Virtual screening using protein-ligand docking: avoiding artificial enrichment.
This study addresses a number of topical issues around the use of protein-ligand docking in virtual screening. We show that, for the validation of such methods, it is key to use focused libraries (containing compounds with one-dimensional properties, similar to the actives), rather than "random" or "drug-like" libraries to test the actives against. We also show that, to obtain good enrichments, the docking program needs to produce reliable binding modes. We demonstrate how pharmacophores can be used to guide the dockings and improve enrichments, and we compare the performance of three consensus-ranking protocols against ranking based on individual scoring functions. Finally, we show that protein-ligand docking can be an effective aid in the screening for weak, fragment-like binders, which has rapidly become a popular strategy for hit identification. All results presented are based on carefully constructed virtual screening experiments against four targets, using the protein-ligand docking program GOLD.
Verdonk
Marcel L
ML
Astex Technology Ltd., 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom. m.verdonk@astex-technology.com
Berdini
Valerio
V
Hartshorn
Michael J
MJ
Mooij
Wijnand T M
WT
Murray
Christopher W
CW
Taylor
Richard D
RD
Watson
Paul
P
D008024:Ligands; D008958:Models, Molecular; D004364:Pharmaceutical Preparations / Q000737:chemistry; D011506:Proteins / Q000378:metabolism*; D014961:X-Ray Diffraction
D008024:Ligands; D004364:Pharmaceutical Preparations; D011506:Proteins