Molecular determinants of MAO selectivity in a series of indolylmethylamine derivatives: Biological activities, 3D-QSAR/CoMFA analysis, and computational simulation of ligand recognition

Jose A. Morón, Mercedes Campillo, Virgili Perez, Mercedes Unzeta, Leonardo Pardo

Research output: Contribution to journalArticlepeer-review

66 Scopus citations

Abstract

A series of indolylmethylamine derivatives were assayed toward MAO-A and MAO-B inhibition. The K(i) values of these compounds are in the range from 0.8 to > 106 nM for MAO-A or from 0.75 to 476000 nM for MAO-B. The most selective MAO-A or MAO-B inhibitors elicit a ratio of K(i) in the order of 1500 or 1000, respectively. Comparison of MAO-A and MAO-B CoMFA models showed that both the steric and electrostatic properties at the 5 position of the indole ring are determinant for MAO selectivity. Computational simulations of the complex between this part of the ligand and Phe-208 of MAO-A or Ile-199 of MAO-B, experimentally identified as responsible for substrate selectivity, allowed us to further characterize the nature of these enzyme-inhibitor interactions.

Original languageEnglish
Pages (from-to)1684-1691
Number of pages8
JournalJournal of Medicinal Chemistry
Volume43
Issue number9
DOIs
StatePublished - Jan 1 2000

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