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

被引：2
|
作者：
Lyu, Weiping [1 ]
Li, Qihang [2 ]
Li, Qi [2 ]
Chen, Ying [4 ]
Wang, Yingming [1 ]
Tang, Tongzhong [4 ]
Feng, Feng [3 ,4 ]
Chi, Heng [6 ]
Li, Yuan [7 ]
Liu, Wenyuan [1 ,5 ]
Sun, Haopeng [2 ]
机构：
[1] China Pharmaceut Univ, Key Lab Drug Qual Control & Pharmacovigilance, Dept Pharmaceut Anal, Nanjing 211198, Peoples R China
[2] China Pharmaceut Univ, Sch Pharm, Nanjing 211198, Peoples R China
[3] Jiangsu Food & Pharmaceut Sci Coll, Inst Food & Pharmaceut Res, Huaian 223003, Peoples R China
[4] China Pharmaceut Univ, Dept Nat Med Chem, Nanjing 211198, Peoples R China
[5] Zhejiang Ctr Safety Study Drug Subst, Ind Technol Innovat Platform, Hangzhou 310018, Peoples R China
[6] Jiangsu Food & Pharmaceut Sci Coll, Food & Pharmaceut Res Inst, Huaian 223003, Peoples R China
[7] Jiangsu Food & Pharmaceut Sci Coll, Dept Pharmaceut Engn, Huaian 223005, Peoples R China
来源：
MOLECULAR INFORMATICS | 2021年 / 40卷 / 12期
基金：
中国国家自然科学基金;
关键词：
GSK-3 beta inhibitor; Alzheimer's disease; Virtual screening; Lead compound; DRUG DISCOVERY; DOCKING; ASSAY;
D O I：
10.1002/minf.202060031
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
Glycogen synthase kinase 3 beta (GSK-3 beta) 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-3 beta to discover new inhibitors. Nine potential hits were retained for biological investigation and four of these compounds showed GSK-3 beta inhibitory activity (with the IC50 values in sub-micromolar range on GSK-3 beta). 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 mu M. 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-3 beta inhibitors for reducing the abnormal hyperphosphorylation of tau protein and relieving AD.
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页数：10
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