γ-Secretase Inhibitors Selected by Molecular Docking, to Develop a New Drug Against Alzheimer’s Disease
Open accessAbstract
Background: Alzheimer´s disease (AD) is one of the most common forms of dementia, is characterized by memory loss and cognitive impairment that affects more than 30 million people worldwide. The pathogenesis of Alzheimer's disease is primary driven by brain accumulation of the amyloid β peptide generated from the amyloid-β precursor protein (APP) via cleavages by β- and γ-secretase. In this study, we propose an approach by molecular docking to select compounds as γ-secretase inhibitors for decreasing the APP generation. Methods: We selected potential γ-secretase inhibitors by molecular docking in the potential site between Asp257, Lue268, Asp385, Ile387, Phe388, and Leu432 amino acids in presenilin-1 (PS-1), using a chemical library of over 500,000 compounds. Results: Eight compounds (AZ1 - AZ8) were selected by molecular docking to develop γ-secretase inhibitors for decreasing the APP generation. Conclusions: AZ1 - AZ8 compounds could be interacting in the potential site between Asp257, Lue268, Asp385, Ile387, Phe388, and Leu432 amino acids in PS-1. These compounds could specifically interact in the binding pocket in PS-1 to prevent/decrease the APP generation, to develop a new drug against Alzheimer's disease.
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γ-secretase inhibitors such as tarenflurbil, avagacestat, and semagacestat lower amyloid beta synthesis by preventing gamma secretase enzyme from functioning.
“This includes γ-secretase inhibitors, such as tarenflurbil (7, Figure 5) [155,156], avagacestat (labeled as 6, Figure 5) [157,158], and semagacestat (5, Figure 5) [159,160]. Their purpose is to lower the synthesis of amyloid beta by preventing the gamma secretase enzyme from functioning.”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [158]
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Research works printed but not linked: 1
- PSEN1 presenilin 1 [ Homo sapiens (human) ] NCBI. 2023. https://www.ncbi.nlm.nih.gov/gene/5663.
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Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease
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“This includes γ -secretase inhibitors, such as tarenflurbil ( 7 , Figure 5) [155,156], avagacestat (labeled as 6 , Figure 5) [157,158], and semagacestat ( 5 , Figure 5) [159,160].”
Background
- Authors
- Trasviña-Arenas, C. H., Ayala Medina, L. A., & Vique-Sanchez, J. L.
- Venue
- Reports of Biochemistry and Molecular Biology
- Publisher
- Apex Publishing
- Published
- 2023-08-01
- Volume
- 12
- Issue
- 2
- Pages
- 340-349
- ISSN
- 1024-9869 (ISSN-L)
- PMC
- PMC10838598
- OpenAlex
- W4390890042
- Cited by
- 5
- References
- 38
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 1
- FWCI
- 0.89
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Reports of Biochemistry and Molecular Biology (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Keywords
- gamma-secretase inhibitors, Alzheimer's disease, presenilin 1, amyloid precursor protein, amyloid-beta production, molecular docking, drug discovery, binding pocket, chemical library screening
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