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

Jordi Juárez-Jiménez, Eduarda Mendes, Carles Galdeano, Carla P Martins, Daniel B. Silva, José Marco-Contelles, Maria Do Carmo Carreiras, F Javier Luque, Rona R. Ramsay*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)389-397
Number of pages9
JournalBBA - Proteins and Proteomics
Volume1844
Issue number2
Early online date15 Nov 2013
DOIs
Publication statusPublished - Feb 2014

Keywords

  • Altered flavin spectrum
  • Carbonitrile aminofuran
  • Docking
  • Molecular dynamics
  • Monoamine oxidase
  • Selective binding

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