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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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Lowest energy Vina (magenta) and most populous cluster Autodock (green) docking poses of the active compounds.The pharmacophore filter points are shown as black spheres. MDM2 is shown as a white transparent surface representation with the backbone visible as black secondary structure. Side chains of residues that line the active site are shown as black sticks. A) Compound 1; B) Compound 2; C) Compound 19 D) Compound 24
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pone.0121424.g009: Lowest energy Vina (magenta) and most populous cluster Autodock (green) docking poses of the active compounds.The pharmacophore filter points are shown as black spheres. MDM2 is shown as a white transparent surface representation with the backbone visible as black secondary structure. Side chains of residues that line the active site are shown as black sticks. A) Compound 1; B) Compound 2; C) Compound 19 D) Compound 24

Mentions: Compound 24 appears more novel, possessing little similarity with the current classes of known MDM2 small molecule inhibitors (Fig 1 and Fig 3). Three similar compounds were inactive, one of which differed by only one methyl group on the piperidine moiety. Compound 26 contains a 4-methylpiperidine, Compound 25 a 2,4-dimethylimidazole, and Compound 32 a cycloheptane group at this location, all of which are larger and, according to the docking results, project deeper into the p53 Trp pocket of MDM2 (Fig 9). The docking and assay results combined suggest a strict size limit on the length of the moiety that this pocket can accommodate.


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)

Lowest energy Vina (magenta) and most populous cluster Autodock (green) docking poses of the active compounds.The pharmacophore filter points are shown as black spheres. MDM2 is shown as a white transparent surface representation with the backbone visible as black secondary structure. Side chains of residues that line the active site are shown as black sticks. A) Compound 1; B) Compound 2; C) Compound 19 D) Compound 24
© Copyright Policy
Related In: Results  -  Collection

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

pone.0121424.g009: Lowest energy Vina (magenta) and most populous cluster Autodock (green) docking poses of the active compounds.The pharmacophore filter points are shown as black spheres. MDM2 is shown as a white transparent surface representation with the backbone visible as black secondary structure. Side chains of residues that line the active site are shown as black sticks. A) Compound 1; B) Compound 2; C) Compound 19 D) Compound 24
Mentions: Compound 24 appears more novel, possessing little similarity with the current classes of known MDM2 small molecule inhibitors (Fig 1 and Fig 3). Three similar compounds were inactive, one of which differed by only one methyl group on the piperidine moiety. Compound 26 contains a 4-methylpiperidine, Compound 25 a 2,4-dimethylimidazole, and Compound 32 a cycloheptane group at this location, all of which are larger and, according to the docking results, project deeper into the p53 Trp pocket of MDM2 (Fig 9). The docking and assay results combined suggest a strict size limit on the length of the moiety that this pocket can accommodate.

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