Molecular determinants of MAO selectivity in a series of indolylmethylamine derivatives: biological activities, 3D-QSAR/CoMFA analysis, and computational simulation of ligand recognition.
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 >10(6) 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.
Morón
J A
JA
Laboratori de Medicina Computacional, Unitat de Bioestadistica, Facultat de Medicina, and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.
Campillo
M
M
Perez
V
V
Unzeta
M
M
Pardo
L
L
D000588:Amines / Q000138:chemical synthesis*; D000818:Animals; D003198:Computer Simulation; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology; D007527:Isoenzymes / Q000737:chemistry / Q000235:genetics; D007532:Isoleucine / Q000737:chemistry; D007700:Kinetics; D008024:Ligands; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects / Q000201:enzymology; D008958:Models, Molecular; D008995:Monoamine Oxidase / Q000737:chemistry* / Q000235:genetics; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010649:Phenylalanine / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D000588:Amines; D007211:Indoles; D007527:Isoenzymes; D008024:Ligands; D008996:Monoamine Oxidase Inhibitors; D007532:Isoleucine; D010649:Phenylalanine; D008995:Monoamine Oxidase