Similarity search combined with docking and molecular dynamics for novel hAChE inhibitor scaffolds

The main purpose of this study was to address the performance of virtual screening methods based on ligands and the protein structure of acetylcholinesterase (AChE) in order to retrieve novel human AChE (hAChE) inhibitors. In addition, a protocol was developed to identify novel hit compounds and propose new promising AChE inhibitors from the ZINC database with 10 million commercially available compounds. In this sense, 3D similarity searches using rapid overlay of chemical structures and similarity analysis through comparison of electrostatic overlay of docked hits were used to retrieve AChE inhibitors from collected databases. Molecular dynamics simulation of 100 ns was carried out to study the best docked compounds from similarity searches. Some key residues were identified as crucial for the dual binding mode of inhibitor with the interaction site. All results indicated the relevant use of EON and docking strategy for identifying novel hit compounds as promising potential anticholinesterase candidates, and seven new structures were selected as potential hAChE inhibitors. Graphical abstract Compound N01 in the 4M0E hAChE crystallography structure from docking results. Yellow dashed lines Hydrogen bonds, blue dashed lines π-stacking interactions, green dashed lines cation-π interactions.