Structure-based virtual screening leading to discovery of highly selective butyrylcholinesterase inhibitors with solanaceous alkaloid scaffolds.

Abstract

According to recent research advance, it is interesting to identify new, potent and selective inhibitors of human butyrylcholinesterase (BChE) for therapeutic treatment of both the Alzheimer's disease (AD) and heroin abuse. In this study, we carried out a structure-based virtual screening followed by in vitro activity assays, with the goal to identify new inhibitors that are selective for BChE over acetylcholinesterase (AChE). As a result, a set of new, selective inhibitors of human BChE were identified from natural products with solanaceous alkaloid scaffolds. The most active one of the natural products (compound 1) identified has an IC50 of 16.8 nM against BChE. It has been demonstrated that the desirable selectivity of these inhibitors for BChE over AChE is mainly controlled by three key residues in the active site cavity, i.e. residues Q119, A277, and A328 in BChE versus the respective residues Y124, W286, and Y337 in AChE. Based on this structural insight, future rational design of new, potent and selective BChE inhibitors may focus on these key structural differences in the active site cavity.

• Authors: Shuo Zhou, Yaxia Yuan, Fang Zheng, Chang-Guo Zhan
• Journal: Chemico-biological interactions (Chem Biol Interact) Vol. 308 Pg. 372-376 (Aug 01 2019) ISSN: 1872-7786 [Electronic] Ireland
• PMID: 31152736 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier B.V. All rights reserved.

Chemical References

• Cholinesterase Inhibitors
• Solanaceous Alkaloids
• Butyrylcholinesterase

Topics

• Binding Sites
• Butyrylcholinesterase (chemistry, metabolism)
• Catalytic Domain
• Cholinesterase Inhibitors (chemistry, metabolism)
• Humans
• Inhibitory Concentration 50
• Molecular Docking Simulation
• Solanaceous Alkaloids (chemistry, metabolism)
• Structure-Activity Relationship