Exploring the structural basis of the selective inhibition of monoamine oxidase A by dicarbonitrile aminoheterocycles: role of Asn181 and Ile335 validated by spectroscopic and computational studies

Biochim Biophys Acta. 2014 Feb;1844(2):389-97. doi: 10.1016/j.bbapap.2013.11.003. Epub 2013 Nov 15.

Abstract

Since cyanide potentiates the inhibitory activity of several monoamine oxidase (MAO) inhibitors, a series of carbonitrile-containing aminoheterocycles was examined to explore the role of nitriles in determining the inhibitory activity against MAO. Dicarbonitrile aminofurans were found to be potent, selective inhibitors against MAO A. The origin of the MAO A selectivity was identified by combining spectroscopic and computational methods. Spectroscopic changes induced in MAO A by mono- and dicarbonitrile inhibitors were different, providing experimental evidence for distinct binding modes to the enzyme. Similar differences were also found between the binding of dicarbonitrile compounds to MAO A and to MAO B. Stabilization of the flavin anionic semiquinone by monocarbonitrile compounds, but destabilization by dicarbonitriles, provided further support to the distinct binding modes of these compounds and their interaction with the flavin ring. Molecular modeling studies supported the role played by the nitrile and amino groups in anchoring the inhibitor to the binding cavity. In particular, the results highlight the role of Asn181 and Ile335 in assisting the interaction of the nitrile-containing aminofuran ring. The network of interactions afforded by the specific attachment of these functional groups provides useful guidelines for the design of selective, reversible MAO A inhibitors.

Keywords: Altered flavin spectrum; Carbonitrile aminofuran; Docking; FAD; MAO; Molecular dynamics; Monoamine oxidase; QM/MM; Selective binding; flavin adenine dinucleotide; monoamine oxidase; quantum mechanics/molecular mechanics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Asparagine / physiology*
  • Binding Sites
  • Flavin-Adenine Dinucleotide / analogs & derivatives
  • Flavin-Adenine Dinucleotide / chemistry
  • Furans / chemistry*
  • Humans
  • Isoleucine / physiology*
  • Models, Molecular
  • Molecular Docking Simulation
  • Monoamine Oxidase / chemistry*
  • Monoamine Oxidase / metabolism
  • Monoamine Oxidase Inhibitors / chemistry*
  • Monoamine Oxidase Inhibitors / metabolism
  • Protein Interaction Domains and Motifs
  • Spectrum Analysis
  • Structure-Activity Relationship

Substances

  • Furans
  • Monoamine Oxidase Inhibitors
  • Isoleucine
  • Flavin-Adenine Dinucleotide
  • flavin semiquinone
  • Asparagine
  • Monoamine Oxidase
  • monoamine oxidase A, human