Selection, application, and validation of a set of molecular descriptors for nuclear receptor ligands.
A methodology for the selection and validation of nuclear receptor ligand chemical descriptors is described. After descriptors for a targeted chemical space were selected, a virtual screening methodology utilizing this space was formulated for the identification of potential NR ligands from our corporate collection. Using simple descriptors and our virtual screening method, we are able to quickly identify potential NR ligands from a large collection of compounds. As validation of the virtual screening procedure, an 8, 000-membered NR targeted set and a 24, 000-membered diverse control set of compounds were selected from our in-house general screening collection and screened in parallel across a number of orphan NR FRET assays. For the two assays that provided at least one hit per set by the established minimum pEC(50) for activity, the results showed a 2-fold increase in the hit-rate of the targeted compound set over the diverse set.
Computational, Analytical, and Structural Sciences, GlaxoSmithKline, Five Moore Drive, Research Triangle Park, NC 27709, USA. eugene.l.stewart@gsk.com
Eugene L
EL
Stewart
Peter J
PJ
Brown
James A
JA
Bentley
Timothy M
TM
Willson
D001185:Artificial Intelligence; D020650:Combinatorial Chemistry Techniques; D003198:Computer Simulation; D004353:Drug Evaluation, Preclinical; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects*; D015203:Reproducibility of Results
D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear