Selective inhibition of monoamine oxidase A by chelerythrine, an isoquinoline alkaloid

Bioorg Med Chem Lett. 2018 Aug 1;28(14):2403-2407. doi: 10.1016/j.bmcl.2018.06.023. Epub 2018 Jun 18.

Abstract

Chelerythrine, an isoquinoline alkaloid isolated from the herbaceous perennial Chelidonium majus, was found to potently and selectively inhibit an isoform of recombinant human monoamine oxidase-A (MAO-A) with an IC50 value of 0.55 µM. Chelerythrine was a reversible competitive MAO-A inhibitor (Ki = 0.22 µM) with a potency much greater than toloxatone (IC50 = 1.10 µM), a marketed drug. Other isoquinoline alkaloids tested did not effectively inhibit MAO-A or MAO-B. A structural comparison with corynoline suggested the 1- and/or 2-methoxy groups of chelerythrine increase its inhibitory activity against MAO-A. Molecular docking simulations revealed that the binding affinity of chelerythrine for MAO-A (-9.7 kcal/mol) was greater than that for MAO-B (-4.6 kcal/mol). Docking simulation implied that Cys323 and Tyr444 of MAO-A are key residues for hydrogen-bond interaction with chelerythrine. Our findings suggest chelerythrine is one of the most reversible selective and potent natural inhibitor of MAO-A, and that it be regarded a potential lead compound for the design of novel reversible MAO-A inhibitors.

Keywords: Chelerythrine; Molecular docking; Monoamine oxidase A; Selective competitive inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzophenanthridines / chemical synthesis
  • Benzophenanthridines / chemistry
  • Benzophenanthridines / pharmacology*
  • Dose-Response Relationship, Drug
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Monoamine Oxidase / metabolism*
  • Monoamine Oxidase Inhibitors / chemical synthesis
  • Monoamine Oxidase Inhibitors / chemistry
  • Monoamine Oxidase Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Benzophenanthridines
  • Monoamine Oxidase Inhibitors
  • chelerythrine
  • Monoamine Oxidase
  • monoamine oxidase A, human