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

Alexander Williams, Shuo Zhou, Chang Guo Zhan

Research output: Contribution to journalArticlepeer-review

18 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 languageEnglish
Article number126754
JournalBioorganic and Medicinal Chemistry Letters
Volume29
Issue number24
DOIs
StatePublished - 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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