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.

中文翻译：

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通过全面的计算机筛查和分子动力学模拟鉴定慢性创伤性脑病的新型 tau 正电子发射断层扫描示踪剂


慢性创伤性脑病 （CTE） 是一种与重复性轻度创伤性脑损伤相关的神经退行性疾病，其神经病理学特征是异常过度磷酸化 tau 积累。早期检测大脑中 tau 沉积对于预防和评估 CTE 至关重要。正电子发射断层扫描 （PET） 示踪剂可以对特定蛋白质进行成像，而 CTE tau 原纤维的最佳 PET 示踪剂仍未确定。在本研究中，利用基于结构的虚拟筛选和 CNS PET MPO 算法从 ChemDiv CNS BBB 库中的 23 000 种化合物中鉴定新型 tau PET 示踪剂的候选者。然后采用总共 8 μs 的分子动力学模拟来评估它们与 CTE tau 原纤维的结合亲和力和原子水平相互作用。结果表明，V017-7820 （CNS-4）、S776-0061 （CNS-12）、S567-0465 （CNS-18） 和 T828-0465 （CNS-25） 表现出更高的对接分数和与 CTE tau 原纤维的结合自由能，同时也满足 PET 示踪剂的基本物理化学性质。进一步的模拟分析表明，CNS-4 与 tau 原纤维的结合亲和力是四种化合物中最强的。疏水、π-π 叠化和氢键相互作用是这些化合物与 CTE tau 原纤维结合的主要驱动力。特别是，CNS-12 和 CNS-25 表现出更强烈的疏水和π-π 叠化相互作用，而 CNS-4 和 CNS-25 表现出更强的氢键相互作用。本研究确定了 tau PET 示踪剂有前途的先导化合物，并强调了它们与 CTE tau 原纤维结合的机制，这为进一步筛选和开发用于 CTE 诊断的新型 PET 示踪剂提供了新的见解。