Designing of dual inhibitors for GSK-3β and CDK5: Virtual screening and in vitro biological activities study.
Designing of dual inhibitors for GSK-3β and CDK5: Virtual screening and in vitro biological activities study.
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GSK-3 beta 和 CDK5 双重抑制剂的设计：虚拟筛选和体外生物活性研究
DOI：
10.18632/oncotarget.15085
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发表时间：
2017-03-14
期刊：
影响因子：
--
通讯作者：
Chen X
中科院分区：
文献类型：
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作者：
Xie H;Wen H;Zhang D;Liu L;Liu B;Liu Q;Jin Q;Ke K;Hu M;Chen X
阿尔茨海默病是一种多因素的神经退行性疾病，其病因有许多药物靶点。尽管这种疾病的破坏性影响，用于治疗阿尔茨海默病的治疗方法仍然有限。阿尔茨海默病的多因素性质强烈支持多靶点理论作为药物设计策略。糖原合酶激酶-3 β和细胞周期蛋白依赖性激酶5已被鉴定为参与tau蛋白的病理性过度磷酸化，其导致神经元缠结的形成并引起阿尔茨海默病。在这项研究中，使用分子对接方法筛选虚拟库，我们发现了可以同时抑制糖原合成酶激酶-3 β和细胞周期蛋白依赖性激酶5的分子，作为治疗阿尔茨海默病的先导化合物。对接结果揭示了糖原合成酶激酶-3 β和细胞周期蛋白依赖性激酶5的底物结合位点中的关键残基。受试者工作特性曲线表明，对接模型一致，并选择性地得分以上诱饵的活性化合物的大多数。用筛选的化合物预处理细胞可使其免受Aβ25-35诱导的细胞死亡，保护率高达80%。总的来说，这些研究结果表明，一些化合物有潜力成为有前途的多功能药物治疗阿尔茨海默病。
Alzheimer's disease is a multifactorial neurodegenerative disorder with many drug targets contributing to its etiology. Despite the devastating effects of this disease, therapeutic methods for treating Alzheimer's disease remain limited. The multifactorial nature of Alzheimer's disease strongly supports a multi-target rationale as a drug design strategy. Glycogen synthase kinase-3 beta and cyclin-dependent kinase 5 have been identified as being involved in the pathological hyperphosphorylation of tau proteins, which leads to the formation of neurofibrillary tangles and causes Alzheimer's disease. In this study, using a molecular docking method to screen a virtual library, we discovered molecules that can simultaneously inhibit Glycogen synthase kinase-3 beta and cyclin-dependent kinase 5 as lead compounds for the treatment of Alzheimer's disease. The docking results revealed the key residues in the substrate binding sites of both Glycogen synthase kinase-3 beta and cyclin-dependent kinase 5. A receiver operating characteristic curve indicated that the docking model consistently and selectively scored the majority of active compounds above decoys. The pre-treatment of cells with screened compounds protected them against Aβ25-35- induced cell death by up to 80%. Collectively, these findings suggest that some compounds have potential to be promising multifunctional agents for Alzheimer's disease treatment.