PMID- 22355395
OWN - NLM
STAT- MEDLINE
DCOM- 20120618
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 7
IP  - 2
DP  - 2012
TI  - Structure based discovery of small molecules to regulate the activity of human 
      insulin degrading enzyme.
PG  - e31787
LID - 10.1371/journal.pone.0031787 [doi]
LID - e31787
AB  - BACKGROUND: Insulin-degrading enzyme (IDE) is an allosteric Zn(+2) 
      metalloprotease involved in the degradation of many peptides including amyloid-beta, 
      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  approximately 30 A 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-beta, 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.
FAU - Cakir, Bilal
AU  - Cakir B
AD  - Department of Chemical and Biological Engineering, Koc University, Sariyer, 
      Istanbul, Turkey.
FAU - Dagliyan, Onur
AU  - Dagliyan O
FAU - Dagyildiz, Ezgi
AU  - Dagyildiz E
FAU - Baris, Ibrahim
AU  - Baris I
FAU - Kavakli, Ibrahim Halil
AU  - Kavakli IH
FAU - Kizilel, Seda
AU  - Kizilel S
FAU - Turkay, Metin
AU  - Turkay M
LA  - eng
PT  - Journal Article
DEP - 20120215
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Enzyme Activators)
RN  - 0 (Insulin)
RN  - 0 (Peptide Fragments)
RN  - EC 3.4.24.56 (Insulysin)
SB  - IM
MH  - Amyloid beta-Peptides/metabolism
MH  - Catalytic Domain
MH  - Cell Survival/drug effects
MH  - Chemistry, Pharmaceutical
MH  - Crystallography, X-Ray
MH  - *Drug Design
MH  - Enzyme Activators/*pharmacology
MH  - HeLa Cells
MH  - Humans
MH  - Insulin/*metabolism
MH  - Insulysin/*chemistry/genetics/*metabolism
MH  - Models, Molecular
MH  - *Molecular Dynamics Simulation
MH  - Mutagenesis, Site-Directed
MH  - Peptide Fragments/pharmacology
MH  - Protein Conformation
MH  - Substrate Specificity
PMC - PMC3280214
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2012/02/23 06:00
MHDA- 2012/06/19 06:00
PMCR- 2012/02/15
CRDT- 2012/02/23 06:00
PHST- 2011/04/13 00:00 [received]
PHST- 2012/01/19 00:00 [accepted]
PHST- 2012/02/23 06:00 [entrez]
PHST- 2012/02/23 06:00 [pubmed]
PHST- 2012/06/19 06:00 [medline]
PHST- 2012/02/15 00:00 [pmc-release]
AID - PONE-D-11-06640 [pii]
AID - 10.1371/journal.pone.0031787 [doi]
PST - ppublish
SO  - PLoS One. 2012;7(2):e31787. doi: 10.1371/journal.pone.0031787. Epub 2012 Feb 15.