title: Comparative virtual and experimental high-throughput screening for glycogen synthase kinase-3beta inhibitors.
abstract: Glycogen synthase kinase-3beta (GSK-3beta) is a serine/threonine kinase that has recently emerged as a key target for neurodegenerative diseases and diabetes. As an initial step of our lead discovery program, we developed a virtual screen to discriminate known GSK-3beta inhibitors and inactive compounds using FlexX, FlexX-Pharm, and FlexE. The maximal enrichment factor (EF = 28) suggests that our protocol identifies potential GSK-3beta inhibitors effectively from large compound collections. The effectiveness of our screening protocol was further investigated by comparative experimental and virtual high-throughput screens (HTSs) performed for the same subset of our corporate library. Enrichment factors, the significantly higher hit rate of virtual screening (12.9%) than that of the HTS (0.55%), and also the comparison of active clusters suggest that our virtual screening protocol is an effective tool in GSK-3beta-based library focusing. Head-to-head comparison of true/false positives and negatives revealed the two approaches to be complementary rather than competitive.
authors.affiliation: CADD&HTS, Gedeon Richter Ltd., P.O. Box 27, H-1475 Budapest, Hungary.
authors.forename: Tímea
authors.initials: T
authors.lastname: Polgár
authors.forename: Andrea
authors.initials: A
authors.lastname: Baki
authors.forename: Györgyi I
authors.initials: GI
authors.lastname: Szendrei
authors.forename: György M
authors.initials: GM
authors.lastname: Keseru
mesh_terms: D018360:Crystallography, X-Ray; D016208:Databases, Factual; D004791:Enzyme Inhibitors / Q000737:chemistry*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D000071679:Glycogen Synthase Kinase 3 beta; D008958:Models, Molecular; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3