WaterMap‐Guided Structure‐Based Virtual Screening for Acetylcholinesterase Inhibitors

• Published in: ChemMedChem Vol. 17; no. 8; pp. e202100721 - n/a
• Main Authors: Targowska‐Duda, Katarzyna M., Maj, Maciej, Drączkowski, Piotr, Budzyńska, Barbara, Boguszewska‐Czubara, Anna, Wróbel, Tomasz M., Laitinen, Tuomo, Kaczmar, Patrycja, Poso, Antti, Kaczor, Agnieszka A.
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 20.04.2022
• Subjects: acetylcholine; acetylcholine inhibitors; Acetylcholinesterase; Acetylcholinesterase - chemistry; Alzheimer's disease; Animals; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - toxicity; Electrophorus; Inhibitors; Molecular Docking Simulation; Screening; Similarity; Toxicity; virtual screening; Zebrafish; zebrafish model; zebrafish model; acetylcholine inhibitors; acetylcholine; virtual screening; Alzheimer's disease
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.202100721

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 acetylcholinesterase (AChE) inhibitors. The inhibitory potency of 29 selected compounds against electric eel (ee) AChE was determined using Ellman's method. Three compounds were found to be active (success rate 10 %). For the most potent compound (∼40 % inhibition at 10 μM), 20 derivatives were discovered based on the Enamine similarity search. Finally, five compounds were found to be promising (IC50 ranged from 6.3 μM to 17.5 μM) inhibitors of AChE. The performed similarity and fragment analysis confirmed significant structural novelty for these AChE inhibitors. Toxicity/safety of selected compounds was determined in zebrafish model. From in silico to in vivo: Novel acetylcholinesterase inhibitors were identified in docking‐based virtual screening followed by WaterMap calculations. The compounds displayed significant structural novelty relative to known acetylcholine inhibitors. The safety/toxicity of these compounds were assessed in a zebrafish model.