5716 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 18 Irwin et al. Figure 4. Ligands from the Astex-85 benchmarks that redock with good pose fidelity and good rank (top 5% of property matched decoys) with all parameter sets used. (A) Nuclear hormone receptors (B) kinases (C) other enzymes. Figure 5. Ligands from the Astex-85 benchmarks that redock with good pose fidelity but poor rank compared to property-matched decoys. We were curious about whether ligand rank was sensitive to the scoring function used. To explore this, we rescored the ligand and all its decoys as docked using DOCK with four widely used, different scoring functions (Table 2 and http:// data.docking.org/2009/RescoringTables.doc), in each case without any change to the receptor or ligand structure. Three of the scoring functions ranked the ligand substantially higher compared to the decoys, resulting in between 4 and 9 more successes. Only PMF resulted in fewer successes than DOCK. GOLD-114 Benchmarking. Because we used the Astex-85 set to tune our protocol and parameter choices, we worried about overfitting.52 To control for protocol bias, we turned to the GOLD-114 benchmark15 for which we did not allow ourselves to adjust the automatic procedure or its parameters in any way. A total of 75 targets were successfully sepa- rated into ligand and receptor automatically from the PDB code alone (Supporting Information Table S1), and a fur- ther 19 cases (94 total) could be run if the ligand three letter