GSK-3β directly phosphorylate tubulin binding site of tau protein, indicating its importance in tau aggregation and, therefore, in Alzheimer's disease pathology. New GSK-3β inhibitors were identified using a structure-based screening, ADMET analysis. These studies revealed that ZINC09036109, ZINC72371723, ZINC72371725, and ZINC01373165 approached optimal ADMET properties along with good MM-GBSA dG binding. Protein kinase assays of these compounds against eight disease-relevant kinases were performed. During disease-relevant kinase profiling, ZINC09036109 ((E)-2-((3,4-dimethylphenyl)imino)-5-(3-methoxy-4-(naphthalen-2-ylmethoxy)benzyl)thiazolidin-4-one) emerged as a selective GSK-3β inhibitor with more than 10-fold selectivity over other disease-relevant kinases. Molecular dynamics study of ZINC09036109 molecule revealed interactions with Ile62, Phe67, Val135, Leu188, Asp200 amino acid residues of the binding site of GSK-3β, which were highly comparable to the co-crystallized molecule and hence validating comparative better activity of this compound compared to overall screened molecules.

GSK-3β 直接磷酸化 tau 蛋白的微管蛋白结合位点，表明其在 tau 聚集以及因此在阿尔茨海默病病理学中的重要性。使用基于结构的筛选、ADMET 分析鉴定了新的 GSK-3β 抑制剂。这些研究表明，ZINC09036109、ZINC72371723、ZINC72371725 和 ZINC01373165 接近最佳 ADMET 特性以及良好的 MM-GBSA dG 结合。对这些化合物进行了针对八种疾病相关激酶的蛋白激酶测定。在疾病相关激酶分析期间，ZINC09036109 ((E)-2-((3,4-二甲基苯基)亚氨基)-5-(3-methoxy-4-(naphthalen-2-ylmethoxy)benzyl)thiazolidin-4-one)作为一种选择性 GSK-3β 抑制剂，其选择性是其他疾病相关激酶的 10 倍以上。ZINC09036109 分子的分子动力学研究揭示了与 Ile62 的相互作用，