Binding models of reversible inhibitors to type-B monoamine oxidase

Interest in the inhibitors of type-B monoamine oxidase has grown in recent years, due to the evidence for multiple roles of one such agent ( selegiline) in the pharmacological management of neurodegenerative disorders. A set of 130 reversible and selective inhibitors of MAO-B ( including tetrazole, oxadiazolone, and oxadiazinone derivatives) were taken from the literature and subjected to a three-dimensional quantitative structure - activity relationship (3D-QSAR) study, using CoMFA and GOLPE procedures. The steric and lipophilic fields, alone and in combination, provided us with informative models and satisfactory predictions (q(2) = 0.73). The validity of these models was checked against the 3D X-ray structure of human MAO-B. Flexible docking calculations, performed by using a new approach which took advantage from QXP and GRID computational tools, showed the diverse inhibitors to interact with MAO-B in a similar binding mode, irrespective of the heterocycle characterizing them. A significant trend of correlation was observed between estimated energies of the complexes and the experimental inhibition data.