Coumarin-Based Allosteric Inhibition of PTP1B: A Potential Strategy for Metabolic Regulation.

Protein Tyrosine Phosphatase 1B (PTP1B) is a key metabolic regulator and a promising therapeutic target for type 2 diabetes and obesity. This study evaluated the inhibitory potential of four coumarins-Bergapten, Imperatorin, Xanthotoxol, and Isopimpinellin, isolated from Ammi majus-through in silico and in vitro approaches. Molecular docking and molecular dynamics (MD) simulations identified Bergapten and Imperatorin as the most stable binders, forming key π-π stacking interactions with Phe280 and Phe196. Principal Energy Landscape (PEL) analysis further confirmed their stable binding conformations, while MM/PBSA calculations ranked Bergapten (-17.21 ± 0.80 kcal/mol) and Imperatorin (-12.76 ± 2.99 kcal/mol) as the strongest binders. ADMET analysis indicated high gastrointestinal absorption, blood-brain barrier permeability, and favorable drug-like properties for all compounds. In vitro PTP1B inhibition assays validated these findings, with Bergapten (IC = 6.64 ± 0.23 μM) and Imperatorin (IC = 9.44 ± 1.05 μM) exhibiting potent inhibition, comparable to the reference inhibitor ursolic acid (IC = 7.43 ± 0.74 μM), whereas Xanthotoxol (IC = 28.60 ± 1.88 μM) and Isopimpinellin (IC = 25.48 ± 1.98 μM) showed significantly weaker inhibition. Enzyme kinetics revealed noncompetitive inhibition mechanisms, with K values of 6.73 μM and 8.44 μM for Bergapten and Imperatorin, respectively, suggesting allosteric binding. These results highlight Bergapten and Imperatorin as promising allosteric inhibitors of PTP1B, warranting further cell-based and preclinical investigations for potential therapeutic applications in metabolic disorders.