Integration of molecular docking, molecular dynamics and network pharmacology to explore the multi-target pharmacology of fenugreek against diabetes

Abstract

Fenugreek is an ancient herb that has been used for centuries to treat diabetes. However, how the fenugreek-derived chemical compounds work in treating diabetes remains unclarified. Herein, we integrate molecular docking and network pharmacology to elucidate the active constituents and potential mechanisms of fenugreek against diabetes. First, 19 active compounds from fenugreek and 71 key diabetes-related targets were identified through network pharmacology analysis. Then, molecular docking and simulations results suggest diosgenin, luteolin and quercetin against diabetes via regulation of the genes ESR1, CAV1, VEGFA, TP53, CAT, AKT1, IL6 and IL1. These compounds and genes may be key factors of fenugreek in treating diabetes. Cells results demonstrate that fenugreek has good biological safety and can effectively improve the glucose consumption of IR-HepG2 cells. Pathway enrichment analysis revealed that the anti-diabetic effect of fenugreek was regulated by the AGE-RAGE and NF-κB signalling pathways. It is mainly associated with anti-oxidative stress, anti-inflammatory response and β-cell protection. Our study identified the active constituents and potential signalling pathways involved in the anti-diabetic effect of fenugreek. These findings provide a theoretical basis for understanding the mechanism of the anti-diabetic effect of fenugreek. Finally, this study may help for developing anti-diabetic dietary supplements or drugs based on fenugreek.

Keywords: anti-inflammatory; anti-oxidative stress; diabetes; fenugreek; molecular docking; network pharmacology.

FIGURE 1

Study workflow comprising a network pharmacology stage and a validation and prediction stage, aimed at elucidating the mechanisms underlying the anti‐diabetic effects of fenugreek.

FIGURE 2

Network pharmacology analyse results. (A) Venn diagram of fenugreek–diabetes targets. (B) Drug‐Compound‐Target‐Disease interaction network. Green diamonds are active compounds, the pink hexagon is the disease, purple circles are the common target genes of the compounds and the disease and the lines represent interactions between compounds and targets. (C) PPI network of the common target genes. Diamonds represent proteins, the colours (from blue to green to yellow) indicate the degree of binding between proteins and the lines represent protein‐protein interactions. (D) Compound‐Gene‐Pathway network. Blue rectangles represent hub genes, purple circles represent active compounds and green diamonds indicate pathways associated with the core targets.

FIGURE 3

Visualization of GO term enrichment.

FIGURE 4

Visualization of KEGG pathway enrichment.

FIGURE 5

Action of the core target on the AGE‐RAGE signalling pathway in diabetic complications. Red rectangles represent the key targets.

FIGURE 6

Molecular docking results of the important compounds and the corresponding proteins of the gene targets.

FIGURE 7

RMSD and RMSF plot of selected receptor‐ligand complexes during molecular dynamics simulations. (Ref): reference system.

FIGURE 8

Effects of fenugreek on cell viability and glucose uptake in IR‐HepG2 cells. (A) Cell viability of HepG2 cells cultured in different concentrations of fenugreek from 0 to 1600 μg/mL for 24 h and 48 h. (B) Glucose consumption of IR HepG2 cells incubated with or without fenugreek for 24 h (****p < 0.001 vs. the model group, ***p < 0.01 vs. the model group, *p < 0.05 vs. the model group).