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Title

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

AuthorsJuárez-Jiménez, Jordi; Mendes, Eduarda; Galdeano, Carles; Martins, Carla; Silva, Daniel B.; Marco-Contelles, José ; do Carmo Carreiras, María; Luque, F. Javier; Ramsay, Rona R.
KeywordsCarbonitrile aminofuran
Monoamine oxidase
Selective binding
Docking
Molecular dynamics
Altered flavin spectrum
Issue Date2014
PublisherElsevier
CitationBiochimica et Biophysica Acta - Proteins and Proteomics 1844: 389- 397 (2014)
AbstractSince 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. © 2013 Elsevier B.V.
URIhttp://hdl.handle.net/10261/97228
DOI10.1016/j.bbapap.2013.11.003
Identifiersdoi: 10.1016/j.bbapap.2013.11.003
issn: 1570-9639
Appears in Collections:(IQOG) Artículos
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