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CSAR benchmark exercise 2011-2012: evaluation of results from docking and relative ranking of blinded congeneric series.

Damm-Ganamet KL, Smith RD, Dunbar JB, Stuckey JA, Carlson HA - J Chem Inf Model (2013)

Bottom Line: Lastly, we found that minimizing the protein and correcting histidine tautomeric states positively trended with low RMSD for pose prediction but minimizing the ligand negatively trended.Optimizing docking parameters and pretraining with the native ligand had a positive effect on the docking performance as did using restraints, substructure fitting, and shape fitting.Here, by combining the results of many methods, we hope to provide a statistically relevant evaluation and elucidate specific shortcomings of docking methodology for the community.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109-1065, USA.

ABSTRACT
The Community Structure-Activity Resource (CSAR) recently held its first blinded exercise based on data provided by Abbott, Vertex, and colleagues at the University of Michigan, Ann Arbor. A total of 20 research groups submitted results for the benchmark exercise where the goal was to compare different improvements for pose prediction, enrichment, and relative ranking of congeneric series of compounds. The exercise was built around blinded high-quality experimental data from four protein targets: LpxC, Urokinase, Chk1, and Erk2. Pose prediction proved to be the most straightforward task, and most methods were able to successfully reproduce binding poses when the crystal structure employed was co-crystallized with a ligand from the same chemical series. Multiple evaluation metrics were examined, and we found that RMSD and native contact metrics together provide a robust evaluation of the predicted poses. It was notable that most scoring functions underpredicted contacts between the hetero atoms (i.e., N, O, S, etc.) of the protein and ligand. Relative ranking was found to be the most difficult area for the methods, but many of the scoring functions were able to properly identify Urokinase actives from the inactives in the series. Lastly, we found that minimizing the protein and correcting histidine tautomeric states positively trended with low RMSD for pose prediction but minimizing the ligand negatively trended. Pregenerated ligand conformations performed better than those that were generated on the fly. Optimizing docking parameters and pretraining with the native ligand had a positive effect on the docking performance as did using restraints, substructure fitting, and shape fitting. Lastly, for both sampling and ranking scoring functions, the use of the empirical scoring function appeared to trend positively with the RMSD. Here, by combining the results of many methods, we hope to provide a statistically relevant evaluation and elucidate specific shortcomings of docking methodology for the community.

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Predicted docking pose (submission; yellow) overlaid withthe experimentalco-crystal structure of Chk1–ligand 1 (blue). Dotted linesillustrate two important hydrogen bonds formed between the ligandand the hinge region of the protein backbone. The RMSD between thecoordinates of the predicted pose and coordinates of the experimentalstructure is equal to 0.702, %Het–Het contacts correct is equalto 0%, and %C–C contacts correct is equal to 37%.
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fig5: Predicted docking pose (submission; yellow) overlaid withthe experimentalco-crystal structure of Chk1–ligand 1 (blue). Dotted linesillustrate two important hydrogen bonds formed between the ligandand the hinge region of the protein backbone. The RMSD between thecoordinates of the predicted pose and coordinates of the experimentalstructure is equal to 0.702, %Het–Het contacts correct is equalto 0%, and %C–C contacts correct is equal to 37%.

Mentions: The data for %C–C contacts correct (Figure 4C) essentially follows the same trend shown in %Total(Figure 4A). On the %Het–Het contactscorrect graph(Figure 4B), there are interesting data pointswhere 0% of the correct contacts are being made at a range of RMSDvalues (even less than 2 Å). Careful examination of the predictedposes elucidated that these points are all from Chk1. As shown inFigure 5, the ligand is just slightly shiftedto the right. Although, the RMSD is equal to 0.702, both of the hingeregion hydrogen bonds have been lost. One must be careful in the interpretationof native contacts data because the number of hydrogen bonds is typicallymuch smaller than the number of carbon–carbon interactions,and the number of hydrogen bonds varies significantly from targetto target. This data will also be influenced by the size and compositionof the ligand.


