Computational Screening of FDA-Approved Drugs as Potential BACE1 Inhibitors for Alzheimer's Disease Drug Repurposing

<title>Abstract</title> <p>Alzheimer's disease is a progressive neurodegenerative disorder affecting over 55 million people worldwide, with no disease-modifying treatments currently approved. Beta-secretase 1 (BACE1) is a key enzyme responsible for the production of amyloid-beta plaques, a hallmark of Alzheimer's pathology, making it a prime drug target. This study employed computational molecular docking to screen six FDA-approved drugs against the BACE1 protein structure obtained from the AlphaFold Protein Structure Database (UniProt ID: P56817) using CB-Dock2 with blind docking methodology. The compounds screened included Minocycline, Rosiglitazone, Sertraline, Ibuprofen, Memantine, and Donepezil. Minocycline demonstrated the strongest binding affinity at - 9.1 kcal/mol, followed by Rosiglitazone at -8.2 kcal/mol and Sertraline at -7.5 kcal/mol. All six compounds exceeded the -6.5 kcal/mol threshold indicative of meaningful protein-ligand interaction. Notably, Sertraline, an antidepressant with no current Alzheimer's indication, exhibited strong binding affinity, suggesting potential as a drug repurposing candidate. These findings provide a computational basis for further experimental investigation of these compounds as BACE1 inhibitors.</p>