Identifying GSK-3β kinase inhibitors of Alzheimer's disease: Virtual screening, enzyme, and cell assays

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• 作者：Chih-Hsin Lin^b ; ¹ ; Yu-Shao Hsieh^a ; ¹ ; Yih-Ru Wu^b ; Chia-Jen Hsu^a ; Hsuan-Chiang Chen^c ; Wun-Han Huang^c ; Kuo-Hsuan Chang^b ; Hsiu Mei Hsieh-Li^c ; Ming-Tsan Su^c ; Ying-Chieh Sun^a ; ^{sun@ntnu.edu.tw" class="auth_mail" title="E-mail the corresponding author} ; Guan-Chiun Lee^c ; ^{gclee@ntnu.edu.tw" class="auth_mail" title="E-mail the corresponding author} ; Guey-Jen Lee-Chen^c ; ^{t43019@ntnu.edu.tw" class="auth_mail" title="E-mail the corresponding author}
• 关键词：GSK-3β kinase inhibitor ; Alzheimer's disease ; Virtual screening ; Enzyme assay ; Cell assay
• 刊名：European Journal of Pharmaceutical Sciences
• 出版年：2016
• 出版时间：30 June 2016
• 年：2016
• 卷：89
• 期：Complete
• 页码：11-19
• 全文大小：1452 K

文摘

Glycogen synthase kinase 3β (GSK-3β) is widely known as a critical target protein for treating Alzheimer's disease (AD). We utilized virtual screening to search databases for compounds with the potential to be used in drugs targeting GSK-3β kinase, and kinase as well as cell assays to investigate top-scored, selected compounds. Virtual screening of > 1.1 million compounds in the ZINC and in-house databases was conducted using an optimized computational protocol in the docking program GOLD. Of the top-ranked compounds, 16 underwent a luminescent kinase assay and a cell assay using HEK293 cells expressing DsRed-tagged ΔK280 in the repeat domain of tau (tau_RD). The compounds VB-003 (a potent GSK-3β inhibitor) and VB-008 (AM404, an anandamide transport inhibitor), with determined IC₅₀ values of 0.25 and 5.4 μM, respectively, were identified as reducing tau aggregation. Both compounds increased expression of phospho-GSK-3β (Ser9) and reduced endogenous tau phosphorylation at the sites of Ser202, Thr231, and Ser396. In the ∆K280 tau_RD-DsRed SH-SY5Y cells, VB-008, but not VB-003, enhanced HSPB1 and GRP78 expression, increased ∆K280 tau_RD-DsRed solubility, and promoted neurite outgrowth. Thus VB-008 performed best to the end of the present study. The identified compound VB-008 may guide the identification and synthesis of potential inhibitors analogous to this compound.