Abstract
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 (tauRD). 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 ΔK280 tauRD-DsRed SH-SY5Y cells, VB-008, but not VB-003, enhanced HSPB1 and GRP78 expression, increased ΔK280 tauRD-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.
| Original language | English |
|---|---|
| Pages (from-to) | 11-19 |
| Number of pages | 9 |
| Journal | European Journal of Pharmaceutical Sciences |
| Volume | 89 |
| DOIs | |
| Publication status | Published - 2016 Jun 30 |
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Keywords
- Alzheimer's disease
- Cell assay
- Enzyme assay
- GSK-3β kinase inhibitor
- Virtual screening
ASJC Scopus subject areas
- Pharmaceutical Science
Cite this
Identifying GSK-3β kinase inhibitors of Alzheimer's disease : Virtual screening, enzyme, and cell assays. / Lin, Chih Hsin; Hsieh, Yu Shao; Wu, Yih Ru; Hsu, Chia Jen; Chen, Hsuan Chiang; Huang, Wun Han; Chang, Kuo Hsuan; Hsieh-Li, Hsiu Mei; Su, Ming-Tsan; Sun, Ying-Chieh; Lee, Guan-Chiun; Lee, Guey-Jen.
In: European Journal of Pharmaceutical Sciences, Vol. 89, 30.06.2016, p. 11-19.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Identifying GSK-3β kinase inhibitors of Alzheimer's disease
T2 - Virtual screening, enzyme, and cell assays
AU - Lin, Chih Hsin
AU - Hsieh, Yu Shao
AU - Wu, Yih Ru
AU - Hsu, Chia Jen
AU - Chen, Hsuan Chiang
AU - Huang, Wun Han
AU - Chang, Kuo Hsuan
AU - Hsieh-Li, Hsiu Mei
AU - Su, Ming-Tsan
AU - Sun, Ying-Chieh
AU - Lee, Guan-Chiun
AU - Lee, Guey-Jen
PY - 2016/6/30
Y1 - 2016/6/30
N2 - 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 (tauRD). 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 ΔK280 tauRD-DsRed SH-SY5Y cells, VB-008, but not VB-003, enhanced HSPB1 and GRP78 expression, increased ΔK280 tauRD-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.
AB - 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 (tauRD). 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 ΔK280 tauRD-DsRed SH-SY5Y cells, VB-008, but not VB-003, enhanced HSPB1 and GRP78 expression, increased ΔK280 tauRD-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.
KW - Alzheimer's disease
KW - Cell assay
KW - Enzyme assay
KW - GSK-3β kinase inhibitor
KW - Virtual screening
UR - http://www.scopus.com/inward/record.url?scp=84964619826&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84964619826&partnerID=8YFLogxK
U2 - 10.1016/j.ejps.2016.04.012
DO - 10.1016/j.ejps.2016.04.012
M3 - Article
C2 - 27094783
AN - SCOPUS:84964619826
VL - 89
SP - 11
EP - 19
JO - European Journal of Pharmaceutical Sciences
JF - European Journal of Pharmaceutical Sciences
SN - 0928-0987
ER -