Novel ligands that target the mitochondrial membrane protein mitoNEET
Graphical abstract
Highlights
► Determination of mitoNEET ligand binding sites. ► Discovery of novel ligands that target mitoNEET. ► In vitro fluorescence binding assay confirmed mitoNEET ligand binding.
Section snippets
Materials and methods
For the molecular docking study, protein structures were obtained from the RCSB Protein Data Bank (http://www.rcsb.org); the mitoNEET structure PDB ID was 2QD0, and the PPAR-γ PDB ID was 1ZGY. Ligand structures were obtained from the PubChem database (http://pubchem.ncbi.nlm.nih.gov). If ligand structures were not available from PubChem, they were drawn using MarvinSketch 5.3.1 (ChemAxon). The UCSF Chimera program (http://www.cgl.ucsf.edu/chimera) was used to prepare the structures for input to
Validation of AutoDock Vina blind docking method
Blind docking (BD) was performed on the PPAR-γ receptor (PDB ID: 1ZGY) to validate its accuracy at reproducing the experimental binding mode of rosiglitazone. The results of BD indicate that the binding conformation of rosiglitazone determined by AutoDock Vina matches well with that of the cocrystallized ligand (Fig. 2). The root mean square deviation (RMSD) of the heavy atoms is only 1.45 Å (Fig. 2). This result, in addition to previous extensive validation [23], [25], [26], demonstrates the
Summary
Even though compounds 4–18 do not contain the TZD ring moiety, our molecular docking and in vitro binding studies predict that they bind with similar or greater affinity to mitoNEET, compared with the known TZD ligands, pioglitazone and rosiglitazone (Table 1). For the first time, these results indicate that it is possible to design novel ligands targeted for mitoNEET that are not structurally related to the TZDs, therefore having less of the undesirable side effects and toxicity associated
Acknowledgements
The project described was supported by Award Number R01DK059766 from the National Institute Of Diabetes And Digestive And Kidney Diseases. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute Of Diabetes And Digestive And Kidney Diseases or the National Institutes of Health. We wish to gratefully acknowledge Max R. Bieganski for creating graphical content and providing technical support, and Dr. Sandra Wiley,
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