Identification of novel tau positron emission tomography tracers for chronic traumatic encephalopathy by comprehensive in silico screening and molecular dynamics simulation†

Chronic traumatic encephalopathy (CTE), a neurodegenerative disease associated with repetitive mild traumatic brain injury, is characterized neuropathologically by abnormal hyperphosphorylated tau accumulation. Early detection of tau deposition in the brain is crucial for the prevention and evaluation of CTE. Positron emission tomography (PET) tracers can image specific proteins, while the optimal PET tracer for CTE tau fibrils remains unidentified. In this study, structure-based virtual screening and CNS PET MPO algorithms were utilized to identify candidates for novel tau PET tracers from 23 000 compounds in the ChemDiv CNS BBB library. A total of 8 μs molecular dynamics simulations were then employed to evaluate their binding affinity and atomic-level interaction with CTE tau protofibrils. The results indicate that V017-7820 (CNS-4), S776-0061 (CNS-12), S567-0465 (CNS-18), and T828-0465 (CNS-25) exhibit higher docking scores and binding free energies with CTE tau protofibrils while also satisfying the fundamental physicochemical properties of PET tracers. Further simulation analyses reveal that CNS-4 has the strongest binding affinity to tau protofibrils among the four compounds. Hydrophobic, π–π stacking, and hydrogen bonding interactions are the primary driving forces for the binding of these compounds to CTE tau protofibrils. In particular, CNS-12 and CNS-25 exhibit more intense hydrophobic and π–π stacking interactions, whereas CNS-4 and CNS-25 exhibit stronger hydrogen bonding interactions. This study identifies promising lead compounds for tau PET tracers and highlights their mechanism of binding to CTE tau protofibrils, which provides new insights for further screening and development of novel PET tracers for CTE diagnosis.