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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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Diphenylamine fragment based on the virtual screening hit 19.
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pone.0121424.g007: Diphenylamine fragment based on the virtual screening hit 19.

Mentions: These initial virtual screening hits, although active, exhibited high molecular weight and low solubility. Therefore it was determined that smaller molecular weight fragments with higher solubility should be identified. Analogues of the virtual screening hit 19 were further explored because the structure was novel and different from known inhibitors. 19 was further explored using the Selcia chemical store substructure search tool in the Selcia compound library. Compounds containing a similar motif as 19 (Fig 7) were tested in the CE and FP assay.


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)

Diphenylamine fragment based on the virtual screening hit 19.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0121424.g007: Diphenylamine fragment based on the virtual screening hit 19.
Mentions: These initial virtual screening hits, although active, exhibited high molecular weight and low solubility. Therefore it was determined that smaller molecular weight fragments with higher solubility should be identified. Analogues of the virtual screening hit 19 were further explored because the structure was novel and different from known inhibitors. 19 was further explored using the Selcia chemical store substructure search tool in the Selcia compound library. Compounds containing a similar motif as 19 (Fig 7) were tested in the CE and FP assay.

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