Optimization of Indole- and Pyrazole-fused Glycyrrhetinic Acid Derivatives as Potent PTP1B Inhibitors: In Silico, In Vitro, In Vivo, and Metabolomic Studies.

ABSTRACT: 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

SUBMITTER: Lopez-Sanchez M 

PROVIDER: S-EPMC12921516 | biostudies-literature | 2026 Feb

REPOSITORIES: biostudies-literature