Quantitative structure-activity relationship and complex network approach to monoamine oxidase A and B inhibitors.
The work provides a new model for the prediction of the MAO-A and -B inhibitor activity by the use of combined complex networks and QSAR methodologies. On the basis of the obtained model, we prepared and assayed 33 coumarin derivatives, and the theoretical prediction was compared with the experimental activity data. The model correctly predicted 27 compounds, and most of the active derivatives showed IC 50 values in the muM-nM range against both the MAO-A and MAO-B isoforms. Compound 14 shows the same MAO-A inhibitory activity (IC 50 = 7.2 nM), as clorgyline used as a reference inhibitor and has the highest MAO-A specificity (1000-fold higher compared to MAO-B). On the other hand, compounds 24 (IC 50 = 1.2 nM) and 28 (IC 50 = 1.5 nM) show higher activity than selegiline (IC 50 = 19.6 nM) and high MAO-B selectivity with 100-fold and 1600-fold inhibition levels, with respect to the MAO-A isoform.
Santana
Lourdes
L
Department of Organic Chemistry, Department of Pharmacology, Faculty of Pharmacy, University of Santiago de Compostela 15782, Spain. qolsant@usc.es
González-Díaz
Humberto
H
Quezada
Elías
E
Uriarte
Eugenio
E
Yáñez
Matilde
M
Viña
Dolores
D
Orallo
Francisco
F
D019295:Computational Biology; D015195:Drug Design; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D015394:Molecular Structure; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship
D007527:Isoenzymes; D008996:Monoamine Oxidase Inhibitors; D008995:Monoamine Oxidase