Watercress-derived glucosinolates as potential allosteric PTP1B inhibitors: a dual in silico and in vitro study on insulin signaling modulation.

This study investigates the inhibitory potential of four glucosinolates-glucoerucin, glucoiberin, gluconasturtiin, and glucotropaeolin-isolated from watercress (Nasturtium officinale) against Protein Tyrosine Phosphatase 1B (PTP1B), a key regulator of insulin signaling. Molecular docking, molecular dynamics (MD) simulations, and MM/PBSA free energy calculations identified glucoerucin (-17.18 ± 3.51 kcal/mol) and gluconasturtiin (-13.54 ± 1.79 kcal/mol) as the strongest binders, with stable interactions involving Phe280 and Phe196 through π-π stacking. Potential Energy Landscape (PEL) analysis further confirmed that these two compounds occupied the most stable low-energy conformational states, reinforcing their favorable binding to PTP1B. In vitro enzyme inhibition assays provided experimental validation that glucoerucin (IC₅₀ = 6.07 ± 0.69 µM) and gluconasturtiin (IC₅₀ = 7.65 ± 0.45 µM) demonstrated the strongest inhibitory effects, comparable to ursolic acid (IC₅₀ = 7.11 ± 0.95 µM). Enzyme kinetics revealed a non-competitive inhibition mechanism, with K values of 6.29 µM and 7.02 µM, suggesting allosteric regulation. ADMET analysis indicated good solubility and metabolic stability but limited oral bioavailability due to low gastrointestinal (GI) absorption. These findings highlight glucoerucin and gluconasturtiin as promising natural PTP1B inhibitors, warranting further optimization for therapeutic applications in type 2 diabetes management.