Rapid discovery of a selective butyrylcholinesterase inhibitor using structure-based virtual screening

Jared A. Miles, Jeevak S. Kapure, Girdhar Singh Deora, Charlotte Courageux, Alexandre Igert, José Dias, Ross P. McGeary, Xavier Brazzolotto, Benjamin P. Ross

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Acetylcholinesterase inhibitors are the mainstay of Alzheimer's disease treatments, despite having only short-term symptomatic benefits and severe side effects. Selective butyrylcholinesterase inhibitors (BuChEIs) may be more effective treatments in late-stage Alzheimer's disease with fewer side effects. Virtual screening is a powerful tool for identifying potential inhibitors in large digital compound databases. This study used structure-based virtual screening combined with physicochemical filtering to screen the InterBioScreen and Maybridge databases for novel selective BuChEIs. The workflow rapidly identified 22 potential hits in silico, resulting in the discovery of a human BuChEI with low-micromolar potency in vitro (IC50 2.4 µM) and high selectivity for butyrylcholinesterase over acetylcholinesterase. The compound was a rapidly reversible BuChEI with mixed-model in vitro inhibition kinetics. The binding interactions were investigated using in silico molecular dynamics and by developing structure-activity relationships using nine analogues. The compound also displayed high permeability in an in vitro model of the blood-brain barrier.

Original languageEnglish
Article number127609
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume30
Issue number24
DOIs
Publication statusPublished - 15 Dec 2020

Keywords

  • Alzheimer's disease
  • Butyrylcholinesterase
  • Inhibitor
  • Virtual screening

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