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

Weiping Lyu; Qihang Li; Qi Li; Ying Chen; Yingming Wang; Tongzhong Tang; Feng Feng; Heng Chi; Yuan Li; Wenyuan Liu; Haopeng Sun

doi:10.1002/minf.202060031

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

Mol Inform. 2021 Dec;40(12):e2060031. doi: 10.1002/minf.202060031. Epub 2021 Jul 29.

Authors

Weiping Lyu¹, Qihang Li², Qi Li², Ying Chen³, Yingming Wang¹, Tongzhong Tang³, Feng Feng^{4

3}, Heng Chi⁵, Yuan Li⁶, Wenyuan Liu^{1

7}, Haopeng Sun²

Affiliations

¹ Department of Pharmaceutical Analysis, Key Laboratory of Drug Quality Control and Pharmacovigilance, China Pharmaceutical University, Nanjing, 211198, People's Republic of China.
² School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, People's Republic of China.
³ Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211198, People's Republic of China.
⁴ Institute of Food and Pharmaceuticals Research, Jiangsu Food and Pharmaceuticals Science College, Huaian, 223003, People's Republic of China.
⁵ Food and Pharmaceutical Research Institute, Jiangsu Food and Pharmaceuticals Science College, Huaian, 223003, People's Republic of China.
⁶ Department of Pharmaceutical Engineering, Jiangsu Food and Pharmaceuticals Science College, Huaian, 223005, People's Republic of China.
⁷ Zhejiang Center for Safety Study of Drug Substances (Industrial Technology Innovation Platform), Hangzhou, 310018.

PMID: 34323388
DOI: 10.1002/minf.202060031

Abstract

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.

Keywords: Alzheimer's disease; GSK-3β inhibitor; Lead compound; Virtual screening.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease* / drug therapy
Alzheimer Disease* / metabolism
Glycogen Synthase Kinase 3 beta / metabolism
Humans
Molecular Dynamics Simulation*
Protein Kinase Inhibitors / pharmacology*

Substances

Protein Kinase Inhibitors
Glycogen Synthase Kinase 3 beta