基于细胞模型和网络药理学探究儿茶素抗炎、抗癌的构效关系

应思慧; 鲁森; 陈忠正; 张媛媛; 李斌; 林晓蓉

doi:10.13386/j.issn1002-0306.2023050014

基于细胞模型和网络药理学探究儿茶素抗炎、抗癌的构效关系

Study on Structure-function Relationship of the Anti-inflammatory and Anti-cancer Effects of Catechins Using Cell Models and Network Pharmacology

摘要

摘要: 目的：系统揭示茶叶儿茶素的抗炎、抗癌构效关系，并初步探究其背后的分子作用机制。方法：利用脂多糖诱导的小鼠巨噬细胞RAW264.7和人结肠癌细胞HCT116为体外炎症、癌症模型，采用格里斯试剂法与四甲基偶氮噻唑蓝比色法分析比较儿茶素的体外抗炎、抗癌活性，借助网络药理学预测各儿茶素抗炎、抗癌的关键靶点与通路，并通过分子对接技术模拟各儿茶素与关键靶点蛋白的相互作用，比较各单体与关键靶点的结合能力。结果：8种儿茶素单体均有较强的体外抗炎、抗癌活性，酯型儿茶素的没食子酰基、焦酚型儿茶素B环的邻苯三酚结构和反式儿茶素C₂、C₃的反式构象使其具有更强的抗炎、抗癌活性，但酯型、焦酚型儿茶素的没食子酰基与其B环的邻苯三酚结构间存在拮抗效应；8种儿茶素通过多靶点、多通路发挥抗炎、抗癌活性，且没食子酰基有利于儿茶素与其关键抗炎、抗癌靶蛋白IL6、TNF、AKT1通过氢键结合。本文揭示了儿茶素的体外抗炎、抗癌活性及构效关系，为系统、深入阐释儿茶素的功能特性与分子结构等关系提供了理论和技术借鉴。

Abstract: Objective: To explore the relationship between the structure of tea catechins and their anti-inflammatory and anti-cancer activities and to preliminarily elucidate the underlining mechanism behind the structure-function relationship. Methods: The lipopolysaccharide-induced murine macrophage cells RAW 264.7 and human colorectal cancer cells HCT116 were used as in vitro models for inflammation and cancer. The in vitro anti-inflammatory and anti-cancer activities of catechins were analyzed by Griess reagent colorimetric method and tetramethyl azothiazole blue colorimetric method. The key targets and pathways of the anti-inflammatory and anti-cancer of each catechin monomer were predicted by network pharmacology. The interactions between catechins and key target proteins were simulated by molecular docking technique, and the binding ability of each component to key targets was compared. Results: The significant in vitro anti-inflammatory and anti-cancer potentials of eight catechins were confirmed. Additionally, the galloyl group in gallated catechins, the pyrogallol moiety of B-ring in pyrogallol-type catechins, and the trans-type structure of C₂-C₃ in trans catechins were found to be beneficial for their anti-inflammatory and anti-cancer activities, however, an antagonistic effect was also observed between the pyrogallol moiety in B-ring and the galloyl group of pyrogallol-type gallated catechins. Furthermore, multiple targets and pathways were predicted to be involved in the anti-inflammatory and anti-cancer effects of eight catechin monomers. The galloyl group in catechins was found to be beneficial for their regulatory effects on multiple targets and their interaction with key target proteins including IL6, TNF, and AKT1 through hydrogen bonding. The present study preliminarily reveals the structure-function relationship behind the anti-inflammatory and anti-cancer functions of catechins. It provides theoretical and technical instruction for further elucidation of the relationship between the functional effects and the molecular structures of catechins.