Limits...
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.

Show MeSH
Outcome ofthe online questionnaire on docking methodology forall poses. The pose prediction results were binned by RMSD and plottedas the percentage of time that a particular feature resulted in apose within the RMSD bin. Distinct trends that are related to dockingRMSD are noted with arrows.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3753884&req=5

fig10: Outcome ofthe online questionnaire on docking methodology forall poses. The pose prediction results were binned by RMSD and plottedas the percentage of time that a particular feature resulted in apose within the RMSD bin. Distinct trends that are related to dockingRMSD are noted with arrows.

Mentions: Figure 10 shows the same analysisfor thedocking methodology that was employed by each group and how it trendswith the RMSD. The data revealed that first training with the nativeligand to determine optimal docking parameters significantly improvedthe docking performance as did using restraints, substructure fitting,and shape fitting. This data implies that results can be enrichedwhen prior information about the system is known. Furthermore, marryingligand- and structure-based approaches has been an area of activeresearch in the field recently, and these hybrid techniques have beenshown to outperform the use of structure-based methods on their own.65−67 Interestingly, the use of special parameters for the catalytic zincin LpxC did not improve docking performance (data not shown).


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)

Outcome ofthe online questionnaire on docking methodology forall poses. The pose prediction results were binned by RMSD and plottedas the percentage of time that a particular feature resulted in apose within the RMSD bin. Distinct trends that are related to dockingRMSD are noted with arrows.
© Copyright Policy
Related In: Results  -  Collection

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

fig10: Outcome ofthe online questionnaire on docking methodology forall poses. The pose prediction results were binned by RMSD and plottedas the percentage of time that a particular feature resulted in apose within the RMSD bin. Distinct trends that are related to dockingRMSD are noted with arrows.
Mentions: Figure 10 shows the same analysisfor thedocking methodology that was employed by each group and how it trendswith the RMSD. The data revealed that first training with the nativeligand to determine optimal docking parameters significantly improvedthe docking performance as did using restraints, substructure fitting,and shape fitting. This data implies that results can be enrichedwhen prior information about the system is known. Furthermore, marryingligand- and structure-based approaches has been an area of activeresearch in the field recently, and these hybrid techniques have beenshown to outperform the use of structure-based methods on their own.65−67 Interestingly, the use of special parameters for the catalytic zincin LpxC did not improve docking performance (data not shown).

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