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

doi:10.1177/1559325820938526

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

Medicinal Chemistry

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

Abstract

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 language	English (US)
Journal	Dose-Response
Volume	18
Issue number	2
DOIs	https://doi.org/10.1177/1559325820938526
State	Published - 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.

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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

abstract = "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.",

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author = "You Zhou and Yanyu Hu and Xin Lu and Hongyu Yang and Qihang Li and Chenxi Du and Yao Chen and Hong, {Kwon Ho} and Haopeng Sun",

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: {\textcopyright} The Author(s) 2020.",

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AU - Zhou, You

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AU - Li, Qihang

AU - Du, Chenxi

AU - Chen, Yao

AU - Hong, Kwon Ho

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N2 - 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.

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

Abstract

Bibliographical note

Keywords

UN SDGs

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