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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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Structural formulae of the 5 hits identified through the initial virtual screen.
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pone.0121424.g003: Structural formulae of the 5 hits identified through the initial virtual screen.

Mentions: An initial ligand-based pharmacophore screen was carried out. A total of 23,588 compounds were returned. Vina and then Autodock were used to dock the top hits from LIDAEUS. A simple pharmacophore filter was designed by identifying the main features of the MI-63-analog ligand that are involved in interactions with MDM2 (Fig 2). This resulted in a final ranked list of 2120 molecules; the predicted binding modes of the top 266 were inspected manually for final selection. 38 of these were chosen for acquisition and assay. S2 Table lists their details. Compound 16 was found to be unavailable for purchase, therefore the most similar compound in stock was selected as a substitute (39, 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)

Structural formulae of the 5 hits identified through the initial virtual screen.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0121424.g003: Structural formulae of the 5 hits identified through the initial virtual screen.
Mentions: An initial ligand-based pharmacophore screen was carried out. A total of 23,588 compounds were returned. Vina and then Autodock were used to dock the top hits from LIDAEUS. A simple pharmacophore filter was designed by identifying the main features of the MI-63-analog ligand that are involved in interactions with MDM2 (Fig 2). This resulted in a final ranked list of 2120 molecules; the predicted binding modes of the top 266 were inspected manually for final selection. 38 of these were chosen for acquisition and assay. S2 Table lists their details. Compound 16 was found to be unavailable for purchase, therefore the most similar compound in stock was selected as a substitute (39, 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
Related in: MedlinePlus