WaterMap‐Guided Structure‐Based Virtual Screening for Acetylcholinesterase Inhibitors

WaterMap‐Guided Structure‐Based Virtual Screening for Acetylcholinesterase Inhibitors

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 e...

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Bibliographic Details
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
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Summary: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.
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content type line 23
ISSN:1860-7179
1860-7187
DOI:10.1002/cmdc.202100721