Discovery of potent and selective butyrylcholinesterase inhibitors through the use of pharmacophore-based screening

Alexander Williams; Shuo Zhou; Chang Guo Zhan

doi:10.1016/j.bmcl.2019.126754

Discovery of potent and selective butyrylcholinesterase inhibitors through the use of pharmacophore-based screening

Alexander Williams, Shuo Zhou, Chang Guo Zhan

Pharmaceutical Sciences

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

14 Scopus citations

Abstract

Cholinesterase inhibitors have long been used in the treatment of Alzheimer's Disease (AD) via the protection of acetylcholine levels. However, recent research has shown that the specific inhibition of butyrylcholinesterase (BChE) could better ameliorate symptoms within patients. In addition, it has recently been shown that selective inhibition of BChE can also significantly attenuate the toxicity and physiological effects of heroin. Currently, there are no specific and potent inhibitors of BChE approved for use in AD or heroin abuse. Through a combined use of in silico and in vitro screening, we have found three compounds with sub-50 nM IC₅₀ values that specifically target BChE. These newly discovered BChE inhibitors can act as the lead scaffolds for future development of the desirably potent and selective BChE inhibitors.

Original language	English
Article number	126754
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	29
Issue number	24
DOIs	https://doi.org/10.1016/j.bmcl.2019.126754
State	Published - Dec 15 2019

Bibliographical note

Funding Information:
This work was supported in part by the funding of the Molecular Modeling and Biopharmaceutical Center at the University of Kentucky College of Pharmacy, the National Science Foundation (NSF grant CHE-1111761), and the National Institutes of Health via the National Institute on Drug Abuse (T32 DA016176) and National Center for Advancing Translational Sciences (UL1TR001998) grants. The authors also acknowledge the Computer Center at University of Kentucky for supercomputing time on a Dell Supercomputer Cluster consisting of 388 nodes or 4,816 processors.

Funding Information:
This work was supported in part by the funding of the Molecular Modeling and Biopharmaceutical Center at the University of Kentucky College of Pharmacy , the National Science Foundation (NSF grant CHE-1111761), and the National Institutes of Health via the National Institute on Drug Abuse (T32 DA016176) and National Center for Advancing Translational Sciences (UL1TR001998) grants. The authors also acknowledge the Computer Center at University of Kentucky for supercomputing time on a Dell Supercomputer Cluster consisting of 388 nodes or 4,816 processors. Appendix A

Publisher Copyright:
© 2019 Elsevier Ltd

Keywords

Acetylcholinesterase
Butyrylcholinesterase
Docking
Inhibitor
Pharmacophore

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmcl.2019.126754

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title = "Discovery of potent and selective butyrylcholinesterase inhibitors through the use of pharmacophore-based screening",

abstract = "Cholinesterase inhibitors have long been used in the treatment of Alzheimer's Disease (AD) via the protection of acetylcholine levels. However, recent research has shown that the specific inhibition of butyrylcholinesterase (BChE) could better ameliorate symptoms within patients. In addition, it has recently been shown that selective inhibition of BChE can also significantly attenuate the toxicity and physiological effects of heroin. Currently, there are no specific and potent inhibitors of BChE approved for use in AD or heroin abuse. Through a combined use of in silico and in vitro screening, we have found three compounds with sub-50 nM IC50 values that specifically target BChE. These newly discovered BChE inhibitors can act as the lead scaffolds for future development of the desirably potent and selective BChE inhibitors.",

keywords = "Acetylcholinesterase, Butyrylcholinesterase, Docking, Inhibitor, Pharmacophore",

author = "Alexander Williams and Shuo Zhou and Zhan, {Chang Guo}",

note = "Funding Information: This work was supported in part by the funding of the Molecular Modeling and Biopharmaceutical Center at the University of Kentucky College of Pharmacy, the National Science Foundation (NSF grant CHE-1111761), and the National Institutes of Health via the National Institute on Drug Abuse (T32 DA016176) and National Center for Advancing Translational Sciences (UL1TR001998) grants. The authors also acknowledge the Computer Center at University of Kentucky for supercomputing time on a Dell Supercomputer Cluster consisting of 388 nodes or 4,816 processors. Funding Information: This work was supported in part by the funding of the Molecular Modeling and Biopharmaceutical Center at the University of Kentucky College of Pharmacy , the National Science Foundation (NSF grant CHE-1111761), and the National Institutes of Health via the National Institute on Drug Abuse (T32 DA016176) and National Center for Advancing Translational Sciences (UL1TR001998) grants. The authors also acknowledge the Computer Center at University of Kentucky for supercomputing time on a Dell Supercomputer Cluster consisting of 388 nodes or 4,816 processors. Appendix A Publisher Copyright: {\textcopyright} 2019 Elsevier Ltd",

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N2 - Cholinesterase inhibitors have long been used in the treatment of Alzheimer's Disease (AD) via the protection of acetylcholine levels. However, recent research has shown that the specific inhibition of butyrylcholinesterase (BChE) could better ameliorate symptoms within patients. In addition, it has recently been shown that selective inhibition of BChE can also significantly attenuate the toxicity and physiological effects of heroin. Currently, there are no specific and potent inhibitors of BChE approved for use in AD or heroin abuse. Through a combined use of in silico and in vitro screening, we have found three compounds with sub-50 nM IC50 values that specifically target BChE. These newly discovered BChE inhibitors can act as the lead scaffolds for future development of the desirably potent and selective BChE inhibitors.

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Discovery of potent and selective butyrylcholinesterase inhibitors through the use of pharmacophore-based screening

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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