Discovery of Selective Butyrylcholinesterase (BChE) Inhibitors through a Combination of Computational Studies and Biological Evaluations.

Cheng Cheng,Zhou Zhou,Wang Wang,Xu Xu,Lu Lu,Yang Yang,Li Li,Tang Tang,Xia Xia,Chen Chen

doi:10.3390/molecules24234217

Abstract

As there are increased levels and activity of butyrylcholiesterase (BChE) in the late stage of Alzheimer’s disease (AD), development of selective BChE inhibitors is of vital importance. In this study, a workflow combining computational technologies and biological assays were implemented to identify selective BChE inhibitors with new chemical scaffolds. In particular, a pharmacophore model served as a 3D search query to screen three compound collections containing 3.0 million compounds. Molecular docking and cluster analysis were performed to increase the efficiency and accuracy of virtual screening. Finally, 15 compounds were retained for biological investigation. Results revealed that compounds 8 and 18 could potently and highly selectively inhibit BChE activities (IC50 values < 10 μM on human BChE, selectivity index BChE > 30). These active compounds with novel scaffolds provided us with a good starting point to further design potent and selective BChE inhibitors, which may be beneficial for the treatment of AD.

Highlights

IntroductionAlzheimer’s disease (AD), an age-related and progressive neurodegenerative disorder featuring memory loss and cognitive impairments, is the most common type of dementia among older adults [1]
Alzheimer’s disease (AD), an age-related and progressive neurodegenerative disorder featuring memory loss and cognitive impairments, is the most common type of dementia among older adults [1].It affects more than 30 million patients worldwide at present, and the prevalence of AD continues to increase due to population aging [2,3]
The IC50 values were calculated by GraphPad Prism 6 (GraphPad Software, San Diego, CA, USA), and the data were shown as mean ± standard error of mean (SEM)

Summary

Introduction

Alzheimer’s disease (AD), an age-related and progressive neurodegenerative disorder featuring memory loss and cognitive impairments, is the most common type of dementia among older adults [1]. Development of highly potent and selective BChE inhibitors that are able to restore Ach levels in the brain, with much reduced peripheral side effects, represents a significant advancement [20]. Multiple X-ray crystallographic structures of complexes between hBChE proteins and hBChE inhibitors with various scaffolds have been determined, which sets the stage for virtual screening [26,27,28]. There are already several reports of using a structure-based virtual screening protocol and successfully obtained potent and highly selective hBChE inhibitors [16,29,30]. Anoverview overviewofofthe thestructure-based structure-based pharmacophore pharmacophore virtual protocol applied to identify selective butyrylcholinesterase (BChE) inhibitors.

Virtual

ChEs Inhibitory Activities of Hit Compounds

Kinetic Studies

Docking

Docking Simulation of Hit Compounds

Molecular Dynamics

Cell Viability Assay

3.53 The classification

Virtual Screening

Biological Evaluation

Kinetic Study

Binding Mode Prediction