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

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Geldenhuys WJ, Darvesh AS, Funk MO, Van der Schyf CJ, Carroll RT

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

Bioorg Med Chem Lett. 2010 Sep 1;20(17):5295-8. doi: 10.1016/j.bmcl.2010.06.128. Epub 2010 Jul 1.

PubMed ID

20650633 [ View in PubMed

]

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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Pioglitazone	Amine oxidase [flavin-containing] B	IC 50 (nM)	298	N/A	N/A	Details