抗肝癌的有效成分及分子靶点：网络药理学、分子对接及分子动力学模拟分析。

Active ingredients and molecular targets of against hepatocellular carcinoma: network pharmacology, molecular docking, and molecular dynamics simulation analysis.

机构信息

Basic Medical College, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China.

出版信息

PeerJ. 2022 Jul 18;10:e13737. doi: 10.7717/peerj.13737. eCollection 2022.

DOI:10.7717/peerj.13737

PMID:35873910

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9302432/

Abstract

BACKGROUND

(TM) is a widely used herb. Studies have reported that TM exhibits growth-inhibitory and apoptosis-inducing on multiple tumors, including hepatocellular carcinoma (HCC). The active ingredients, targets, and molecular mechanisms of TM against HCC need to be further elucidated.

METHODS

We identified the active ingredients and targets of TM via HERB, PubChem, SwissADME, SwissTargetPrediction, and PharmMapper. We searched HCC targets from GeneCards, Comparative Toxicogenomics Database (CTD), and DisGeNET. Then, the intersection of drug targets and disease targets was uploaded to the STRING database to construct protein-protein interactions (PPI) networking whose topology parameters were analyzed in Cytoscape software to screen hub targets. Next, we used Metascape for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and we employed AutoDock vina, AMBER18 and PyMOL software along with several auxiliary tools for molecular docking and molecular dynamics (MD) simulation. Finally, based on the in silico findings, cellular experiments were conducted to investigate the effect of TM on HSP90AA1 gene expression.

RESULTS

A total of 228 targets and 35 active ingredients were identified. Twenty two hub targets were selected through PPI networking construction for further investigation. The enrichment analysis showed that protein kinase binding, mitogenactivated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways were mainly involved. Molecular docking and MD simulation results supported good interaction between HSP90 protein and Austricin/Quercetin. The assay showed that TM inhibited the proliferation of HepG2 cells and the expression of HSP90AA1 gene.

CONCLUSIONS

This study is the first to use network pharmacology, molecular docking, MD simulation and cellular experiments to elucidate the active ingredients, molecular targets, and key biological pathways responsible for TM anti-HCC, providing a theoretical basis for further research.

摘要

背景

（TM）是一种广泛使用的草药。研究报道，TM 对多种肿瘤，包括肝癌（HCC），具有生长抑制和诱导凋亡的作用。TM 对 HCC 的活性成分、靶点和分子机制仍需进一步阐明。

方法

我们通过 HERB、PubChem、SwissADME、SwissTargetPrediction 和 PharmMapper 鉴定 TM 的活性成分和靶点。我们从 GeneCards、Comparative Toxicogenomics Database（CTD）和 DisGeNET 中搜索 HCC 靶点。然后，将药物靶点和疾病靶点的交集上传到 STRING 数据库，构建蛋白质-蛋白质相互作用（PPI）网络，并用 Cytoscape 软件分析其拓扑参数，筛选出关键靶点。接下来，我们使用 Metascape 进行基因本体论（GO）和京都基因与基因组百科全书（KEGG）富集分析，并使用 AutoDock vina、AMBER18 和 PyMOL 软件以及其他辅助工具进行分子对接和分子动力学（MD）模拟。最后，根据计算机模拟结果，进行细胞实验以研究 TM 对 HSP90AA1 基因表达的影响。

结果

共鉴定出 228 个靶点和 35 种活性成分。通过 PPI 网络构建，选择了 22 个关键靶点进行进一步研究。富集分析表明，蛋白激酶结合、丝裂原激活蛋白激酶（MAPK）和磷脂酰肌醇 3-激酶（PI3K）/Akt 信号通路是主要涉及的通路。分子对接和 MD 模拟结果支持 HSP 蛋白与 Austricin/Quercetin 之间的良好相互作用。实验表明，TM 抑制 HepG2 细胞的增殖和 HSP90AA1 基因的表达。