title: Binding models of reversible inhibitors to type-B monoamine oxidase.
abstract: 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 (q2 = 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.
authors.affiliation: Dipartimento Farmaco-Chimico, Università di Bari, Via Orabona 4, 70125 Bari, Italy. carrieri@farmchim.uniba.it
authors.forename: Antonio
authors.initials: A
authors.lastname: Carrieri
authors.forename: Andrea
authors.initials: A
authors.lastname: Carotti
authors.forename: M Letizia
authors.initials: ML
authors.lastname: Barreca
authors.forename: Cosimo
authors.initials: C
authors.lastname: Altomare
mesh_terms: D020134:Catalytic Domain; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D008958:Models, Molecular; D008995:Monoamine Oxidase / Q000737:chemistry*; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D008024:Ligands; D008996:Monoamine Oxidase Inhibitors; D008995:Monoamine Oxidase