PTP1B inhibitors(Jiangxi University of Traditional Chinese Medicine)

Indian gooseberry (Phyllanthus emblica L.) fruits are traditionally consumed for their nutritional value and diverse medicinal properties. In this study, the ethanol extract of the fruits exhibited potential effects on the inhibition of protein tyrosine phosphatase 1B (PTP1B). Two novel galloylated phenolics (1 and 2) and nine known compounds (3-11) were isolated and structurally identified. The absolute configurations of new compounds were determined using spectroscopic analyses, Mosher's ester method, and quantum chemical calculations. PTP1B inhibitory activities of compounds 1-10 were evaluated, with compound 10 exhibiting the strongest inhibition (IC₅₀ = 16.3 μM), whereas other compounds did not show inhibitory activity at concentrations up to 80 μM. Kinetic analysis revealed compound 10 as a mixed inhibitor, and molecular docking provided insights into its interaction with PTP1B. This is the first time that the PTP1B inhibition of galloylated phenolics from P. emblica fruit was reported. Our findings suggest Indian gooseberry fruits as a promising source of bioactive phenolics for developing PTP1B inhibitors with potential antidiabetic properties.

Sepsis-induced cardiovascular dysfunction (SICD) poses a serious threat to human life. Protein tyrosine phosphatase 1B (PTP1B) displays an essential role in SICD occurrence, so discovering novel inhibitors targeting PTP1B is an effective strategy for SICD treatment. In this research, we exploited a novel virtual screening pipeline consisting of both ligand-based and structure-based modules to find novel PTP1B inhibitors, and compound PI-2 with IC₅₀ = 4.1 ± 0.3 μM was successfully discovered. Enzymatic and cellular thermal shift assay showed PI-2 displayed a moderate PTP1B inhibitory activity and a good selectivity towards both PTP1B and TCPTP. Besides, PI-2 effectively protected Lipopolysaccharide (LPS) induced AC16 injury by reducing cell ROS levels and enhancing mitochondrial membrane potential. Overall, this research not only provides a novel virtual screening strategy for discovering novel PTP1B inhibitors, but also supplies a potential candidate for further optimisation for the treatment of SICD.