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

Simple Summary: Traditional cancer treatments have long struggled with issues such as toxicity, drug resistance, and financial burdens. However, there is growing interest in using natural compounds, like those found in complementary alternative medicine, due to their ability to influence various molecular pathways with fewer side effects. In our study, we focused on understanding how active components of Cordia myxa could potentially treat liver cancer (LC). By employing network pharmacology techniques, we identified key molecular targets and pathways involved. Through a combination of data analysis and computational modeling, we found that certain genes, including HSP90AA1, ESR1, CYP3A4, CDK1, and MMP9, play crucial roles in LC patient survival. Specifically, our findings suggest that compounds like cosmosiin, rosmarinic acid, quercetin, and rubinin may interact with HSP90AA1, offering a promising avenue for therapeutic intervention. Molecular dynamics simulations further validated these interactions, highlighting the stability of the drug–protein complexes. Overall, our integrated approach underscores the potential of C. myxa in combating LC by modulating cancer-related signaling pathways. 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. [ABSTRACT FROM AUTHOR]