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Author Notes:

E-mail: gzapata@uchile.cl

AF and DEE contributed equally to this work. For the complete list of author contributions, see the full article.

The authors have declared that no competing interests exist.

Subjects:

Research Funding:

Funding was provided by Fondecyt Grant Number 1120280, GZT, Fondo Nacional de Desarollo Cientifico y Tecnologico.

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • MONOAMINE-OXIDASE-B
  • NONCOVALENT INTERACTION REGIONS
  • CHEMICAL CLUSTER APPROACH
  • BENZYLAMINE ANALOGS
  • SELECTIVE-INHIBITION
  • MAO-B
  • SUBSTRATE
  • MODEL
  • MECHANISMS
  • RESOLUTION
  • Transition state
  • Hydrogen bonding
  • Crystal structure
  • Computer software
  • Enzymes
  • Gibbs free energy
  • Oxidation
  • Cofactors (biochemistry)

Journal Title:

PLoS ONE

Volume:

Volume 11, Number 5

Publisher:

, Pages e0154989-e0154989

Type of Work:

Article | Final Publisher PDF

Abstract:

Despite their structural and chemical commonalities, p-chloro-β-methylphenethylamine and p-methoxy-β-methylphenethylamine display distinct inhibitory and substrate activities upon MAO-B binding. Density Functional Theory (DFT) quantum chemical calculations reveal that β-methylation and para-substitution underpin the observed activities sustained by calculated transition state energy barriers, attained conformations and key differences in their interactions in the enzyme's substrate binding site. Although both compounds meet substrate requirements, it is clear that β-methylation along with the physicochemical features of the para-substituents on the aromatic ring determine the activity of these compounds upon binding to the MAO B-isoform. While data for a larger set of compounds might lend generality to our conclusions, our experimental and theoretical results strongly suggest that the contrasting activities displayed depend on the conformations adopted by these compounds when they bind to the enzyme.

Copyright information:

© 2016 Fierro et al.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/).

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