PDF(Pubmed)
Abstract：
The tau-tubulin kinase 1 (TTBK1) protein is a casein kinase 1 superfamily member located at chromosome 6p21.1. It is expressed explicitly in the brain, particularly in the cytoplasm of cortical and hippocampal neurons. TTBK1 has been implicated in the phosphorylation and aggregation of tau in Alzheimer\'s disease (AD). Considering its significance in AD, TTBK1 has emerged as a promising target for AD treatment. In the present study, we identified novel TTBK1 inhibitors using various computational techniques. We performed a virtual screening-based docking study followed by E-pharmacophore modeling, cavity-based pharmacophore, and ligand design techniques and found ZINC000095101333, LD7, LD55, and LD75 to be potential novel TTBK1 lead inhibitors. The docking results were complemented by Molecular Mechanics/Generalized Born Surface Area (MMGBSA) calculations. The molecular dynamics (MD) simulation studies at a 500 ns scale were carried out to monitor the behavior of the protein toward the identified ligands. Pharmacological and ADME/T studies were carried out to check the drug-likeness of the compounds. In summary, we identified a new series of compounds that could effectively bind the TTBK1 receptor. The newly designed compounds are promising candidates for developing therapeutics targeting TTBK1 for AD.
摘要：
tau-微管蛋白激酶1（TTBK1）蛋白是位于染色体6p21.1的酪蛋白激酶1超家族成员。它在大脑中明确表达，特别是在皮质和海马神经元的细胞质中。TTBK1与阿尔茨海默病(AD)中tau的磷酸化和聚集有关。考虑到它在AD中的重要性，TTBK1已成为AD治疗的有希望的靶标。在本研究中,我们使用各种计算技术鉴定了新型TTBK1抑制剂。我们进行了基于虚拟筛选的对接研究，然后进行了E药效团建模，基于腔的药效团，和配体设计技术，并发现ZINC000095101333，LD7，LD55和LD75是潜在的新型TTBK1铅抑制剂。对接结果由分子力学/广义玻恩表面积（MMGBSA）计算补充。在500ns规模下进行分子动力学(MD)模拟研究以监测蛋白质对所鉴定的配体的行为。进行药理学和ADME/T研究以检查化合物的药物相似性。总之,我们发现了一系列能有效结合TTBK1受体的化合物。新设计的化合物是开发靶向TTBK1治疗AD的有希望的候选化合物。
