Targowska-Duda_2022_ChemMedChem__

Structure-based virtual screening of the Enamine database of 1.7 million compounds followed by WaterMap calculations (a molecular dynamics simulation-based method) was applied to identify novel AChE inhibitors. The inhibitory potency of 29 selected compounds against electric eel (ee) AChE was determined using the Ellman's method. Three compounds were found active (success rate 10%). For the most potent compound (~40% of inhibition at 10 microM), 20 derivatives were discovered based on the Enamine similarity search. Finally, five compounds were found promising (IC 50 ranged from 6.3 microM to 17.5 microM) inhibitors of AChE. The performed similarity and fragment analysis confirmed significant structural novelty of novel AChE inhibitors. Toxicity/safety of selected compounds was determined in zebrafish model.