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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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Related in: MedlinePlus

Further exploration of analogues of virtual screening hit 19.6 analogues selected on the basis of the hits showed inhibition in both the CE and FP assays.
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pone.0121424.g008: Further exploration of analogues of virtual screening hit 19.6 analogues selected on the basis of the hits showed inhibition in both the CE and FP assays.

Mentions: A total of 5 of the 38 compounds acquired on the basis of the analogue exploration showed inhibition of MDM2 in the CE assay at 300 μM (Fig 8). An additional compound was tested at only 50 μM due to solubility issues and this also showed inhibition. Of these 6 compounds, 4 showed greater than 10% inhibition of MDM2 in the orthogonal FP assay at 700 μM (Fig 8). The less soluble compound again could only be tested at 50 μM and showed no inhibition in the FP assay at this concentration.


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)

Further exploration of analogues of virtual screening hit 19.6 analogues selected on the basis of the hits showed inhibition in both the CE and FP assays.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0121424.g008: Further exploration of analogues of virtual screening hit 19.6 analogues selected on the basis of the hits showed inhibition in both the CE and FP assays.
Mentions: A total of 5 of the 38 compounds acquired on the basis of the analogue exploration showed inhibition of MDM2 in the CE assay at 300 μM (Fig 8). An additional compound was tested at only 50 μM due to solubility issues and this also showed inhibition. Of these 6 compounds, 4 showed greater than 10% inhibition of MDM2 in the orthogonal FP assay at 700 μM (Fig 8). The less soluble compound again could only be tested at 50 μM and showed no inhibition in the FP assay at this concentration.

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
Related in: MedlinePlus