A comparison of ligand based virtual screening methods and application to corticotropin releasing factor 1 receptor.
Ligand based virtual screening approaches were applied to the CRF1 receptor. We compared ECFP6 fingerprints, FTrees, Topomers, Cresset FieldScreen, ROCS OpenEye shape Tanimoto, OpenEye combo-score and OpenEye electrostatics. The 3D methods OpenEye Shape Tanimoto, combo-score and Topomers performed the best at separating actives from inactives in retrospective experiments. By virtue of their higher enrichment the same methods identified more active scaffolds. However, amongst a given number of active compounds the Cresset and OpenEye electrostatic methods contained more scaffolds and returned ranked compounds with greater diversity. A selection of the methods were employed to recommend compounds for screening in a prospective experiment. New CRF1 actives antagonists were found. The new actives contained different underlying chemical architecture to the query molecules, results indicative of successful scaffold-hopping.
Tresadern
Gary
G
Johnson & Johnson, Pharmaceutical Research & Development, Janssen-Cilag S.A., Calle Jarama, 75, Poligono Industrial, 45007 Toledo, Spain. gtresade@its.jnj.com
Bemporad
Daniele
D
Howe
Trevor
T
D000631:Aminopyridines / Q000737:chemistry; D003198:Computer Simulation; D008958:Models, Molecular; D015394:Molecular Structure; D011725:Pyridines / Q000737:chemistry; D011743:Pyrimidines / Q000737:chemistry; D011758:Pyrroles / Q000737:chemistry; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*
C529296:(3,6-dimethyl-2-(2,4,6-trimethylphenoxy)pyridin-4-yl)(1-ethylpropyl)amine; C529295:4-(1-ethylpropoxy)-3,6-dimethyl-2-(2,4,6-trimethylphenoxy)pyridine; D000631:Aminopyridines; C101628:CP 154526; D011725:Pyridines; D011743:Pyrimidines; D011758:Pyrroles; D018019:Receptors, Corticotropin-Releasing Hormone; C103016:antalarmin