Molecular Insights into Human Monoamine Oxidase B Inhibition by the Glitazone Antidiabetes Drugs
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- 作者：Claudia Binda ; Milagros Aldeco ; Werner J. Geldenhuys ; Marcello Tortorici ; Andrea Mattevi ; Dale E. Edmondson
- 刊名：ACS Medicinal Chemistry Letters
- 出版年：2012
- 出版时间：January 12, 2012
- 年：2012
- 卷：3
- 期：1
- 页码：39-42
- 全文大小：259K
- 年卷期：v.3,no.1(January 12, 2012)
- ISSN：1948-5875
文摘
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鈥搃nhibitor 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 鈥渞epurposed鈥?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.