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Structure- and ligand-based virtual screening identifies new scaffolds for inhibitors of the oncoprotein MDM2.

Houston DR, Yen LH, Pettit S, Walkinshaw MD - PLoS ONE (2015)

Bottom Line: A major challenge in the field of ligand discovery is to identify chemically useful fragments that can be developed into inhibitors of specific protein-protein interactions.Low molecular weight fragments (with molecular weight less than 250 Da) are likely to bind weakly to a protein's surface.Here we use a new virtual screening procedure which uses a combination of similarity searching and docking to identify chemically tractable scaffolds that bind to the p53-interaction site of MDM2.

View Article: PubMed Central - PubMed

Affiliation: Institute of Structural and Molecular Biology, University of Edinburgh, Edinburgh, United Kingdom.

ABSTRACT
A major challenge in the field of ligand discovery is to identify chemically useful fragments that can be developed into inhibitors of specific protein-protein interactions. Low molecular weight fragments (with molecular weight less than 250 Da) are likely to bind weakly to a protein's surface. Here we use a new virtual screening procedure which uses a combination of similarity searching and docking to identify chemically tractable scaffolds that bind to the p53-interaction site of MDM2. The binding has been verified using capillary electrophoresis which has proven to be an excellent screening method for such small, weakly binding ligands.

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Competition of Nutlin-3 with p53-F for MDM2-N measured by FP assay.The graph shows anisotropy plotted against Nutlin-3 concentration. An IC50 of 266 nM was determined.
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pone.0121424.g006: Competition of Nutlin-3 with p53-F for MDM2-N measured by FP assay.The graph shows anisotropy plotted against Nutlin-3 concentration. An IC50 of 266 nM was determined.

Mentions: The FP competition experiment was carried out to test whether the FP assay was suitable for identifying small molecule inhibitors for MDM2-N. A dose response experiment was performed using Nutlin-3 from 0.02 μM to 10 μM. MDM2-N concentration was held constant at 500 nM and p53-F was 2 nM in the mixture. The anisotropy was fitted against Nutlin-3 concentration in GraphPad Prism and IC50 was calculated to be 266 nM (Fig 6). Five of the virtual screening compounds were identified to be active in both CE and FP assay (Fig 3).


Structure- and ligand-based virtual screening identifies new scaffolds for inhibitors of the oncoprotein MDM2.

Houston DR, Yen LH, Pettit S, Walkinshaw MD - PLoS ONE (2015)

Competition of Nutlin-3 with p53-F for MDM2-N measured by FP assay.The graph shows anisotropy plotted against Nutlin-3 concentration. An IC50 of 266 nM was determined.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4401541&req=5

pone.0121424.g006: Competition of Nutlin-3 with p53-F for MDM2-N measured by FP assay.The graph shows anisotropy plotted against Nutlin-3 concentration. An IC50 of 266 nM was determined.
Mentions: The FP competition experiment was carried out to test whether the FP assay was suitable for identifying small molecule inhibitors for MDM2-N. A dose response experiment was performed using Nutlin-3 from 0.02 μM to 10 μM. MDM2-N concentration was held constant at 500 nM and p53-F was 2 nM in the mixture. The anisotropy was fitted against Nutlin-3 concentration in GraphPad Prism and IC50 was calculated to be 266 nM (Fig 6). Five of the virtual screening compounds were identified to be active in both CE and FP assay (Fig 3).

Bottom Line: A major challenge in the field of ligand discovery is to identify chemically useful fragments that can be developed into inhibitors of specific protein-protein interactions.Low molecular weight fragments (with molecular weight less than 250 Da) are likely to bind weakly to a protein's surface.Here we use a new virtual screening procedure which uses a combination of similarity searching and docking to identify chemically tractable scaffolds that bind to the p53-interaction site of MDM2.

View Article: PubMed Central - PubMed

Affiliation: Institute of Structural and Molecular Biology, University of Edinburgh, Edinburgh, United Kingdom.

ABSTRACT
A major challenge in the field of ligand discovery is to identify chemically useful fragments that can be developed into inhibitors of specific protein-protein interactions. Low molecular weight fragments (with molecular weight less than 250 Da) are likely to bind weakly to a protein's surface. Here we use a new virtual screening procedure which uses a combination of similarity searching and docking to identify chemically tractable scaffolds that bind to the p53-interaction site of MDM2. The binding has been verified using capillary electrophoresis which has proven to be an excellent screening method for such small, weakly binding ligands.

Show MeSH