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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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A) Vina docking poses of Compound 16 (magenta) and Compound 39 (orange); B) Vina docking poses of Compound 19 (magenta) and diphenylamine (orange).
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pone.0121424.g010: A) Vina docking poses of Compound 16 (magenta) and Compound 39 (orange); B) Vina docking poses of Compound 19 (magenta) and diphenylamine (orange).

Mentions: Compound 19 is also novel compared to known inhibitors. It was also the only compound tested that contained a diphenylamine group. Seven of the compounds tested contain diphenylmethane groups, which are superficially similar, but none were active. This prompted an investigation of the contribution the diphenylamine group makes to binding. Several diphenylamine-containing fragments were tested, five of which showed inhibition in both assays (Fig 8). Docking these fragments suggests that they adopt the same binding conformation as the equivalent group in 19 (Fig 10 and S1 Fig and S3 Table). The predicted binding mode suggests that the central NH group does not take part in any hydrogen bonding with the protein, therefore it appears likely that it is the difference in configuration between the secondary carbon and the amine group (pyramidal vs. planar) that is responsible for the difference in activity. However, analysis of additional low energy binding modes for these molecules suggests that they may adopt alternate binding positions in the pocket (S1 Fig and S3 Table). Indeed it is to be expected that the limited number of interactions small fragments can make with a pocket bestows them with pharmacophores of limited structural specificity and thus a propensity to promiscuity. Both in silico studies and in vitro assay experiments confirm this [10, 82–84]. This is borne out when a comparison of ΔG is made between Vina's top docking solutions; this indicates that larger molecules tend to exhibit clearer docking solutions than fragments (S4 Table). Telmisartan appears to be the exception to this, likely due to the relatively large number of rotatable torsions making this compound more flexible, and multiplying the number of ways it can potentially fit the binding site. MI-63 has only four rotatable bonds, whereas Telmisartan has seven; this makes MI-63 more likely than Telmisartan to have only one way it can fit the pocket with significantly lower energy, as reflected both in the shape of its graph in S4 Table and the consensus exhibited between consecutive Autodock docking attempts (S3 Table).


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)

A) Vina docking poses of Compound 16 (magenta) and Compound 39 (orange); B) Vina docking poses of Compound 19 (magenta) and diphenylamine (orange).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0121424.g010: A) Vina docking poses of Compound 16 (magenta) and Compound 39 (orange); B) Vina docking poses of Compound 19 (magenta) and diphenylamine (orange).
Mentions: Compound 19 is also novel compared to known inhibitors. It was also the only compound tested that contained a diphenylamine group. Seven of the compounds tested contain diphenylmethane groups, which are superficially similar, but none were active. This prompted an investigation of the contribution the diphenylamine group makes to binding. Several diphenylamine-containing fragments were tested, five of which showed inhibition in both assays (Fig 8). Docking these fragments suggests that they adopt the same binding conformation as the equivalent group in 19 (Fig 10 and S1 Fig and S3 Table). The predicted binding mode suggests that the central NH group does not take part in any hydrogen bonding with the protein, therefore it appears likely that it is the difference in configuration between the secondary carbon and the amine group (pyramidal vs. planar) that is responsible for the difference in activity. However, analysis of additional low energy binding modes for these molecules suggests that they may adopt alternate binding positions in the pocket (S1 Fig and S3 Table). Indeed it is to be expected that the limited number of interactions small fragments can make with a pocket bestows them with pharmacophores of limited structural specificity and thus a propensity to promiscuity. Both in silico studies and in vitro assay experiments confirm this [10, 82–84]. This is borne out when a comparison of ΔG is made between Vina's top docking solutions; this indicates that larger molecules tend to exhibit clearer docking solutions than fragments (S4 Table). Telmisartan appears to be the exception to this, likely due to the relatively large number of rotatable torsions making this compound more flexible, and multiplying the number of ways it can potentially fit the binding site. MI-63 has only four rotatable bonds, whereas Telmisartan has seven; this makes MI-63 more likely than Telmisartan to have only one way it can fit the pocket with significantly lower energy, as reflected both in the shape of its graph in S4 Table and the consensus exhibited between consecutive Autodock docking attempts (S3 Table).

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