A QSAR model for in silico screening of MAO-A inhibitors. Prediction, synthesis, and biological assay of novel coumarins.
This work explores the potential of the MARCH-INSIDE methodology to seek a QSAR for MAO-A inhibitors from a heterogeneous series of compounds. A Markov model was used to quickly calculate the molecular electron delocalization, polarizability, refractivity, and n-octanol/water partition coefficients for a series of 1406 active/nonactive compounds. LDA was subsequently used to fit a classification function. The model showed 92.8% and 91.8% global accuracy and predictability in training and validation studies. This QSAR model was validated through a virtual screening of a series of coumarin derivatives. The 15 selected compounds were prepared and evaluated as in vitro MAO-A inhibitors. The theoretical prediction was compared with the experimental results and the model correctly predicted 13 compounds with only two mistakes on compounds with activities very close to the cutoff point established for the model. Consequently, this method represents a useful tool for the "in silico" screening of MAO-A inhibitors.
Santana
Lourdes
L
Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela, 15872 Santiago de Compostela, Spain. qolsant@usc.es
Uriarte
Eugenio
E
González-Díaz
Humberto
H
Zagotto
Giuseppe
G
Soto-Otero
Ramón
R
Méndez-Alvarez
Estefanía
E
D000465:Algorithms; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D003374:Coumarins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry; D008297:Male; D008390:Markov Chains; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D008958:Models, Molecular; D008995:Monoamine Oxidase / Q000737:chemistry*; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D017207:Rats, Sprague-Dawley
D003374:Coumarins; D007527:Isoenzymes; D008996:Monoamine Oxidase Inhibitors; D008995:Monoamine Oxidase