Computer Designed Small Molecule Acetylcholinerase Inhibitors As Potential Treatment for Alzheimer’s Disease
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Liu Zihan
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Alzheimer’s disease is a chronic illness that most commonly manifests in its victims as a degeneration of their cognitive function and memory. It is also the most prominent cause of dementia. Currently treatment of Alzheimer’s disease revolves around two major theories: Amyloid Aggregation Hypothesis and the Cholinergic Deficiency Hypothesis. The Amyloid Aggregation Hypothesis focuses on abnormally processed Amyloid Precursor Protein (APP) protein and neurotoxic Aβ oligomers as a result. In recent years, drugs aimed to eliminate Aβ oligomers from neurons were unable to meet the desired clinical efficiency, and the Cholinergic Deficiency Hypothesis is now seen as a promising potential alternative. This hypothesis focuses the treatment on enhancing the cholinergic pathway centered around the neurotransmitter Acetylcholine (ACh), an important component in cognition, learning and memory retention. This hypothesis attributes the neurodegeneration to the abnormal activity of Acetylcholinerase (AChE), resulting in the dysfunction of the entire pathway. Small molecule AChE inhibitors have been proven effective by multiple clinical trials as well as usage among AD patients, but the process of discovering a new drug is long, complex and costly. Online web servers dedicated to simulate compound-compound interaction and ligand design can serve as a highly cost effective alternative. Using computer algorithms, potential drug candidates can be identified and pre-tested efficiently. In this study, 40 compounds potentially capable of inhibiting AChE are selected using pharmacophore-based virtual screening. 5 compounds that are shown to have the lowest Gibbs free energy (ΔG) values in docking simulations are chosen for further examination. These compounds are: ZINC04716517, ZINC05514424, ZINC19877680, ZINC00754301, ZINC12925747 and ZINC89735569, and they are assessed in terms of absorption, distribution, metabolism, excretion and toxicity. This study follows the process of binding site identification, pharmacophore based virtual screening, docking simulation, and drug-likeness prediction. Thcompounds identified can serve as a starting point for future drug development aimed to create an effective cholinergic drug for Alzheimer’s disease, and as an example to test the potential of computer-based drug design.
Authors
Liu Zihan
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References:
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