Multivalent butyrylcholinesterase inhibitor discovered by exploiting dynamic combinatorial chemistry

Bioorg Chem. 2021 Mar:108:104656. doi: 10.1016/j.bioorg.2021.104656. Epub 2021 Jan 27.

Abstract

In this study, we report the generation of a polymer-based dynamic combinatorial library (DCL) incorporating exchangeable side chains using acylhydrazone formation reaction. In combination with tetrameric butyrylcholinesterase (BChE), the most potent binding side chain was identified, and the information obtained was further used for the synthesis of a multivalent BChE inhibitor. In the in vitro biological evaluation, this multivalent inhibitor exhibited not only better inhibitory effect than the commercial reference but also high selectivity on BChE over acetylcholinesterase (AChE).

Keywords: Butyrylcholinesterase; Dynamic combinatorial chemistry; Macromolecule; Multivalent interaction; Protein inhibition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / metabolism
  • Butyrylcholinesterase / metabolism*
  • Cell Line, Tumor
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Combinatorial Chemistry Techniques*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Cholinesterase Inhibitors
  • Acetylcholinesterase
  • Butyrylcholinesterase