Network Pharmacology, Molecular Docking, and Molecular Dynamics Simulation Analysis Reveal Insights into the Molecular Mechanism of Cordia myxa in the Treatment of Liver Cancer

Abstract

Traditional treatments of cancer have faced various challenges, including toxicity, medication resistance, and financial burdens. On the other hand, bioactive phytochemicals employed in complementary alternative medicine have recently gained interest due to their ability to control a wide range of molecular pathways while being less harmful. As a result, we used a network pharmacology approach to study the possible regulatory mechanisms of active constituents of Cordia myxa for the treatment of liver cancer (LC). Active constituents were retrieved from the IMPPAT database and the literature review, and their targets were retrieved from the STITCH and Swiss Target Prediction databases. LC-related targets were retrieved from expression datasets (GSE39791, GSE76427, GSE22058, GSE87630, and GSE112790) through gene expression omnibus (GEO). The DAVID Gene Ontology (GO) database was used to annotate target proteins, while the Kyoto Encyclopedia and Genome Database (KEGG) was used to analyze signaling pathway enrichment. STRING and Cytoscape were used to create protein-protein interaction networks (PPI), while the degree scoring algorithm of CytoHubba was used to identify hub genes. The GEPIA2 server was used for survival analysis, and PyRx was used for molecular docking analysis. Survival and network analysis revealed that five genes named heat shot protein 90 AA1 (HSP90AA1), estrogen receptor 1 (ESR1), cytochrome P450 3A4 (CYP3A4), cyclin-dependent kinase 1 (CDK1), and matrix metalloproteinase-9 (MMP9) are linked with the survival of LC patients. Finally, we conclude that four extremely active ingredients, namely cosmosiin, rosmarinic acid, quercetin, and rubinin influence the expression of HSP90AA1, which may serve as a potential therapeutic target for LC. These results were further validated by molecular dynamics simulation analysis, which predicted the complexes with highly stable dynamics. The residues of the targeted protein showed a highly stable nature except for the N-terminal domain without affecting the drug binding. An integrated network pharmacology and docking study demonstrated that C. myxa had a promising preventative effect on LC by working on cancer-related signaling pathways.

Keywords: Cordia myxa; bioinformatics; liver cancer; molecular docking; network pharmacology; survival analysis; traditional Chinese medicine.

Figure 1

Graphical representation of the workflow of this study.

Figure 2

Compound–target network of 173 common targets of 10 active compounds. Blue color represents the compounds, and yellow color represents the targets.

Figure 3

Volcano plots of DEGs. (A) GSE39791, (B) GSE76427, (C) GSE22058, (D) GSE87630, and (E) GSE112790. Blue and red colors represent down-regulated and up-regulated genes, respectively. (F) With a total of 173 overlapping genes, the Venn diagram shows the targets of C. myxa and LC.

Figure 4

(A–D) depicts a bubble chart of the top 20 enriched GO terms (BP, CC, MF) and KEGG pathways, respectively.

Figure 5

(A) Ten hub genes based on degree. (B) Bar chart of 10 hub genes. (C) Co-expression of hub genes in Homo sapiens.

Figure 6

Compound/drug–target–pathways network. The orange V shapes represent the active constituents/drugs associated with hub genes, the green circles represent hub genes, and the cyan triangles represent the pathways linked to the hub genes.

Figure 7

The GEPIA 2 was used to evaluate the survival data of the hub genes including (A) ALB, (B) IL6, (C) HSP90AA1, (D) ESR1, (E) CYP3A4, (F) PTGS2, (G) TLR4, (H) CDK1, (I) MMP9, and (J) CYP1A1. The red line shows patients with expression levels above the median, whereas the black line reflects expression levels below the median. HR stands for the hazard ratio.

Figure 8

Docking position and interactions of 3 highly bounded compounds with HSP90AA1.

Figure 9

(A) RMSD, (B) RMSF, (C) RoG, and (D) Beta Factor plots for the complexes.

Figure 10

SASA analysis for the studied complexes.