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Text
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<a href="http://doi.org/10.1016/j.bmcl.2009.12.088" target="_blank" rel="noreferrer noopener">http://doi.org/10.1016/j.bmcl.2009.12.088</a>
Pages
819–823
Issue
3
Volume
20
Dublin Core
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Title
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Structure-based design of a thiazolidinedione which targets the mitochondrial protein mitoNEET.
Publisher
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Bioorganic & medicinal chemistry letters
Date
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2010
2010-02
Subject
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*Drug Design; Animals; Binding Sites/drug effects/physiology; Dose-Response Relationship; Drug; Drug Delivery Systems/*methods; Liver/drug effects/metabolism; Mitochondria; Mitochondrial Proteins/*metabolism; Protein Structure; Rats; Secondary; Structure-Activity Relationship; Thiazolidinediones/administration & dosage/*chemical synthesis/*metabolism
Creator
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Geldenhuys Werner J; Funk Max O; Barnes Kendra F; Carroll Richard T
Description
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Several PPAR-gamma agonists containing a thiazolidinedione moiety (referred to as glitazones) have been proposed to be neuroprotective and appear to alter mitochondrial function. Recently, a search for mitochondrial proteins that bind pioglitazone identified a novel protein, mitoNEET, which was later shown to regulate the oxidative capacity of the mitochondria. This identified an alternative target for the glitazones suggesting a possible new drug target for the treatment of neurodegenerative diseases. Molecular docking studies employing the reported crystal structure revealed five possible binding pockets on mitoNEET. We focused on two sites based on their physical characteristics. Using binding information gained from the analysis of two glitazones docked in these pockets, we designed and synthesized a ligand (NL-1) that would preferentially bind to site 1. Based on [(3)H]-binding data of the glitazones and comparisons to computer generated K(i)s, we were able to predict that site 1 was likely the target of the glitazones. NL-1 uncoupled isolated mitochondrial complex I respiration with an IC(50) of 2.4 microM and inhibited state III respiration up to 45%. To investigate the ability of NL-1 to block rotenone initiated free radicals from complex I, we found it was able to protect the human neuronal cell line SH-SY5Y against rotenone induced cell death. These data demonstrate that mitoNEET is a viable target for the design and synthesis of novel therapeutic agents aimed at altering mitochondrial function.
Identifier
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<a href="http://doi.org/10.1016/j.bmcl.2009.12.088" target="_blank" rel="noreferrer noopener">10.1016/j.bmcl.2009.12.088</a>
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*Drug Design
2010
Animals
Barnes Kendra F
Binding Sites/drug effects/physiology
Bioorganic & medicinal chemistry letters
Carroll Richard T
Dose-Response Relationship
Drug
Drug Delivery Systems/*methods
Funk Max O
Geldenhuys Werner J
Liver/drug effects/metabolism
Mitochondria
Mitochondrial Proteins/*metabolism
Protein Structure
Rats
Secondary
Structure-Activity Relationship
Thiazolidinediones/administration & dosage/*chemical synthesis/*metabolism