Structure-based design of a thiazolidinedione which targets the mitochondrial protein mitoNEET.

Title

Structure-based design of a thiazolidinedione which targets the mitochondrial protein mitoNEET.

Creator

Geldenhuys Werner J; Funk Max O; Barnes Kendra F; Carroll Richard T

Publisher

Bioorganic & medicinal chemistry letters

Date

2010
2010-02

Description

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.

Subject

*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

Rights

Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).

Pages

819–823

Issue

3

Volume

20

Citation

Geldenhuys Werner J; Funk Max O; Barnes Kendra F; Carroll Richard T, “Structure-based design of a thiazolidinedione which targets the mitochondrial protein mitoNEET.,” NEOMED Bibliography Database, accessed February 27, 2021, https://neomed.omeka.net/items/show/3489.

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