Exploring active ingredients and mechanisms of Coptidis Rhizoma-ginger against colon cancer using network pharmacology and molecular docking

Abstract

Background: Colon cancer is the most prevalent and rapidly increasing malignancy globally. It has been suggested that some of the ingredients in the herb pair of Coptidis Rhizoma and ginger (Zingiber officinale), a traditional Chinese medicine, have potential anti-colon cancer properties.

Objective: This study aimed to investigate the molecular mechanisms underlying the effects of the Coptidis Rhizoma-ginger herb pair in treating colon cancer, using an integrated approach combining network pharmacology and molecular docking.

Methods: The ingredients of the herb pair Coptidis Rhizoma-ginger, along with their corresponding protein targets, were obtained from the Traditional Chinese Medicine System Pharmacology and Swiss Target Prediction databases. Target genes associated with colon cancer were retrieved from the GeneCards and OMIM databases. Then, the protein targets of the active ingredients in the herb pair were identified, and the disease-related overlapping targets were determined using the Venn online tool. The protein-protein interaction (PPI) network was constructed using STRING database and analyzed using Cytoscape 3.9.1 to identify key targets. Then, a compound-target-disease-pathway network map was constructed. The intersecting target genes were subjected to Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses for colon cancer treatment. Molecular docking was performed using the Molecular Operating Environment (MOE) software to predict the binding affinity between the key targets and active compounds.

Results: Besides 1922 disease-related targets, 630 targets associated with 20 potential active compounds of the herb pair Coptidis Rhizoma-ginger were collected. Of these, 229 intersection targets were obtained. Forty key targets, including STAT3, Akt1, SRC, and HSP90AA1, were further analyzed using the ClueGO plugin in Cytoscape. These targets are involved in biological processes such as miRNA-mediated gene silencing, phosphatidylinositol 3-kinase (PI3K) signaling, and telomerase activity. KEGG enrichment analysis showed that PI3K-Akt and hypoxia-inducible factor 1 (HIF-1) signaling pathways were closely related to colon cancer prevention by the herb pair Coptidis Rhizoma-ginger. Ten genes (Akt1, TP53, STAT3, SRC, HSP90AA1, JAK2, CASP3, PTGS2, BCl2, and ESR1) were identified as key genes for validation through molecular docking simulation.

Conclusions: This study demonstrated that the herb pair Coptidis Rhizoma-ginger exerted preventive effects against colon cancer by targeting multiple genes, utilizing various active compounds, and modulating multiple pathways. These findings might provide the basis for further investigations into the molecular mechanisms underlying the therapeutic effects of Coptidis Rhizoma-ginger in colon cancer treatment, potentially leading to the development of novel drugs for combating this disease.

Keywords: Colon cancer; Coptidis Rhizoma; ginger; molecular docking; network pharmacology.

Figure 1.

Detailed workflow of the study design.

Figure 2.

Potential target genes and PPI network map of the herb pair Coptidis Rhizoma-ginger for treating colon cancer.

Figure 3.

Representative map of protein-protein cluster network. The darker the red color, the stronger the correlation. (A) One protein-protein cluster with 31 nodes and 337 edges. (B) One protein-protein cluster with 31 nodes and 149 edges. (C) One protein-protein cluster with 26 nodes and 93 edges.

Figure 4.

Potential target gene network of the herb pair Coptidis Rhizoma-ginger.

Figure 5.

Enrichment analysis of BPs, CCs, and MFs of the top 10 key targets. (A) Bubble chart illustrating GO enrichment analysis. (B) Visualization analysis of the 40 key genes.

Figure 6.

Top 20 remarkably enriched KEGG signaling pathway analyses of the herb pair in colon cancer.

Figure 7.

Main pathways were colored using a KEGG mapper. The red color denotes the targets of the herb pair C. Rhizoma-ginger regulation in colon cancer. (A) PI3K-Akt signaling pathway. (B) HIF-1 signaling pathway.

Figure 8.

Results of analysis of the mode of action of active compounds with five protein targets using molecular docking. (A) Action mode of palmidin A (MOL000762) with target BCl2 (PDB:5uuk). (B–F) Action mode of 6-gingerol (MOL002467) with targets HSP90AA1 (PDB:1BYQ) and STAT3 (PDB:6gfa). (C–F) Action mode of berberine (MOL001454) with targets JAK2 (PDB:5aep) and STAT3 (PDB:6gfa). (D and E) Action mode of coptisine (MOL001454) with targets JAK2 (PDB:5aep) and ESR1 (PDB:6v8t).

Figure 8.

(G and H) Action mode of quercetin (MOL001454) with targets STAT3 (PDB:6gfa) and SRC (PDB:2bdf). (I and J) Action mode with targets TP53 (PDB:5O1F) and Akt1 (PDB:2uzs).