2016 Fiscal Year Annual Research Report
Discovery of human Glutaminyl Cyclase inhibitors for the treatment of Alzheimer's disease
| Project/Area Number |
16F16385
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| Research Institution | Institute of Physical and Chemical Research |
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Principal Investigator |
ZHANG KAM 国立研究開発法人理化学研究所, ライフサイエンス技術基盤研究センター, チームリーダー (60558906)
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| Co-Investigator(Kenkyū-buntansha) |
VIJAYAN DILEEP 国立研究開発法人理化学研究所, ライフサイエンス技術基盤研究センター, 外国人特別研究員
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| Project Period (FY) |
2016-11-07 – 2019-03-31
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| Keywords | Alzheimer's disease / Glutaminyl cyclase / Drug design / Virtual screening |
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| Outline of Annual Research Achievements |
Alzheimer's disease (AD) is a chronic neurodegenerative disorder that has no cure. Aβ aggregation and accumulation into plaques are considered to be the hallmark events. Recent studies suggested that human Glutaminyl cyclase (hQC) enzyme is critically involved in the AD progression by catalyzing the cyclization of N-terminal glutamate of β amyloid peptide (Aβ) into pGlu which results in the formation of pGlu-Aβ peptides. pGlu-Aβ peptides are more hydrophobic and rapidly aggregate into plaques causing severe neurotoxicity. The inhibition of hQC will limit the production of pGlu-Aβ peptides and thereby control the AD progression. The present study focuses on the identification highly specific small molecule inhibitors against hQC using both in silico and in vitro techniques.
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| Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
High throughput virtual screening of Namiki-Shoji database has been performed towards hQC and the promising ligands (top 50) were selected based on the MM/GBSA score. A diverse class of compounds with proposed QC inhibitory activities were identified. These compounds were purchased and their in vitro activity profiling is being carried out. The overexpression of hQC is also in progress and the co-crystallization of the purified protein with active ligands is underway. By comparing multiple hQC structures available in the PDB, 37 invariant water molecules were identified and their importance in maintaining the active site geometry and their role in the binding of inhibitors are under investigation.
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| Strategy for Future Research Activity |
The purpose of this proposal is the identification of target-specific hQC inhibitors through sophisticated in silico and in vitro analysis. By using techniques like virtual screening, molecular docking and molecular dynamic simulation, potential inhibitors of hQC will be proposed and its validation will be carried out through a series of biophysical experiments such as X-ray crystallography, ITC etc. Moreover, using the in vitro assay kits, the IC50 values of the proposed compounds will be predicted. The in vivo studies will be carried out with promising ligand molecules. It is also planned to design specific multi-target ligand molecules which can inhibit both human glutaminyl cyclase and acetylcholinesterase simultaneously.
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