Exploring Novel GSK-3β Inhibitors for Anti-Neuroinflammatory and Neuroprotective Effects: Synthesis, Crystallography, Computational Analysis, and Biological Evaluation.

ABSTRACT: In the pathogenesis of Alzheimer's disease, the overexpression of glycogen synthase kinase-3β (GSK-3β) stands out due to its multifaced nature, as it contributes to the promotion of amyloid β and tau protein accumulation, as well as neuroinflammatory processes. Therefore, in the present study, we have designed, synthesized, and evaluated a new series of GSK-3β inhibitors based on the N-(pyridin-2-yl)cyclopropanecarboxamide scaffold. We identified compound 36, demonstrating an IC₅₀ of 70 nM against GSK-3β. Subsequently, through crystallography studies and quantum mechanical analysis, we elucidated its binding mode and identified the structural features crucial for interactions with the active site of GSK-3β, thereby understanding its inhibitory potency. Compound

SUBMITTER: Goral I 

PROVIDER: S-EPMC11378298 | biostudies-literature | 2024 Sep

REPOSITORIES: biostudies-literature