Inhibition of protein tyrosine phosphatase 1B by phenolics and neolignans from Myristica fragrans seeds: Enzyme kinetics and molecular docking

초록

Myristica fragrans Houtt. seeds, a recognized herbal remedy with diverse phytoconstituents and biological activities, have been traditionally used to manage various health conditions. While numerous studies have demonstrated the anti-diabetic properties of this plant, research focusing on the mechanism of protein tyrosine phosphatase 1B (PTP1B) inhibition remains limited. This study aimed to isolate and evaluate the PTP1B inhibitory activity of phenolics and neolignans from M. fragrans seeds. We successfully isolated a new benzofuranoid neolignan, 5-methoxy-eupomatenoid-7 (16), along with 15 known compounds (1-15). The chemical structure of the isolated secondary metabolites was elucidated using spectroscopic analyses, including nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HR-MS), and confirmed by comparison with previously reported data. The inhibitory potential of all isolated compounds against PTP1B was assessed, with isodihydrocarinatidin (11) identified as the most potent inhibitor, exhibiting an IC50 value of 9.6 +/- 0.65 mu M. Notably, enzyme kinetic studies revealed that compound 11 inhibits PTP1B through an uncompetitive mechanism, a relatively uncommon mode of inhibition. Molecular docking analysis revealed the binding interactions between compound 11 and PTP1B, while treatment with compound 11 significantly enhanced glucose uptake. This study provides the first evidence that isodihydrocarinatidin acts as a novel PTP1B inhibitor, establishing a foundation for further investigations toward the development of antidiabetic therapies.

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