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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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Nutlin-3 titration.As the Nutlin-3 concentration increases the peak shifted back to p53-F control peak. Top trace is the p53-F alone followed by p53-F with MDM2-N. Nutlin-3 was then added into the sample with increasing concentration.
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pone.0121424.g004: Nutlin-3 titration.As the Nutlin-3 concentration increases the peak shifted back to p53-F control peak. Top trace is the p53-F alone followed by p53-F with MDM2-N. Nutlin-3 was then added into the sample with increasing concentration.

Mentions: Racemic Nutlin-3 was used to confirm if the p53-F/MDM2-N peak shifted to its original “apo” position in the presence of a known inhibitor. Upon adding Nutlin-3 (100nM), the peak shifted back to the p53-F peak position with a change in peak shape indicating the competition between p53-F and Nutlin-3 in the MDM2-N binding site (Fig 4, lower trace).


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)

Nutlin-3 titration.As the Nutlin-3 concentration increases the peak shifted back to p53-F control peak. Top trace is the p53-F alone followed by p53-F with MDM2-N. Nutlin-3 was then added into the sample with increasing concentration.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0121424.g004: Nutlin-3 titration.As the Nutlin-3 concentration increases the peak shifted back to p53-F control peak. Top trace is the p53-F alone followed by p53-F with MDM2-N. Nutlin-3 was then added into the sample with increasing concentration.
Mentions: Racemic Nutlin-3 was used to confirm if the p53-F/MDM2-N peak shifted to its original “apo” position in the presence of a known inhibitor. Upon adding Nutlin-3 (100nM), the peak shifted back to the p53-F peak position with a change in peak shape indicating the competition between p53-F and Nutlin-3 in the MDM2-N binding site (Fig 4, lower trace).

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