Discovery of dual binding site acetylcholinesterase inhibitors identified by pharmacophore modeling and sequential virtual screening techniques

Dual binding site acetylcholinesterase (AChE) inhibitors are promising for the treatment of Alzheimer’s disease (AD). They alleviate the cognitive deficits and AD-modifying agents, by inhibiting the β-amyloid (Aβ) peptide aggregation, through binding to both the catalytic and peripheral anionic sites, the so called dual binding site of the AChE enzyme. In this Letter, chemical features based 3D-pharmacophore models were developed based on the eight potent and structurally diverse AChE inhibitors (I–VIII) obtained from high-throughput in vitro screening technique. The best 3D-pharmacophore model, Hypo1, consists of two hydrogen-bond acceptor lipid, one hydrophobe, and two hydrophobic aliphatic features obtained by Catalyst/HIPHOP algorithm adopted in Discovery studio program. Hypo1 was used as a 3D query in sequential virtual screening study to filter three small compound databases. Further, a total of nine compounds were selected and followed on in vitro analysis. Finally, we identified two leads—Specs1 (IC50 = 3.279 μM) and Spec2 (IC50 = 5.986 μM) dual binding site compounds from Specs database, having good AChE enzyme inhibitory activity.

Graphical abstractDual binding site acetylcholinesterase (AChE) inhibitors are promising for the treatment of Alzheimer’s disease (AD). Inhibitors showing both the anti-aggregating Aβ and anti-cholinesterase effect bind to these sub-sites, the so called dual binding site in AChE enzyme. We adopted a strategy, by systematically integrating the in vitro and in silico techniques throughout the present work, to discover new cholinesterase inhibitors Specs1 and Specs2, having good ADMET properties for the treatment of AD.Figure optionsDownload full-size imageDownload as PowerPoint slide