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

Abstract

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 (IC₅₀ = 6.64 ± 0.23 μM) and Imperatorin (IC₅₀ = 9.44 ± 1.05 μM) exhibiting potent inhibition, comparable to the reference inhibitor ursolic acid (IC₅₀ = 7.43 ± 0.74 μM), whereas Xanthotoxol (IC₅₀ = 28.60 ± 1.88 μM) and Isopimpinellin (IC₅₀ = 25.48 ± 1.98 μM) showed significantly weaker inhibition. Enzyme kinetics revealed noncompetitive inhibition mechanisms, with K_i 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.