Structure based discovery of small molecules to regulate the activity of human insulin degrading enzyme.

PloS One
Bilal ÇakirMetin Türkay

Abstract

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. 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. This paper describes the first examples of a computer-aided discovery of IDE reg...Continue Reading

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Citations

Mar 8, 2014·European Journal of Medicinal Chemistry·Jhansi Rani VangavaraguShirley ShiDu Yan
Mar 13, 2016·Biochimica Et Biophysica Acta·Ellen HubinKerensa Broersen
Dec 30, 2014·Journal of Chemical Information and Modeling·Carlos H B da Cruz, G M Seabra
Jun 21, 2016·Annals of Medicine·Olga PivovarovaNatalia Rudovich
Jun 22, 2017·Critical Reviews in Biochemistry and Molecular Biology·Grazia R TundoMassimo Coletta
Feb 6, 2020·The Journal of Biological Chemistry·Yagmur Umay DorukIbrahim Halil Kavakli
Nov 24, 2020·BioMed Research International·Namdoo Kim, Hyuck Jin Lee
Mar 7, 2021·Chemistry and Physics of Lipids·Sara García-ViñualesDanilo Milardi
Jun 12, 2020·Neuropharmacology·Kinga HartmanJerzy Silberring
Jul 25, 2021·International Journal of Molecular Sciences·Namdoo Kim, Hyuck Jin Lee
Feb 27, 2013·Journal of Medicinal Chemistry·Samer O Abdul-HayMalcolm A Leissring

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Methods Mentioned

BETA
enzymatic assay
PCR
fluorescence assay
electrophoresis
ELISA

Software Mentioned

NAMD
AutoDock
SigmaPlot
CHARMM

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