Parameters for irreversible inactivation of monoamine oxidase

Rona R. Ramsay, Livia Basile, Antonin Maniquet, Stefanie Hagenow, Matteo Pappalardo, Maria Chiara Saija, Sharon Bryant, Alen Albreht, Salvatore Guccione

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)


The irreversible inhibitors of monoamine oxidases (MAO) slow neurotransmitter metabolism in depression and neurodegenerative diseases. After oxidation by MAO, hydrazines, cyclopropylamines and propargylamines form a covalent adduct with the flavin cofactor. To assist the design of new compounds to combat neurodegeneration, we have updated the kinetic parameters defining the interaction of these established drugs with human MAO-A and MAO-B and analyzed the required features. The Ki values for binding to MAO-A and molecular models show that selectivity is determined by the initial reversible binding. Common to all the irreversible inhibitor classes, the non-covalent 3D-chemical interactions depend on a H-bond donor and hydrophobic-aromatic features within 5.7 angstroms apart and an ionizable amine. Increasing hydrophobic interactions with the aromatic cage through aryl halogenation is important for stabilizing ligands in the binding site for transformation. Good and poor inactivators were investigated using visible spectroscopy and molecular dynamics. The initial binding, close and correctly oriented to the FAD, is important for the oxidation, specifically at the carbon adjacent to the propargyl group. The molecular dynamics study also provides evidence that retention of the allenyl imine product oriented towards FADH influences the formation of the covalent adduct essential for effective inactivation of MAO.
Original languageEnglish
Article number5908
Number of pages25
Issue number24
Publication statusPublished - 13 Dec 2020


  • FAD
  • Irreversible inhibition
  • Enzyme kinetics
  • Computational modeling
  • Pharmacophore
  • Spectrum
  • Adduct


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