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

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.

SUBMITTER: Damm-Ganamet KL

PROVIDER: S-EPMC3753884 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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

Damm-Ganamet Kelly L KL Smith Richard D RD Dunbar James B JB Stuckey Jeanne A JA Carlson Heather A HA

Journal of chemical information and modeling 20130510 8

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 ...[more]

PMID: 23548044

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Project description:A major goal in drug design is the improvement of computational methods for docking and scoring. The Community Structure Activity Resource (CSAR) has collected several data sets from industry and added in-house data sets that may be used for this purpose ( www.csardock.org). CSAR has currently obtained data from Abbott, GlaxoSmithKline, and Vertex and is working on obtaining data from several others. Combined with our in-house projects, we are providing a data set consisting of 6 protein targets, 647 compounds with biological affinities, and 82 crystal structures. Multiple congeneric series are available for several targets with a few representative crystal structures of each of the series. These series generally contain a few inactive compounds, usually not available in the literature, to provide an upper bound to the affinity range. The affinity ranges are typically 3-4 orders of magnitude per series. For our in-house projects, we have had compounds synthesized for biological testing. Affinities were measured by Thermofluor, Octet RED, and isothermal titration calorimetry for the most soluble. This allows the direct comparison of the biological affinities for those compounds, providing a measure of the variance in the experimental affinity. It appears that there can be considerable variance in the absolute value of the affinity, making the prediction of the absolute value ill-defined. However, the relative rankings within the methods are much better, and this fits with the observation that predicting relative ranking is a more tractable problem computationally. For those in-house compounds, we also have measured the following physical properties: logD, logP, thermodynamic solubility, and pK(a). This data set also provides a substantial decoy set for each target consisting of diverse conformations covering the entire active site for all of the 58 CSAR-quality crystal structures. The CSAR data sets (CSAR-NRC HiQ and the 2012 release) provide substantial, publically available, curated data sets for use in parametrizing and validating docking and scoring methods.

Dataset Information

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

Publications

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

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