ABSTRACT:
Approximately 4.6 million individuals worldwide are affected by Alzheimer's disease, a prevalent neurodegenerative disorder. The disease is caused by beta-amyloid buildup, which forms insoluble plaques in the brain. This triggers a series of secondary events within the "amyloid cascade," which includes protein tau hyperphosphorylation, inflammation, oxidation, and excitotoxicity, ultimately leading to the activation of apoptosis. A study compared the potential anti-Alzheimer's activity of heterocyclic nitrogen-containing compounds from a database with pyrimidine, triazole, or pyrrolidine nuclei known to exhibit activity against neurodegeneration. The compounds (3r,4s)-1-benzyl-3-nitro-4-phenylpyrrolidine, 5-bromo-1-[(2r,4s,5r)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidine-2,4-dione, 6-[4-(2-piperidin-1-ylethoxy)phenyl]-3-pyridin-4-ylpyrazolo[1,5-a]pyrimidine, 6-(4-methoxyphenyl)-3-pyridin-4-ylpyrazolo[1,5-a]pyrimidine, 4-(5-pyridin-4-yl-1h-1,2,4-triazol-3-yl)pyridine-2-carbonitrile, and 5-pyridin-4-yl-1,2-dihydro-1,2,4-triazole-3-thione were tested in silico against the receptor Donepezil complexed with its target acetylcholinesterase (1EVE). PyRX Docking and Auto Dock 4 were used in the study. The comparative analysis of docking results revealed that (3r,4s)-1-benzyl-3-nitro-4-phenylpyrrolidine and 5-bromo-1-[(2r,4s,5r)-4-hydroxy-5-(hydroxymethyl) oxolan-2-yl] pyrimidine-2,4-dione had favorable binding affinities, indicating potential anti-cholinesterase activity. A redocking study used Ligand Donepezil to confirm the binding modes and test the method's validity. The study also included a comparative analysis of results obtained through two different docking software.