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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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Crystal structures of MDM2 with bound small molecules.
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pone.0121424.g001: Crystal structures of MDM2 with bound small molecules.

Mentions: There are several different classes of small molecule inhibitors of MDM2 that are able to interfere with MDM2-p53 binding with potency in the nM range (see Fig 1 for details of a selection of these). One such molecule, named reactivation of p53 and induction of tumour cell apoptosis (RITA), has been shown to induce apoptosis in some cancer cell lines [30–32], although it may not be a classical MDM2-p53 interaction disruptor [33]. A second class of small molecules, the Nutlins, are high affinity inhibitors of MDM2 and induce activation of p53 by binding to the p53 binding pocket of MDM2 [34]. Spiro-oxindoles comprise a third class [25, 26, 35, 36]. In this work we identified a number of lead-like compounds, which led to the discovery of several fragments that provide new chemical scaffolds that could serve as the core of novel MDM2 inhibitor families.


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)

Crystal structures of MDM2 with bound small molecules.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0121424.g001: Crystal structures of MDM2 with bound small molecules.
Mentions: There are several different classes of small molecule inhibitors of MDM2 that are able to interfere with MDM2-p53 binding with potency in the nM range (see Fig 1 for details of a selection of these). One such molecule, named reactivation of p53 and induction of tumour cell apoptosis (RITA), has been shown to induce apoptosis in some cancer cell lines [30–32], although it may not be a classical MDM2-p53 interaction disruptor [33]. A second class of small molecules, the Nutlins, are high affinity inhibitors of MDM2 and induce activation of p53 by binding to the p53 binding pocket of MDM2 [34]. Spiro-oxindoles comprise a third class [25, 26, 35, 36]. In this work we identified a number of lead-like compounds, which led to the discovery of several fragments that provide new chemical scaffolds that could serve as the core of novel MDM2 inhibitor families.

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