阿尔茨海默病 (AD) 是最常见的神经退行性疾病，需要有效的药物来缓解症状。这项研究的重点是将睡眠障碍作为一种明显的临床症状，并将 tau 蛋白病作为该疾病的一个突出的分子症状。分别使用 AutoDock Vina 和 pkCSM 评估来自三个生物分子库的多种化合物（719 种化合物；ChemDiv:366 - ChEMBL:180 - PubChem:173）的潜在结合亲和力和安全性，从而选择了四种候选化合物（Lestaurtinib、Repotrectinib） 、Bemcentinib 和 Zotiraciclib）。由于 Repotrectinib 和 Bemcentinib 与 ATP 结合位点的相似性，通过 NAMD 对这两个分子和 ATP 进行了 300ns Martini 3 粗粒度分子动力学 (MD)。使用 200 ns Martini 3 MD 模拟评估 tau 蛋白在药物存在下的稳定性。结合位点分析揭示了 Bemcentinib 和 Repotrectinib 作为与 ATP 结合时占据最多氨基酸的两种抑制剂。 RMSD 和 RMS 平均相关结果显示，在第一个 220ns 模拟中，包含 Bemcentinib 和 Repotrectinib 的蛋白质与 ATP 相比具有更稳定的状态。 Bemcentinib 仅发生一次脱离，而 Repotrictinib 在模拟结束时发生两次脱离。最终，在酶-tau 复合物中添加 Bemcentinib 和 Repotrectinib 显着增加了 200 ns 模拟期间 tau 脱离的数量。我们报告 Bemcentinib 和 Repotrectinib（以前用于治疗癌症）是 CK1 δ 的潜在抑制剂。除了与 ATP 相比具有高结合亲和力外，它们还可以抑制所有 ATP 结合位点并改变 tau 结合稳定性。Ramaswamy H. Sarma 通讯。

Alzheimer's disease (AD), the most prevalent neurodegenerative disease, demands effective medication to alleviate symptoms. This study focused on sleep impairment as an overt clinical symptom and tauopathy as a prominent molecular symptom of this disease. Multiple compounds from three biomolecule libraries (719 compounds; ChemDiv:366 - ChEMBL:180 - PubChem:173) were evaluated for potential binding affinity and safety using AutoDock Vina and pkCSM, respectively, resulting in the selection of four candidate compounds (Lestaurtinib, Repotrectinib, Bemcentinib, and Zotiraciclib). Due to the similarity of Repotrectinib and Bemcentinib binding sites to ATP, 300 ns Martini 3 coarse-grained molecular dynamics (MD) was performed on these two molecules and ATP by NAMD. The stability of tau protein in the presence of drugs was assessed using a 200 ns Martini 3 MD simulation. Binding site analysis discloses Bemcentinib and Repotrectinib as two inhibitors occupying most amino acids in binding with ATP. The RMSD and RMS average correlation results revealed protein containing Bemcentinib and Repotrectinib to have a more stable state compared to ATP in the first 220 ns simulation. There was only a single detachment of Bemcentinib, while Repotrictinib detached twice at the end of the simulation. Eventually, adding Bemcentinib and Repotrectinib to the enzyme-tau complex significantly increased the number of tau detachments during the 200 ns simulation. We report Bemcentinib and Repotrectinib, formerly prescribed for cancer, as potential inhibitors of the CK1 δ. Besides their high binding affinity compared to ATP, they can inhibit all ATP-binding sites and alter the tau binding stability.Communicated by Ramaswamy H. Sarma.