ArticlePloS one2012
Structure based discovery of small molecules to regulate the activity of human insulin degrading enzyme.
Article in PloS one, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 39 citations in OpenAlex.
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- Sustainable Synthesis of 1,2-Disubstituted Benzimidazoles as Promising α-Glucosidase Inhibitors: In Vitro and In Silico Evaluation.Pharmaceuticals (Basel, Switzerland) · 2025Article
- Discovery of a small molecule that selectively destabilizes Cryptochrome 1 and enhances life span in p53 knockout mice.Nature communications · 2022Article
- Inhibition of Insulin Degrading Enzyme to Control Diabetes Mellitus and its Applications on some Other Chronic Disease: a Critical Review.Pharmaceutical research · 2022Review
- In silico identification of widely used and well-tolerated drugs as potential SARS-CoV-2 3C-like protease and viral RNA-dependent RNA polymerase inhibitors for direct use in clinical trials.Journal of biomolecular structure & dynamics · 2021Article
- Redox-Active Metal Ions and Amyloid-Degrading Enzymes in Alzheimer's Disease.International journal of molecular sciences · 2021Review
- A CLOCK-binding small molecule disrupts the interaction between CLOCK and BMAL1 and enhances circadian rhythm amplitude.The Journal of biological chemistry · 2020Article
- Target Enzymes Considered for the Treatment of Alzheimer's Disease and Parkinson's Disease.BioMed research international · 2020Review
- Dual Exosite-binding Inhibitors of Insulin-degrading Enzyme Challenge Its Role as the Primary Mediator of Insulin Clearance in Vivo.The Journal of biological chemistry · 2015Article
- Structure-activity relationships of imidazole-derived 2-[N-carbamoylmethyl-alkylamino]acetic acids, dual binders of human insulin-degrading enzyme.European journal of medicinal chemistry · 2015Article
- Imidazole-derived 2-[N-carbamoylmethyl-alkylamino]acetic acids, substrate-dependent modulators of insulin-degrading enzyme in amyloid-β hydrolysis.European journal of medicinal chemistry · 2014Article
- Identification of human presequence protease (hPreP) agonists for the treatment of Alzheimer's disease.European journal of medicinal chemistry · 2014Article
- Optimization of peptide hydroxamate inhibitors of insulin-degrading enzyme reveals marked substrate-selectivity.Journal of medicinal chemistry · 2013Article
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundInsulin-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
findingsIn 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.
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