title: Structure based discovery of small molecules to regulate the activity of human insulin degrading enzyme.
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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Chemical and Biological Engineering, Koç University, Sariyer, Istanbul, Turkey.
authors.forename: Bilal
authors.initials: B
authors.lastname: Çakir
authors.forename: Onur
authors.initials: O
authors.lastname: Dağliyan
authors.forename: Ezgi
authors.initials: E
authors.lastname: Dağyildiz
authors.forename: İbrahim
authors.initials: İ
authors.lastname: Bariş
authors.forename: Ibrahim Halil
authors.initials: IH
authors.lastname: Kavakli
authors.forename: Seda
authors.initials: S
authors.lastname: Kizilel
authors.forename: Metin
authors.initials: M
authors.lastname: Türkay
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism; D020134:Catalytic Domain; D002470:Cell Survival / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D018360:Crystallography, X-Ray; D015195:Drug Design; D020536:Enzyme Activators / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007339:Insulysin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D016297:Mutagenesis, Site-Directed; D010446:Peptide Fragments / Q000494:pharmacology; D011487:Protein Conformation; D013379:Substrate Specificity
chemical_list: D016229:Amyloid beta-Peptides; D020536:Enzyme Activators; D007328:Insulin; D010446:Peptide Fragments; D007339:Insulysin