Automated docking screens: a feasibility study

Abstract

Molecular docking is the most practical approach to leverage protein structure for ligand discovery, but the technique retains important liabilities that make it challenging to deploy on a large scale. We have therefore created an expert system, DOCK Blaster, to investigate the feasibility of full automation. The method requires a PDB code, sometimes with a ligand structure, and from that alone can launch a full screen of large libraries. A critical feature is self-assessment, which estimates the anticipated reliability of the automated screening results using pose fidelity and enrichment. Against common benchmarks, DOCK Blaster recapitulates the crystal ligand pose within 2 A rmsd 50-60% of the time; inferior to an expert, but respectrable. Half the time the ligand also ranked among the top 5% of 100 physically matched decoys chosen on the fly. Further tests were undertaken culminating in a study of 7755 eligible PDB structures. In 1398 cases, the redocked ligand ranked in the top 5% of 100 property-matched decoys while also posing within 2 A rmsd, suggesting that unsupervised prospective docking is viable. DOCK Blaster is available at http://blaster.docking.org .

Figure 1

The DOCK Blaster web interface, available starting from http://blaster.docking.org/.

Figure 2

DOCK Blaster pipeline schematic. Left: two starting points for DOCK Blaster. Center: six main modules of the automatic docking pipeline. Right: four places in which automatic docking can fail.

Figure 3

Calibration docking report, containing pose fidelity (Å, rmsd) and enrichment (% rank) of the redocked crystallographic ligand compared to 100 property matched decoys using four parametrizations, separated by a forward slash (/) in each cell. Successful runs are in green, unsuccessful ones in red, and marginal ones in yellow.

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.

Figure 6

Ligands from the Astex-85 benchmark that do not achieve good pose fidelity under any circumstances.

Figure 7

Histogram and cumulative frequency of pose fidelity (Å, rmsd) using the best parameter set. Astex-85 benchmark.

Figure 8

Plot of pose fidelity (Å, rmsd) versus % rank compared to about 100 property matched decoys (log scale). For Astex-85 benchmark. In each case, the parameter set that gave the best pose fidelity was used.

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.