Discovery of a Selective 6-Hydroxy-1, 4-Diazepan-2-one Containing Butyrylcholinesterase Inhibitor by Virtual Screening and MM-GBSA Rescoring

You Zhou, Yanyu Hu, Xin Lu, Hongyu Yang, Qihang Li, Chenxi Du, Yao Chen, Kwon Ho Hong, Haopeng Sun

Research output: Contribution to journalArticlepeer-review


Alzheimer disease (AD) is the most common form of dementia characterized by the loss of cognitive abilities through the death of central neuronal cells. In this study, structure-based virtual screens of 2 central nervous system-targeted libraries followed by molecular mechanics/generalized born surface area rescoring were performed to discover novel, selective butyrylcholinesterase (BChE) inhibitors, which are one of the most effective therapeutic strategies for the treatments in late-stage AD. Satisfyingly, compound 5 was identified as a highly selective low micromolar inhibitor of BChE (BChE IC50 = 1.4 μM). The binding mode prediction and kinetic analysis were performed to obtain detailed information about compound 5. Besides, a preliminary structure–activity relationship investigation of compound 5 was carried out for further development of the series. The present results provided a valuable chemical template with a novel scaffold for the development of selective BChE inhibitors.

Original languageEnglish (US)
Issue number2
StatePublished - Apr 1 2020

Bibliographical note

Funding Information:
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by Fundamental Research Funds for the Central Universities under Grant No. XDJK2019C103; National Natural Science Foundation of China [grant numbers 81803367, 81872728, and 81573281]; Basic Research and Frontier Exploration Project of Chongqing [grant number cstc2018jcyjAX0715]; Natural Science Foundation of Jiangsu Province [grant number BK20191411]; Jiangsu Qinglan Project and Venture & Innovation Support Program for Chongqing Overseas Returnees.

Publisher Copyright:
© The Author(s) 2020.


  • Alzheimer disease
  • MM-GBSA rescoring
  • preliminary structure–activity relationship study
  • selective butyrylcholinesterase inhibitors
  • structure-based virtual screening

PubMed: MeSH publication types

  • Journal Article


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