Abstract
This manuscript presents the latest algorithmic and methodological developments to the structure-based design program DOCK 6.7 focused on an updated internal energy function, new anchor selection control, enhanced minimization options, a footprint similarity scoring function, a symmetry-corrected RMSD algorithm, a database filter, and docking forensic tools. An important strategy during development involved use of three orthogonal metrics for assessment and validation:
pose reproduction
over a large database of 1043 protein-ligand complexes (SB2012 test set),
cross-docking
to 24 drug-target protein families, and
database enrichment
using large active and decoy data sets (DUD-E test set) for 5 important proteins including HIV protease and IGF-1R. Relative to earlier versions, a key outcome of the work is a significant
increase
in pose reproduction success in going from DOCK 4.0.2 (51.4%) → 5.4 (65.2%) → 6.7 (73.3%) as a result of significant
decreases
in failure arising from both sampling 24.1% → 13.6% → 9.1% and scoring 24.4% → 21.1% → 17.5%. Companion cross-docking and enrichment studies with the new version highlight other strengths and remaining areas for improvement, especially for systems containing metal ions. The source code for DOCK 6.7 is available for download and free for academic users at
http://dock.compbio.ucsf.edu/
.
DOCK is a structure-based design program developed over the past 30+ years. The current performance of DOCK version 6.7, made possible by new advances to the codebase, algorithmic updates, and optimized input parameters, is presented. The effectiveness of DOCK is demonstrated in pose reproduction, cross-docking (pictured), and enrichment experiments to systems that are of interest as drug targets. The current release is available for download at:
http://dock.compbio.ucsf.edu/
.