PTP1B inhibitors(Jiangxi University of Traditional Chinese Medicine)

Protein tyrosine phosphatase 1B (PTP1B) is a crucial enzyme involved in regulating insulin and leptin signaling pathways, making it a promising target for treating type 2 diabetes. In this study, we synthesized 14 derivatives of indole- and pyrazole-fused glycyrrhetinic acid (GA) and evaluated their effects on PTP1B, using both its long (hPTP1B_1-400) and short (hPTP1B_1-285) forms. We analyzed enzymatic kinetics and selectivity over T-cell protein tyrosine phosphatase (TCPTP). Molecular docking and molecular dynamics simulations were performed to understand the binding mode of the compounds within PTP1B. Untargeted metabolomics, using gas chromatography-mass spectrometry, assessed metabolic changes caused by the most potent PTP1B inhibitors in HepG2 cells. We also evaluated these inhibitors in vivo to determine their effects on insulin sensitivity through the insulin tolerance test (ITT) in streptozotocin (STZ)-induced diabetic mice. Two compounds, 4b (indole-fused) and 5g (pyrazole-fused), showed greater potency against the long form of PTP1B compared to the short form, indicating that both compounds preferentially bind to the disordered C-terminal region of PTP1B. Molecular docking and molecular dynamics studies supported this finding. Furthermore, enzymatic kinetics revealed that compounds 4b and 5g function as uncompetitive inhibitors of PTP1B, with K _i values of 0.32 and 0.72 μM, respectively. Notably, both GA derivatives exhibited more pronounced inhibition of PTP1B compared to the well-established inhibitors ursolic acid and Ertiprotafib, while also demonstrating selectivity over TCPTP. Metabolomic analysis revealed that these compounds increased pantothenic acid and glycine levels, while decreasing glucose and fatty acid levels in HepG2 cells, suggesting enhanced glycolysis and reduced lipogenesis. Both compounds exhibited low cytotoxicity in HFF-1 cells and significantly reduced glucose levels in the ITT in STZ-induced diabetic mice, outperforming the insulin-sensitizing drug Pioglitazone.

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.