CSAR benchmark exercise 2011-2012: evaluation of results from docking and relative ranking of blinded congeneric series.

Damm-Ganamet KL, Smith RD, Dunbar JB, Stuckey JA, Carlson HA - J Chem Inf Model (2013)

Predicted docking pose (submission; yellow) overlaid withthe experimentalco-crystal structure of Chk1–ligand 1 (blue). Dotted linesillustrate two important hydrogen bonds formed between the ligandand the hinge region of the protein backbone. The RMSD between thecoordinates of the predicted pose and coordinates of the experimentalstructure is equal to 0.702, %Het–Het contacts correct is equalto 0%, and %C–C contacts correct is equal to 37%.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3753884&req=5

fig5: Predicted docking pose (submission; yellow) overlaid withthe experimentalco-crystal structure of Chk1–ligand 1 (blue). Dotted linesillustrate two important hydrogen bonds formed between the ligandand the hinge region of the protein backbone. The RMSD between thecoordinates of the predicted pose and coordinates of the experimentalstructure is equal to 0.702, %Het–Het contacts correct is equalto 0%, and %C–C contacts correct is equal to 37%.
Mentions: The data for %C–C contacts correct (Figure 4C) essentially follows the same trend shown in %Total(Figure 4A). On the %Het–Het contactscorrect graph(Figure 4B), there are interesting data pointswhere 0% of the correct contacts are being made at a range of RMSDvalues (even less than 2 Å). Careful examination of the predictedposes elucidated that these points are all from Chk1. As shown inFigure 5, the ligand is just slightly shiftedto the right. Although, the RMSD is equal to 0.702, both of the hingeregion hydrogen bonds have been lost. One must be careful in the interpretationof native contacts data because the number of hydrogen bonds is typicallymuch smaller than the number of carbon–carbon interactions,and the number of hydrogen bonds varies significantly from targetto target. This data will also be influenced by the size and compositionof the ligand.

Bottom Line: Lastly, we found that minimizing the protein and correcting histidine tautomeric states positively trended with low RMSD for pose prediction but minimizing the ligand negatively trended.Optimizing docking parameters and pretraining with the native ligand had a positive effect on the docking performance as did using restraints, substructure fitting, and shape fitting.Here, by combining the results of many methods, we hope to provide a statistically relevant evaluation and elucidate specific shortcomings of docking methodology for the community.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109-1065, USA.

ABSTRACT
The Community Structure-Activity Resource (CSAR) recently held its first blinded exercise based on data provided by Abbott, Vertex, and colleagues at the University of Michigan, Ann Arbor. A total of 20 research groups submitted results for the benchmark exercise where the goal was to compare different improvements for pose prediction, enrichment, and relative ranking of congeneric series of compounds. The exercise was built around blinded high-quality experimental data from four protein targets: LpxC, Urokinase, Chk1, and Erk2. Pose prediction proved to be the most straightforward task, and most methods were able to successfully reproduce binding poses when the crystal structure employed was co-crystallized with a ligand from the same chemical series. Multiple evaluation metrics were examined, and we found that RMSD and native contact metrics together provide a robust evaluation of the predicted poses. It was notable that most scoring functions underpredicted contacts between the hetero atoms (i.e., N, O, S, etc.) of the protein and ligand. Relative ranking was found to be the most difficult area for the methods, but many of the scoring functions were able to properly identify Urokinase actives from the inactives in the series. Lastly, we found that minimizing the protein and correcting histidine tautomeric states positively trended with low RMSD for pose prediction but minimizing the ligand negatively trended. Pregenerated ligand conformations performed better than those that were generated on the fly. Optimizing docking parameters and pretraining with the native ligand had a positive effect on the docking performance as did using restraints, substructure fitting, and shape fitting. Lastly, for both sampling and ranking scoring functions, the use of the empirical scoring function appeared to trend positively with the RMSD. Here, by combining the results of many methods, we hope to provide a statistically relevant evaluation and elucidate specific shortcomings of docking methodology for the community.

Show MeSH