Design of Acetylcholinesterase Inhibitors for Alzheimer's Disease
Authors
Jiawei Ren, Moustafa Gabr
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Introduction
Alzheimer’s disease is a worldwide progressive neurodegenerative disease. In the past two decades, acetylcholinesterase (AChE) inhibitors have been the most popular medication in mitigating Alzheimer’s disease symptoms. However, all common AChE inhibitors have side effects, and traditional inhibitor discovery is a very expensive and timely process. Replacing the traditional workflow with computational experiments, this research selected novel candidate AChE inhibitors for future drug development.
Methods
18 compounds were retrieved after virtually screening for pharmacophore structures affinitive to AChE. After compounds’ interaction simulations with the AChE , their inhibition efficiencies were ranked based on Gibb’s free energy of. Then the research further evaluated the compounds’ oral bioavailability and ability to across the blood brain barrier by comparing their properties with the Lipinski’s rule of 5.
Results
Overall, 17 out of 18 compounds passed the Lipinski’s rule of 5, qualifying good absorption and permeation. While compound ZINC04713297 featured the best inhibition efficiency (-9.37kcal/mol), both ZINC92926669 and ZINC08756522 required the second lowest reaction energy (-9.20kcal/mol). ZINC92926669 stood out among the two in the absorption assessment for its stability and portability in the blood stream.
Conclusion
This research discovered 17 novel AChE inhibitors through the workflow combining virtual screening, interaction simulation and absorption assessment. It highlighted compound ZINC04713297 and ZIN92926669, which served as a starting point for development of novel acetylcholinesterase inhibitors for Alzheimer’s disease.
Keywords
Authors
Jiawei Ren, Moustafa Gabr
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