Generation of a focused set of GSK compounds biased toward ligand-gated ion-channel ligands.
A "data mining" methodology based on substructural analysis and standard 1024 Daylight fingerprints as descriptors was applied to a set of known antagonists of a subfamily of ligand-gated ion channels comprising nicotinic acetylcholine receptors (nAChR's), 5-hydroxytryptamine, gamma-amino butyric acid-A, and glycine receptors. The derived scoring function was used to generate a focused set that was screened for alpha7 nAChR, resulting in the identification of novel alpha7 ligands easily amenable to chemical modification. Finally, the same scoring function was applied retrospectively to other in-house sets screened for the same target in the same assay. The results and performance of the method are described in detail.
Capelli
Anna Maria
AM
Computational, Analytical, and Structural Sciences, GlaxoSmithKline S.p.A. Medicines Research Centre, Via A. Fleming, 4-37135 Verona, Italy. Anna-Maria.M.Capelli@gsk.com
Feriani
Aldo
A
Tedesco
Giovanna
G
Pozzan
Alfonso
A
D000465:Algorithms; D015195:Drug Design; D015640:Ion Channel Gating; D008024:Ligands; D008956:Models, Chemical; D004364:Pharmaceutical Preparations / Q000737:chemistry; D011978:Receptors, Nicotinic / Q000737:chemistry*
D008024:Ligands; D004364:Pharmaceutical Preparations; D011978:Receptors, Nicotinic