In Silico Drug Repositioning Identifies SYK Kinase Inhibitors as Potential Neuroprotective Agents for...

Ataxia-Telangiectasia (AT) is a rare neurodegenerative disorder characterized by progressive neuronal loss and chronic neuroinflammation. Emerging evidence indicates that aberrant overexpression of the adaptor protein TYROBP promotes sustained recruitment and activation of spleen tyrosine kinase (SYK), contributing to pathogenic inflammatory signaling in AT. In this study, we applied a drug repositioning strategy to identify clinically approved compounds that inhibit SYK activity. An integrated in silico workflow was employed, combining convolutional neural network (CNN)-based molecular docking with network medicine analysis using the SAveRUNNER platform to screen a library of 2342 FDA-approved drugs. The top-ranked candidates were further evaluated using long-timescale molecular dynamics simulations and post-simulation redocking to assess their binding stability and conformational persistence within the SYK catalytic pocket under explicit solvent conditions. This multilevel computational analysis identified vemurafenib and palbociclib as the most promising SYK inhibitors, both exhibiting sustained binding affinity and stable intermolecular interactions following protein relaxation. These findings support the feasibility of repurposing FDA-approved drugs to modulate SYK-driven neuroinflammatory pathways and provide a mechanistic framework for developing novel neuroprotective interventions for AT.