期刊
CHEMICO-BIOLOGICAL INTERACTIONS
卷 308, 期 -, 页码 372-376出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.cbi.2019.05.051
关键词
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资金
- National Institutes of Health (NIH) [UH2/UH3 DA041115, R01 DA035552, R01 DA032910, R01 DA013930, R01 DA025100]
- National Science Foundation (NSF) [CHE-1111761]
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.
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