Exploring the Active Ingredients and Mechanism of Action of Huanglian Huazhuo Capsule for the Treatment of Obese Type-2 Diabetes Mellitus Based on Using Network Pharmacology and Molecular Docking

Abstract

Background: Obese type 2 diabetes mellitus (obese T2DM) is one of the prime diseases that endangers human health. Clinical studies have confirmed the ability of the Huanglian Huazhuo capsule to treat obese T2DM; however, its mechanism of action is still unclear. In this study, effects and mechanisms of the Huanglian Huazhuo capsule in obese T2DM were systematically investigated using network pharmacology and molecular docking techniques.

Methods: The active ingredients and targets of the Huanglian Huazhuo capsule were extracted from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). Obese T2DM diabetes-related targets were retrieved from a geographic dataset combined with a gene card database. A protein-protein interaction (PPI) network was constructed to screen core targets. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted using Database for Annotation Visualization and Integrated Discovery (DAVID). Interactions between potential targets and active compounds were assessed using molecular docking. Molecular docking was performed on the best core protein complexes obtained using molecular docking.

Results: A total of 89 and 108 active ingredients and targets, respectively, were identified. Seven core targets were obtained using a topological analysis of the PPI network. The GO and KEGG pathway enrichment analyses showed that the effects of the Huanglian Huazhuo capsules were mediated by inflammation, lipid response, oxidative stress-related genes, and HIF-1 and IL-17 signaling pathways. Good binding ability was observed between the active compounds and screened targets using molecular docking.

Conclusions: The active ingredients, potential targets, and pathways of the Huanglian Huazhuo capsule for the treatment of obese T2DM were successfully predicted, providing a new strategy for further investigation of its molecular mechanisms. In addition, the potential active ingredients provide a reliable source for drug screening in obese T2DM.

Figure 1

Screening of common targets for the Huanglian Huazhuo capsule-obese T2DM. (a) The differential gene volcano plot shows gene distribution in the disease samples. Red and green represent upregulated and downregulated genes, respectively, and black indicates no significant difference. (b) The heat map shows the expression patterns of 28 DEGs. Columns correspond to samples, and rows correspond to genes.

Figure 2

Venn diagram of the Huanglian Huazhuo capsule corresponding to target and disease corresponding to target intersection. Green represents the number of targets of the active components of the drug, and pink represents the number of disease-related genes, which are 108 cross-targeted genes.

Figure 3

(a) In the “drug-component-target-disease” network, the pink circles represent the Huanglian Huazhuo capsules, the blue rectangles represent drugs, the green diamonds represent drug compounds, the purple circles represent diseases, and the blue triangles represent target proteins. (b) In the small molecule network plot, blue represents quercetin and its corresponding target, purple represents beta-sitosterol and its corresponding target, cyan represents stigmasterol and its corresponding target, red represents kaempferol and its corresponding target, pink represents luteolin and its corresponding target, red represents tanshinone IIA and its corresponding targets, and green represents naringenin and its corresponding targets.

Figure 4

Topological screening process of the PPI network. A total of 85 common targets were screened using degree centrality (DC), betweenness centrality (BC), and closeness centrality (CC), and seven core targets were obtained.

Figure 5

GO enrichment analysis. (a) Histogram of biological process category terms in the GO enrichment analysis. (b) Bubble diagram of biological process category terms in the GO enrichment analysis.

Figure 6

KEGG enrichment analysis and critical path network construction. (a) Histogram of the top 20 pathways based on KEGG enrichment analysis. (b) Bubble diagram of the top 20 pathways based on KEGG enrichment analysis. (c) Compound-target-pathway network associated with the mechanism of the Huanglian Huazhuo capsule for obese T2DM treatment. Purple nodes represent targets, dark green nodes represent compounds, and light green nodes represent pathways.

Figure 7

Distribution of key targets in the most relevant paths.

Figure 8

Thermogram of molecular docking fractions. Binding energy of key targets and herbal active compounds (kcal/mol).

Figure 9

Docking patterns of key targets and specific active compounds. Tanshinone IIA-STAT3 (a), tanshinone IIA-MAPK1 (b), luteolin-RELA (c), tanshinone IIA-IL6 (d), stigmasterol-TNF (e), quercetin-ESR1 (f), and tanshinone IIA-IL10 (g).