Article system and assessed its performance in retrospective tests. Five results emerge from this study. First, DOCK Blaster, an automatic docking system, is now available for free public use and can produce useful results starting with as little as a PDB code. Second, useful results as judged by good pose fidelity and rank compared to property matched decoys were achieved in around 30% of cases against common bench- marks. Third, surprisingly, pose fidelity as measured by rmsd is not predictive of rank and is therefore not a useful metric of docking success by itself.54 Fourth, a single ligand metric using the crystallographic ligand is predictive of the multiligand enrichment over property-matched decoys 72% of the time. Finally, DOCK Blaster has been deployed on a large scale and produced screening results that deserve further considera- tion for experimental testing in 1398 of 7755 cases drawn from the PDB. The result that will have perhaps the greatest pragmatic impact is the creation of the DOCK Blaster server itself. Because DOCK Blaster can start from as little as a PDB code, can produce results like an expert in some cases, and can self- evaluate, it is suitable for use by nonexperts and for large-scale experiments. When docking performs poorly or fails comple- tely, this can usually be deduced automatically from failures in pose fidelity and rank-to-decoys statistics. Thus the prospec- tive user of this system can estimate whether the docking results are likely to be useful for discovery, should be ignored completely, or perhaps fall somewhere in between. Of course, any system of this complexity is bound to have flaws, and some projects will simply not work. Still, it is our hope that DOCK Blaster will be useful for nonexperts, lowering barriers to entry to the field. Pose fidelity using DOCK Blaster in retrospective studies is not quite as good as when performed by an expert. Our black- box system achieves pose fidelity within 2 A˚ rmsd for about 50-60% of targets, compared to 70-80% for expert-guided docking. Perhaps surprisingly, pose fidelity as measured by rmsd deviation did not correlate at all with rank. For enrich- ment, again our results are not quite as good as reported in other available studies. This should be unsurprising, however, because experts are at liberty to manually curate sites, ligands, and protocols to maximize performance. Useful results, i.e., good pose fidelity and good enrichment, were obtained in 25-40% of benchmark cases. The success rates for Astex-85 was 29 out of 85, for GOLD-114 it was 27 out of 114, and for DUD-38 15 out of 38 were successful for both pose-fidelity and enrichment. Whereas this might not seem a very high success rate, no study has ever held itself to such a stringent standard before, and this was only possible with an automated program. As a basis for performance assessment, a single ligand with generated property-matched decoys predicts the multiligand assessment three times out of four. Because only one ligand is needed, this has significant advantages for automation, en- abling automatic self-assessment of docking results, which would be impractical if a list of actives had to be assembled to benchmark each target. The correlation was largely insensitive to the precise cutoffs used to characterize docking success or to which scoring function was used. Of course, this result is provisional, as it is based on the DUD-38 benchmark and may be revised as larger benchmarks appear. DOCK Blaster has been deployed on a near-proteome scale, and produced useful results for 1398 of 7755 targets or 18% of the PDB structures that were amenable to this method. Because docking can recapitulate what is already Journal of Medicinal Chemistry, 2009, Vol. 52, No. 18 5719 known about the site in these cases, there is a reasonable hope for prospective docking to suggest ligands that might actually bind. Many of these problems were previously known (conformational sampling, ligand representation, structural waters), but their prevalence is now better quantified. There is a critical need to find new small molecule reagents for biology. At the same time, a rapidly growing backlog of uninterpreted structures has accumulated in the PDB. Yet in an age of plentiful target structures, freely available small molecule databases, many sophisticated docking programs, and fast computers to run them on, many biologically or- iented investigators still find docking for ligand discovery daunting. We have developed DOCK Blaster to help non- specialists find new reagents for biology without the need for an expert. As for experts, DOCK Blaster does not produce compelling results for all targets. But for the nearly 20% of targets we tried where it does produce results deserving of further investigation, DOCK Blaster offers a way to auto- matically leverage structure for ligand discovery. Acknowledgment. This work is supported by NIH GM71896 (to J.J.I. and B.K.S.) and the Buchheit Family Foundation. We thank OpenEye Scientific Software (Santa Fe, NM) for the use of Omega, OEChem, Vida, Ogham, QuacPAC, and other tools. We thank Schrodinger Inc. (New York, NY) for the use of Ligprep and Epik, Dr. Peter Ertl for the Java Molecular Editor, molinspiration.com for the use of mitools, Dr. Martin Stahl for the SCORE program, and Dr. W. D. Ihlenfeldt of Xemistry GmbH (Germany) for Catvs. F.C. was supported by the University of Bologna and a Marco Polo fellowship. We are grateful to Drs. Austin Kirschner, Ruth Brenk, Binqing Wei, and David Lorber for scripts. 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