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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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Graph showing inhibition (%) plotted against Nutlin-3 concentration.From the data an IC50 of 37.3nM was determined.
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pone.0121424.g005: Graph showing inhibition (%) plotted against Nutlin-3 concentration.From the data an IC50 of 37.3nM was determined.

Mentions: With additional titration, the IC50 of Nutlin-3 could be calculated. Nutlin-3 was titrated from 400 nM to 0.5 nM and % inhibition was calculated from the migration time of Nutlin-3 (Fig 5). The % inhibition was fitted against Nutlin-3 concentration in log scale in GraphPad Prism and IC50 was calculated to be 37.50 nM. The calculated IC50 is similar to the literature value for racemic Nutlin-3 of 100 nM [34]. This confirms that CE is able to recognise inhibitor binding and able to calculate an accurate IC50.


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)

Graph showing inhibition (%) plotted against Nutlin-3 concentration.From the data an IC50 of 37.3nM was determined.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0121424.g005: Graph showing inhibition (%) plotted against Nutlin-3 concentration.From the data an IC50 of 37.3nM was determined.
Mentions: With additional titration, the IC50 of Nutlin-3 could be calculated. Nutlin-3 was titrated from 400 nM to 0.5 nM and % inhibition was calculated from the migration time of Nutlin-3 (Fig 5). The % inhibition was fitted against Nutlin-3 concentration in log scale in GraphPad Prism and IC50 was calculated to be 37.50 nM. The calculated IC50 is similar to the literature value for racemic Nutlin-3 of 100 nM [34]. This confirms that CE is able to recognise inhibitor binding and able to calculate an accurate IC50.

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