Non-Catalytic Inhibitors of the p38/MK2 Interface: Repurposing Approved Drugs to Target Neuroinflammation in Alzheimer's Disease.

ABSTRACT: Neuroinflammation is a key driver of Alzheimer's disease and an emerging therapeutic target. The p38/MK2 pathway regulates microglial cytokine production, yet previous attempts have not yielded modulators with clinically suitable properties. Here, we apply an integrative structure-guided and screening strategy to identify small-molecule disruptors of the p38/MK2 protein-protein interaction (PPI). Virtual screening of FDA-approved drugs prioritized nilotinib, a BCR-ABL inhibitor, as a putative PPI disruptor. Biochemical and molecular dynamics analyses confirmed that nilotinib binds to p38, blocks MK2 association, and suppresses cytokine release in microglia. Guided by these findings, we developed a lysate-based TR-FRET ultrahigh-throughput assay that identified additional inhibitors, includ

SUBMITTER: Hu M 

PROVIDER: S-EPMC12751014 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature