Design, Bio-evaluation and Molecular Dynamics Simulation of Novel GSK-3β Inhibitors,Molecular Informatics

当前位置： X-MOL 学术 › Mol. Inform. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Design, Bio-evaluation and Molecular Dynamics Simulation of Novel GSK-3β Inhibitors
Molecular Informatics ( IF 2.8 ) Pub Date : 2021-07-29 , DOI: 10.1002/minf.202060031
Weiping Lyu ₁ , Qihang Li ₂ , Qi Li ₂ , Ying Chen ₃ , Yingming Wang ₁ , Tongzhong Tang ₃ , Feng Feng _{3,

4} , Heng Chi ₅ , Yuan Li ₆ , Wenyuan Liu _{1,

7} , Haopeng Sun ₂

Affiliation

Glycogen synthase kinase 3 beta (GSK-3β) is considered as a promising drug target for the treatment of Alzheimer's disease (AD). In the present study, two compound libraries were selected for virtual screening based on pharmacophore models of GSK-3β to discover new inhibitors. Nine potential hits were retained for biological investigation and four of these compounds showed GSK-3β inhibitory activity (with the IC₅₀ values in sub-micromolar range on GSK-3β). Compounds 6 and 9 have good safety. They do not have any significant in vitro cytotoxicity against PC12 and SH-SY5Y neuroblastoma cells at concentrations up to 90 μM. Based on the inhibitory activity and druggability properties, compound 8 is the preferred molecule, and it is a promising lead for the development of the GSK-3β inhibitors for reducing the abnormal hyperphosphorylation of tau protein and relieving AD.

中文翻译：

新型 GSK-3β 抑制剂的设计、生物评价和分子动力学模拟

糖原合酶激酶 3 β (GSK-3β) 被认为是治疗阿尔茨海默病 (AD) 的有希望的药物靶点。在本研究中，基于 GSK-3β 的药效团模型选择了两个化合物库进行虚拟筛选，以发现新的抑制剂。九个潜在的命中被保留用于生物学研究，其中四种化合物显示出 GSK-3β 抑制活性（在 GSK-3β 上的 IC ₅₀值在亚微摩尔范围内）。化合物6和9具有良好的安全性。在浓度高达 90 μM 时，它们对 PC12 和 SH-SY5Y 神经母细胞瘤细胞没有任何显着的体外细胞毒性。基于抑制活性和成药性，化合物8是首选分子，它是开发用于减少 tau 蛋白异常过度磷酸化和缓解 AD 的 GSK-3β 抑制剂的有希望的先导。

更新日期：2021-07-29

点击分享查看原文

点击收藏

阅读更多本刊新发论文本刊介绍/投稿指南