilation activity through multiple target interactions.