Why p-OMe- and p-Cl-beta-Methylphenethylamines Display Distinct Activities uponMAO-B Binding

• Type of Material: Article
• Authors: Angélica Fierro, Pontificia Universidad Católica de Chile; Dale Edmondson, Emory University; Cristian Celis-Barros, Universidad Andres Bello; Marco Rebolledo-Fuentes, University of Chile; Gerald Zapata-Torres, University of Chile
• Language: English
• Date: 2016-05-06
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2016 Fierro et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.pone.0154989
• Title of Journal or Parent Work: PLoS ONE
• ISSN: 1932-6203
• Volume: 11
• Issue: 5
• Start Page: e0154989
• End Page: e0154989
• Grant/Funding Information: Funding was provided by Fondecyt Grant Number 1120280, GZT, Fondo Nacional de Desarollo Cientifico y Tecnologico.
• Keywords: Hydrogen bonding; Gibbs free energy; Crystal structure; MECHANISMS; Multidisciplinary Sciences; Oxidation; SELECTIVE-INHIBITION; Computer software; MODEL; MONOAMINE-OXIDASE-B; Transition state; SUBSTRATE; Enzymes; BENZYLAMINE ANALOGS; NONCOVALENT INTERACTION REGIONS; RESOLUTION; Cofactors (biochemistry); CHEMICAL CLUSTER APPROACH; Science & Technology; MAO-B
• Research Categories: Chemistry, Pharmaceutical; Chemistry, Biochemistry; Chemistry, General

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.