Virtual Screening of Acetylcholinesterase-centered Inhibitors as Potential Therapies for Alzheimer’s Disease
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Benjamin Liu
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Acetylcholinesterase inhibitors(AChE-Is) are currently one of the most popular treatments for Alzheimer’s disease(AD). Despite their proven effectiveness in easing symptoms of cognitive decline, their limited efficacy and strong adverse side effects demand the urgent need to develop better treatment for AD patients. This study explores a new series of ligands targeted towards inhibiting AChE as an anti-AD drug. Findings from various binding site detection methods, such as geometric, machine learning, and energetic-based methods, showed that AChE is a suitable binding target for ligands. The research utilized ZINCPharmer to identify compounds with good binding interactions with different pharmacophore maps of AChE. Molecular docking using SwissDock revealed multiple ligands with an impressive SwissParam score range of -7.2 to -8.9 kcal/mol, confirming their strong binding interaction with AChE binding sites. The top compounds were tested for their absorption, distribution, metabolism, and excretion(ADME) using SwissADME. Three promising compounds L_6(ZINC12232928), L_7(ZINC92176885), and L_9(ZINC92189850) were able to cross the Blood Brain Barrier while adhering to Lipinski’s rule. The toxicity of the compounds was also examined using a computational prediction tool ProTox 3.0. Most compounds have acceptable toxicity, with compound L_18(ZINC03302264) having the best predicted LD50 of 5240 mg/kg and predicted toxicity class 6. Finally, ligands L_7 and L_9 are the most promising candidates as potential lead compounds for future AChE-I studies as they maintained excellent results in all experiments.
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Authors
Benjamin Liu
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References:
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