Identification of novel monoamine oxidase B inhibitors by structure-based virtual screening

Bioorganic & Medicinal Chemistry Letters
Werner J GeldenhuysRichard T Carroll

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.

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Citations

Apr 3, 2012·Journal of Physiology and Biochemistry·Nadia Z ShabanOmayma M Sadek
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Apr 29, 2015·Journal of Medicinal Chemistry·Simone Carradori, Romano Silvestri
Jul 12, 2011·Bioorganic & Medicinal Chemistry Letters·Richard T CarrollWerner J Geldenhuys

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