title: Identification of novel monoamine oxidase B inhibitors by structure-based virtual screening.
abstract: Parkinson's disease is a severe debilitating neurodegenerative disorder. Recently, it was shown that the peroxisome proliferating-activator receptor-gamma agonist pioglitazone protected mice from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity due to its ability to inhibit monoamine oxidase B (MAO-B). Docking studies were initiated to investigate pioglitazone's interactions within the substrate cavity of MAO-B. Modeling studies indicated that the thiazolidinedione (TZD) moiety was a likely candidate for its specificity to MAO-B. To explore this potential novel MAO-B scaffold, we performed a structure-based virtual screen to identify additional MAO-B inhibitors. Our search identified eight novel compounds containing the TZD-moiety that allowed for a limited study to identify structural requirements for binding to MAO-B. Inhibition assays identified two TZDs (A6355 and L136662) which were found to inhibit recombinant human MAO-B with IC(50) values of 82 and 195 nM, respectively.
authors.affiliation: Department of Pharmaceutical Sciences, Northeastern Ohio Universities Colleges of Medicine and Pharmacy, Rootstown, OH 44272, USA.
authors.forename: Werner J
authors.initials: WJ
authors.lastname: Geldenhuys
authors.forename: Altaf S
authors.initials: AS
authors.lastname: Darvesh
authors.forename: Max O
authors.initials: MO
authors.lastname: Funk
authors.forename: Cornelis J
authors.initials: CJ
authors.lastname: Van der Schyf
authors.forename: Richard T
authors.initials: RT
authors.lastname: Carroll
mesh_terms: D008958:Models, Molecular; D008995:Monoamine Oxidase / Q000187:drug effects*; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D008996:Monoamine Oxidase Inhibitors; D008995:Monoamine Oxidase