5718 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 18 Irwin et al. Figure 9. Receiver operator characteristic (ROC) plots comparing enrichment by DOCK Blaster (magenta) versus an expert (dark blue) against four targets from the DUD benchmark. (A) COX-2 (B) RXR alpha (C) ER-agonist (D) SAHH. Random enrichment shown by a thin gray line. Table 3. Correlation of Docking Success Assessment between the Single Molecule Metric and Multiple Molecule Metric for the DUD-38 Bench- mark. a single molecule metric good bad multiple molecule metric (DUD) good 12 6 bad 4 14 a Success for the single molecule metric has pose fidelity within 2 A˚ RMSD and rank in the top 5% of property-matched decoys. Success for the DUD metric is adjusted logAUC > 10 or EF1 > 10% or EF5 > 20%. Diagonal: 26. Off diagonal: 10. Automatic docking failure: 2. Correlation: 72%. fraction of ligands found by the first percentile, was greater than 10%, or that EF5 was greater than 20%. Our results show that in 26 of 36 or 72% of cases where automatic docking completed normally, the single ligand metric of docking success predicted the multiligand assessment. This result allows us to deploy the single ligand metric as a reasonable predictor of overall enrichment. PDB Benchmarking. A common criticism of docking is that it often seems to encounter unforeseen problems with each new target, and correspondingly one never knows in advance whether docking will “work”. Equipped with a fully automated system and single-ligand based assessment tools, we turned to a larger set of targets to investigate the prevalence of situations that are not well handled by our scripts. Of the 9050 eligible PDB targets submitted to the parser, 7755 produced a docked ligand structure that could Table 4. Attrition of PDB Structures Subjected to Fully Automated Docking Using DOCK Blastera ligand identified, DOCK Blaster job started ligand docked and scored pose good (<2 A˚ rmsd) may be useful prospectively (<2 A˚ rmsd; rank top 5%) count 9050 7755 3056 1398 as % of previous row 86 39 46 a Aug 1, 2008 version, of the PDB having 52000 x-ray crystal structures in total. be scored and ranked (Table 4). Of these, 3056 had the ligand redock within 2 A˚ rmsd of the crystal structure (http://data.docking.org/2009/PDB3056.xls). About 100 property-matched decoys were generated automatically for each ligand, docked, and used to calculate the rank of the redocked ligand using each of four parameter sets. In 1398 of these cases, the ligand also scored in the top 5%, representing 18% of the 7755 targets that were viable for automatic docking. Discussion Recognizing the potential benefit of automated high throughput docking to interpret the growing number of protein structures, we have developed an automatic docking