Models of monoamine oxidase A and B active sites obtained by using 3D QSARwith CoMFA analysis

The monoamine oxidase catalyses the oxidative deamination of neuroactive am ines. This enzyme exists in two forms A and B, which differ by substrates p reference and inhibitors specificity. Investigation of the structures of th ese enzymes and design new selective inhibitors are of greatly interesting since MAO A inhibitors are used in therapeutic practice as antidepressants and MAO B inhibitors - in the treatment Parkinson's diseases, The three dim ension structures of monoamine oxidases are still unknown. Therefore, one o f the most perspective approach to define significant Features of structure active site is method based on analysis of structure-activity relationship (3D QSAR) with comparison of molecular fields analysis (CoMFA) allowing to get the spatial distribution of important properties affecting the activit y. In present study we investigate the structures of active sites MAO A and B using 16 pyrazinocarbazole derivatives in variant conformation. Majority of pyrazinocarbazole derivatives have a rigit conformation, but three of thos e is sufficiently flexible. The latters can be in two conformation types: l ong molecules (substitution accommodate along axis of main structure) and s hort molecules (substitution accommodate at acute angle about of main struc ture). Several 3D QSAR and CoMFA models of MAO A and B active sites were de sign for data sets containing various types of flexible molecules conformat ion. All obtained models are statistical reliable and have sufficient predi ctive power for tested compound tetrindole. The best MAO A model that inclu de two flexible molecules in long conformations was obtained, and the longe st one of those in short conformation. In contrast, for MAO B model contain ing all flexible molecules in the short conformations is more preferred. On the basis of obtained data the schematic models of MAO A and B active si tes structures are proposed. According to these models MAO A active site ha ve the narrow long cavity that accommodate long molecules, while MAO B acti ve site is broader and shorter.