Molecular Insights Into Human Monoamine Oxidase B Inhibition By The Glitazone Antidiabetes Drugs

Title

Molecular Insights Into Human Monoamine Oxidase B Inhibition By The Glitazone Antidiabetes Drugs

Creator

Binda C; Aldeco M; Geldenhuys W J; Tortorici M; Mattevi A; Edmondson D E

Publisher

Acs Medicinal Chemistry Letters

Date

2012
2012-01

Description

The widely employed antidiabetic drug pioglitazone (Actos) is shown to be a specific and reversible inhibitor of human monoamine oxidase B (MAO B). The crystal structure of the enzyme-inhibitor complex shows that the R-enantiomer is bound with the thiazolidinedione ring near the flavin. The molecule occupies both substrate and entrance cavities of the active site, establishing noncovalent interactions with the surrounding amino acids. These binding properties differentiate pioglitazone from the clinically used MAO inhibitors, which act through covalent inhibition mechanisms and do not exhibit a high degree of MAO A versus B selectivity. Rosiglitazone (Avandia) and troglitazone, other members of the glitazone class, are less selective in that they are weaker inhibitors of both MAO A and MAO B. These results suggest that pioglitazone may have utility as a "repurposed" neuroprotectant drug in retarding the progression of disease in Parkinson's patients. They also provide new insights for the development of reversible isoenzyme-specific MAO inhibitors.

Subject

Antidiabetes drug; Chemistry; drug design; gamma agonist pioglitazone; high-level expression; lsd1; monoamine oxidase; mouse model; neurodegeneration; neuroprotection; parkinsons-disease; parkinsons-disease; Pharmacology & Pharmacy; pichia-pastoris; pioglitazone; rosiglitazone

Identifier

Format

Journal Article or Conference Abstract Publication

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Rights

Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).

Pages

39-42

Issue

1

Volume

3

Citation

Binda C; Aldeco M; Geldenhuys W J; Tortorici M; Mattevi A; Edmondson D E, “Molecular Insights Into Human Monoamine Oxidase B Inhibition By The Glitazone Antidiabetes Drugs,” NEOMED Bibliography Database, accessed January 17, 2021, https://neomed.omeka.net/items/show/9979.

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