AI Article Synopsis
- Insulin-degrading enzyme (IDE) is crucial for breaking down peptides like amyloid-β and insulin, making it a potential target for treating Alzheimer's disease and type 2 diabetes.
- Researchers used structure-based drug design and experiments to identify four new compounds (D3, D4, D6, D10) that boost IDE's activity, especially towards insulin and amyloid-β.
- This study is significant as it demonstrates the successful computer-aided discovery of small molecules that can activate IDE, paving the way for new treatments.
Article Abstract
Background: Insulin-degrading enzyme (IDE) is an allosteric Zn(+2) metalloprotease involved in the degradation of many peptides including amyloid-β, and insulin that play key roles in Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM), respectively. Therefore, the use of therapeutic agents that regulate the activity of IDE would be a viable approach towards generating pharmaceutical treatments for these diseases. Crystal structure of IDE revealed that N-terminal has an exosite which is ∼30 Å away from the catalytic region and serves as a regulation site by orientation of the substrates of IDE to the catalytic site. It is possible to find small molecules that bind to the exosite of IDE and enhance its proteolytic activity towards different substrates.
Methodology/principal Findings: In this study, we applied structure based drug design method combined with experimental methods to discover four novel molecules that enhance the activity of human IDE. The novel compounds, designated as D3, D4, D6, and D10 enhanced IDE mediated proteolysis of substrate V, insulin and amyloid-β, while enhanced degradation profiles were obtained towards substrate V and insulin in the presence of D10 only.
Conclusion/significance: This paper describes the first examples of a computer-aided discovery of IDE regulators, showing that in vitro and in vivo activation of this important enzyme with small molecules is possible.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3280214 | PMC |
| http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0031787 | PLOS |
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