Chemical space sampling in virtual screening by different crystal structures.
Retrospective virtual screening experiments were carried out to investigate the effects of combining hit lists from different crystal structures of the same target using consensus scoring. An in-house High Throughput Screening (HTS) dataset from PI3K-γ was used and docked against five diverse PI3K-γ crystal structures. The results show that consensus scoring prioritizes compounds that score moderately against individual crystal structures and is thus complementary to individual crystal structure screening leading to an increase in the diversity of hits. Enrichment factors (EFs) of the consensus score for two or three structures are often as high as or higher than the EF of the individual structures used in the consensus score. Combining four or five structures in the consensus score generally yields lower enrichments. Compounds in the top 500 of the consensus score that are also found in the top 500 of an individual X-ray structure used in the consensus score calculations yield the largest number of hits with the lowest number of false positives.
Brooijmans
Natasja
N
Chemical Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, USA. reprints@prodigy.net
Humblet
Christine
C
D003198:Computer Simulation; D018360:Crystallography, X-Ray; D015195:Drug Design; D008024:Ligands; D008958:Models, Molecular; D011487:Protein Conformation
D008024:Ligands