Abstract
This study aimed to develop a potent, safe, and cost-effective small-molecule hypoglycemic agent derived from Loureirin B, with preliminary evaluation of its efficacy and mechanistic underpinnings. Thirty structural analogs of Loureirin B were synthesized. Molecular docking identified LB-A as the lead compound targeting GLP-1R. Its hypoglycemic activity was initially assessed in a murine model. Molecular dynamics simulations, surface plasmon resonance (SPR), and circular dichroism (CD) were employed to characterize LB-A-GLP-1R interactions. The involvement of the GLP-1R/cAMP/PKA pathway and downstream mediators was examined using cellular assays, gene knockout, and Western blotting, with emphasis on FOXO1. LB-A exhibited the strongest binding affinity for GLP-1R among the analogs and significantly reduced blood glucose levels in mice. It formed hydrogen bonds and hydrophobic interactions with key residues (e.g., LYS197) and induced conformational changes in GLP-1R. LB-A activation of GLP-1R upregulated cAMP, PKA, and pCREB, suppressed PTEN/FOXO1 signaling, and subsequently stimulated insulin secretion. LB-A represents a novel small molecule agonist that ameliorates hyperglycemia in diabetic mice through specific activation of the GLP-1R/cAMP/PKA/pCREB/PTEN/FOXO1 pathway.