Antidiabetic Bioactive Compounds from <i>Juglans regia</i> L. Fruit Endocarp: Isolation, Characterization, and In Silico Molecular Dynamics Simulations

Abstract This study explores the antidiabetic potential of bioactive compounds isolated from Juglans regia Linn. fruit endocarp fractions. The ethanolic extract was screened for α ‐amylase inhibition, revealing the chloroform fraction as the most potent (18.45 ± 0.76%), followed by the n ‐hexane fraction (12.65 ± 0.52%) and results were compared to acarbose (21.84 ± 1.67%). These results were further supported by the nonenzymatic glycosylation of hemoglobin assay. Five compounds were isolated by employing column chromatography from both fractions and were structurally characterized using ¹H NMR and ¹ 3 C NMR spectroscopy. Density functional theory (DFT) analysis confirmed their stability and reactivity. Molecular docking, molecular dynamics (MD) simulations, and MM/GBSA calculations revealed that compounds 2 and 5 displayed strong interactions with human pancreatic α ‐amylase (PDB: 4GQR) and hemoglobin (PDB: 2D60), respectively. MM/GBSA analysis quantified the binding free energies, reinforcing the stability of these interactions, while MD simulations validated the dynamic behavior of these complexes over time, confirming their potential as stable inhibitors. ADMET analysis confirmed favorable pharmacokinetic and toxicity profiles, suggesting these compounds as promising candidates for diabetes treatment. This study provides a strong foundation for further drug development targeting diabetes management.