Discovery of F-18 labeled repurposed CNS drugs by computational strategy for effective tau imaging and alzheimer's diagnosis.

Abstract

Alzheimer's disease (AD) remains a significant challenge in diagnosis and treatment, with current methods insufficient for early detection. A major obstacle is the lack of effective imaging agents targeting the Tau protein, which plays a key role in AD pathology. To address this, we developed a computational methodology for selecting F-18 labeled drug candidates from a library of CNS-penetrant compounds curated from literature and databases. The library, consisting of 977 compounds, was evaluated based on clinical data, target proteins, pathways, toxicity, and other relevant factors. We implemented Python-based algorithms to select the top 39 compounds from virtual screening results, prioritizing those with optimal Tau binding affinity and BBB permeability. Additionally, we developed an algorithm to identify F-18 labeling candidates that maintain their biological activity post-labeling. We then performed virtual screening of an F-18 labeled drug library and selected the top 3 compounds based on stability and imaging potential. The selected compounds exhibited molecular weights of 350-520 Da, favorable logP values (2.05-2.72), and high BBB permeability. Our findings indicate that Drug 388 (BI-D1870), binds to Tau with a binding free energy of ΔG = -8.79 kcal/mol. Drug 416 (reported BRAF inhibitor, RG6344) shows a binding free energy of ΔG = -7.91 kcal/mol, while Drug 610 (Iloperidone/HP 873), a D2/5-HT2 receptor antagonist, exhibits a predicted binding free energy of ΔG = -6.88 kcal/mol with the target Tau protein respectively. Molecular dynamics simulations confirmed stable Tau-drugs interactions, with minimal RMSD fluctuations, indicating strong binding. The F-18 label enabled real-time PET imaging, allowing non-invasive tracking of the drug's binding to Tau in the brain. Our approach provides a comprehensive solution to the current limitations in Alzheimer's diagnosis by offering F-18 labeled drugs that effectively target Tau protein without compromising their biological activity, advancing both diagnostic and therapeutic strategies for AD.