期刊
JOURNAL OF COMPUTATIONAL CHEMISTRY
卷 32, 期 10, 页码 2273-2289出版社
WILEY-BLACKWELL
DOI: 10.1002/jcc.21814
关键词
molecular footprints; molecular fingerprints; pose comparison; pose rescoring; docking; virtual screening; enrichment; ROC curves; Euclidean distance; Pearson correlation
资金
- U.S. Department of Energy
- State of New York [DE-AC02-98CH10886]
- Stony Brook University Office of the Vice President for Research
- New York State Office of Science Technology and Academic Research (NYSTAR)
- NIH [R01GM083669, F31CA134201]
A docking-rescoring method, based on per-residue van der Waals (VDW), electrostatic (ES), or hydrogen bond (HB) energies has been developed to aid discovery of ligands that have interaction signatures with a target (footprints) similar to that of a reference. Biologically useful references could include known drugs, inhibitors, substrates, transition states, or side-chains that mediate protein-protein interactions. Termed footprint similarity (FPS) score, the method, as implemented in the program DOCK, was validated and characterized using: (1) pose identification, (2) crossdocking, (3) enrichment, and (4) virtual screening. Improvements in pose identification (6-12%) were obtained using footprint-based (FPS(VDW+ES)) vs. standard DOCK (DCE(VDW+ES)) scoring as evaluated on three large datasets (680-775 systems) from the SB2010 database. Enhanced pose identification was also observed using FPS (45.4% or 70.9%) compared with DCE (17.8%) methods to rank challenging crossdocking ensembles from carbonic anhydrase. Enrichment tests, for three representative systems, revealed FPS(VDW+ES) scoring yields significant early fold enrichment in the top 10% of ranked databases. For EGFR, top FPS poses are nicely accommodated in the molecular envelope defined by the reference in comparison with DCE, which yields distinct molecular weight bias toward larger molecules. Results from a representative virtual screen of ca. 1 million compounds additionally illustrate how ligands with footprints similar to a known inhibitor can readily be identified from within large commercially available databases. By providing an alternative way to rank ligand poses in a simple yet directed manner we anticipate that FPS scoring will be a useful tool for docking and structure-based design. (C) 2011 Wiley Periodicals, Inc. J Comput Chem 32: 2273-2289, 2011
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