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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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Control docking results.Crystallographic pose is coloured black, intermolecular hydrogen bonds are shown as orange dashes, Autodock result is red, Vina result is magenta. Pharmacaphore filter points are shown as black spheres. The protein is represented as a white transparent surface and cartoon secondary structure; residue side chains within 5 Å of the ligand are shown as black lines.
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pone.0121424.g002: Control docking results.Crystallographic pose is coloured black, intermolecular hydrogen bonds are shown as orange dashes, Autodock result is red, Vina result is magenta. Pharmacaphore filter points are shown as black spheres. The protein is represented as a white transparent surface and cartoon secondary structure; residue side chains within 5 Å of the ligand are shown as black lines.

Mentions: The structure of MDM2 in complex with an MI-63 analogue was used for the docking studies (PDB 3LBL, Fig 1). Its high resolution (1.60 Å), good R-factors (R = 0.193, Rfree = 0.236) and the small molecule ligand-binding conformation of the protein made it ideal for this purpose. The ligand present in the structure was redocked to verify that the docking programs used for the virtual screening were successfully able to correctly predict its binding conformation. Autodock successfully reproduced the crystallographic binding mode of the ligand, the result being within an RMSD of 0.83 Å. Vina also correctly predicted the binding pose of the ligand, with an RMSD of 0.67 Å. Autodock predicted the free energy of binding to be -9.4 kcal/mol, Vina predicted -9.8 kcal/mol. These are both roughly equivalent to a Ki around the 100 nM mark, and are remarkably close to the measured Ki of 36 nM [36]. Fig 2 shows a superposition of the docking results with the crystal structure.


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)

Control docking results.Crystallographic pose is coloured black, intermolecular hydrogen bonds are shown as orange dashes, Autodock result is red, Vina result is magenta. Pharmacaphore filter points are shown as black spheres. The protein is represented as a white transparent surface and cartoon secondary structure; residue side chains within 5 Å of the ligand are shown as black lines.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0121424.g002: Control docking results.Crystallographic pose is coloured black, intermolecular hydrogen bonds are shown as orange dashes, Autodock result is red, Vina result is magenta. Pharmacaphore filter points are shown as black spheres. The protein is represented as a white transparent surface and cartoon secondary structure; residue side chains within 5 Å of the ligand are shown as black lines.
Mentions: The structure of MDM2 in complex with an MI-63 analogue was used for the docking studies (PDB 3LBL, Fig 1). Its high resolution (1.60 Å), good R-factors (R = 0.193, Rfree = 0.236) and the small molecule ligand-binding conformation of the protein made it ideal for this purpose. The ligand present in the structure was redocked to verify that the docking programs used for the virtual screening were successfully able to correctly predict its binding conformation. Autodock successfully reproduced the crystallographic binding mode of the ligand, the result being within an RMSD of 0.83 Å. Vina also correctly predicted the binding pose of the ligand, with an RMSD of 0.67 Å. Autodock predicted the free energy of binding to be -9.4 kcal/mol, Vina predicted -9.8 kcal/mol. These are both roughly equivalent to a Ki around the 100 nM mark, and are remarkably close to the measured Ki of 36 nM [36]. Fig 2 shows a superposition of the docking results with the crystal structure.

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