Antidiabetic Activity, Molecular Docking, and ADMET Properties of Compounds Isolated from Bioactive Ethyl Acetate Fraction of Ficus lutea Leaf Extract

Abstract

Diabetes contributes to the rising global death rate. Despite scientific advancements in understanding and managing diabetes, no single therapeutic agent has been identified to effectively treat and prevent its progression. Consequently, the exploration for new antidiabetic therapeutics continues. This study aimed to investigate the antidiabetic bioactive ethyl acetate fraction of F. lutea at the molecular level to understand the molecular interactions and ligand-protein binding. To do this, the fraction underwent column chromatography fractionation to yield five compounds: lupeol, stigmasterol, α-amyrin acetate, epicatechin, and epiafzelechin. These compounds were evaluated in vitro through α-glucosidase inhibition and glucose utilization assays in C2C12 muscle and H-4-11-E liver cells using standard methods. In silico analysis was conducted using molecular docking and ADMET studies. Epicatechin exhibited the most potent α-glucosidase inhibition (IC₅₀ = 5.72 ± 2.7 µg/mL), while epiafzelechin stimulated superior glucose utilization in C2C12 muscle cells (33.35 ± 1.8%) and H-4-11-E liver cells (46.7 ± 1.2%) at a concentration of 250 µg/mL. The binding energies of the isolated compounds for glycogen phosphorylase (1NOI) and α-amylase (1OSE) were stronger (<-8.1) than those of the positive controls. Overall, all tested compounds exhibited characteristics indicative of their potential as antidiabetic agents; however, toxicity profiling predicted epiafzelechin and epicatechin as better alternatives. The ethyl acetate fraction and its compounds, particularly epiafzelechin, showed promise as antidiabetic agents. However, further comprehensive studies are necessary to validate these findings.

Keywords: ADMET; Ficus lutea; antidiabetic; molecular docking; phytochemical.

Figure 1

Elucidated structures of compounds of the ethyl acetate fraction of F. lutea leaf acetone extract.

Figure 2

Glucose utilization in (a) C2C12 muscle cells and (b) H-4-11-E rat liver cells (expressed as a percentage of untreated control cells ± standard error of the mean, n = 9) exposed to compounds isolated from the ethyl acetate fraction of F. lutea leaf acetone extract.

Figure 3

Molecular interactions of the isolated compounds ((A) = Lupeol, (B) = a-Amyrin-acetate, (C) = Stigmasterol, (D) = Epiafzelechin, and (E) =Epicatechin) from the ethyl acetate fraction with the lowest binding affinity against the Glycogen phosphorylase receptor (PDB ID: 1NOI).

Figure 4

Molecular interactions of the isolated compounds ((A) = Lupeol, (B) = a-Amyrin-acetate) from ethyl acetate fraction with the lowest binding affinity against the Dipeptidyl peptidase 4 (DPP-IV) receptor (PDB ID: 2P8S).

Figure 5

Molecular interactions of the isolated compounds ((A) = Stigmasterol, (B) =Lupeol) from the ethyl acetate fraction with the lowest binding affinity against the D α-Amylase receptor (PDB ID: 1OSE).