Drug Repurposing Effort for the Novel Acetylcholinesterase and Butyrylcholinesterase Targets: A Combined in Silico and in Vitro Study

Abstract

In the current drug repurposing study, 7822 small compounds were fetched from NIH small molecule library and are screened through a binary Alzheimer’s Disease (AD)-QSAR model. The cut-off value for AD therapeutic activity set as (>0.75), and the molecules with higher values identified and then tested in the 26 different toxicity-QSAR models. Selected hits with no predicted toxicities were then interacted with acetylcholinesterase (AChE), and butyrylcholinesterase (BuChE) targets using combined molecular docking and molecular dynamics (MD) simulations. Our in silico screening results identified five hit compounds: Ocaperidone, cafedrine, isosulpride, risperidone, and nelfinavir. Three of these compounds together with FDA approved compounds against AD were used in in vitro tests against AChE and BChE, and our experimental results confirmed in silico predictions. All of three selected hits (ocaperidone, risperidone, and nelfinavir) represented nM-level IC50 values for both AChE and BChE targets. The results of the conducted drug repurposing study may open a new perspective for the development of novel small molecule cholinesterase inhibitors.