Structure based discovery of small molecules to regulate the activity of human insulin degrading enzyme.
<h4>Background</h4>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 u...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2012-01-01
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| Series: | PLoS ONE |
| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22355395/?tool=EBI |
| _version_ | 1828973088860012544 |
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| author | Bilal Çakir Onur Dağliyan Ezgi Dağyildiz İbrahim Bariş Ibrahim Halil Kavakli Seda Kizilel Metin Türkay |
| author_facet | Bilal Çakir Onur Dağliyan Ezgi Dağyildiz İbrahim Bariş Ibrahim Halil Kavakli Seda Kizilel Metin Türkay |
| author_sort | Bilal Çakir |
| collection | DOAJ |
| description | <h4>Background</h4>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.<h4>Methodology/principal findings</h4>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.<h4>Conclusion/significance</h4>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. |
| first_indexed | 2024-12-14T13:40:00Z |
| format | Article |
| id | doaj.art-3dd7ae4f82a24c09a82745dfaee9413e |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-14T13:40:00Z |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-3dd7ae4f82a24c09a82745dfaee9413e2022-12-21T22:59:28ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0172e3178710.1371/journal.pone.0031787Structure based discovery of small molecules to regulate the activity of human insulin degrading enzyme.Bilal ÇakirOnur DağliyanEzgi Dağyildizİbrahim BarişIbrahim Halil KavakliSeda KizilelMetin Türkay<h4>Background</h4>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.<h4>Methodology/principal findings</h4>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.<h4>Conclusion/significance</h4>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.https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22355395/?tool=EBI |
| spellingShingle | Bilal Çakir Onur Dağliyan Ezgi Dağyildiz İbrahim Bariş Ibrahim Halil Kavakli Seda Kizilel Metin Türkay Structure based discovery of small molecules to regulate the activity of human insulin degrading enzyme. PLoS ONE |
| title | Structure based discovery of small molecules to regulate the activity of human insulin degrading enzyme. |
| title_full | Structure based discovery of small molecules to regulate the activity of human insulin degrading enzyme. |
| title_fullStr | Structure based discovery of small molecules to regulate the activity of human insulin degrading enzyme. |
| title_full_unstemmed | Structure based discovery of small molecules to regulate the activity of human insulin degrading enzyme. |
| title_short | Structure based discovery of small molecules to regulate the activity of human insulin degrading enzyme. |
| title_sort | structure based discovery of small molecules to regulate the activity of human insulin degrading enzyme |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22355395/?tool=EBI |
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