3D-pharmacophore model based virtual screening to identify dual-binding site and selective acetylcholinesterase inhibitors

Abstract

The formation of β-amyloid plaques in the brain is a key neurodegenerative event in Alzheimer’s disease (AD). Interestingly, research on acetylcholinesterase (AChE) enzyme has increased due to findings supporting this enzyme involvement in the β-amyloid peptide fibril formation during AD pathogenesis. In this investigation, chemical features based 3D pharmacophore models were developed from structurally diverse xanthostigmine derivatives, known inhibitors of AChE enzyme, using 3D-QSAR pharmacophore generation module in Discovery Studio2.5 (DS2.5). The constructed pharmacophore models for AChE inhibitors was further cross-validated using test set and Cat-Scramble methodology. The best quantitative pharmacophore model Hypo1, was used for screening the chemical databases of small compounds including Specs, NCI, and IBScreen, to identify the new compounds that are presumably able to act as dual-binding site AChE inhibitors. The screened virtual hits were then subjected to the Lipinski’s rule of five, blood–brain barrier (BBB), PSA, LogS, percent human oral absorption, and toxicity analysis. Finally, 32 compounds were identified as potential leads against AChE enzyme, showing good estimated activities and promising ADMET properties. Molecular docking of these compounds using FlexX software showed catalytic and peripheral anionic binding site interactions, so called dual binding of the AChE enzyme. Docking study was also performed on butyrylcholinesterase in order to understand the compound selectivity. This study may assist in the discovery and design of novel dual binding site and selective AChE inhibitors with potent inhibitory activity.