Targeting the Metabolic-Neurodegenerative Axis: In Silico Repurposing of FDA-Approved Pleiotropic Metabolic Modulators for Alzheimer's Tau Protein

Targeting the Metabolic-Neurodegenerative Axis: In Silico Repurposing of FDA-Approved Pleiotropic Metabolic Modulators for Alzheimer's Tau Protein

Alvin Sherman Library

Extensive research has established a link between insulin deficiency and insulin resistance and Alzheimer's Disease (AD) type-neurodegeneration, coining it "Type 3 Diabetes". While research typically focuses on glucose regulation, the comparative structural efficacy of broader metabolic agents against neuropathology remains distinctively underexplored. This study addresses this gap by performing a novel in silico comparison of three drug classes (Glucose, Lipid, and Cardio-Metabolic regulators) to identify superior scaffolds for obstructing the pathological Tau protein, which plays a major role in causing AD through its hyperphosphorylation. The Tau paired helical filament (PDB ID: 5O3L) was retrieved from the RCSB Protein Data Bank. A library of thirty FDA-approved modulators, categorized into Glucose (e.g., Metformin, Sitagliptin), Lipid (e.g., Atorvastatin), and Cardio-Metabolic (e.g., Digoxin, Telmisartan) groups, was docked using CB-Dock2. Results revealed a definitive structure-activity hierarchy where Cardio-Metabolic agents outperformed standard metabolic treatments, measured by the Vina score. Digoxin emerged as the lead candidate with an elite affinity of -9.0 kcal/mol, significantly surpassing the standard glucose regulator Metformin (-4.5 kcal/mol). Structural analysis indicates that Digoxin's dense, planar steroid nucleus facilitates extensive hydrophobic stacking against the planar topology of the Tau filament. In contrast, Metformin's small, hydrophilic structure lacked sufficient surface area to maintain stable contact. These findings suggest that instead of focusing on simple insulin-sensitizing drugs, current repurposing efforts should shift toward more complex cardio-metabolic compounds that are better suited to physically block Tau aggregation.