title: Frontal affinity chromatography with MS detection of EphB2 tyrosine kinase receptor. 2. Identification of small-molecule inhibitors via coupling with virtual screening.
abstract: We have integrated two complementary methods, high-throughput virtual screening with a "high-content" wet screening technique based on frontal affinity chromatography with mass spectrometry detection (FAC-MS), for identification of hits against the erythropoietin-producing hepatocellular B2 (EphB2) receptor tyrosine kinase domain. Both an EphB2-directed virtual screen combining docking and scoring and a kinase-directed pharmacophore search strategy were used to identify a compound set enriched in bioactive compounds against EphB2. The coupling of virtual screening methodologies with FAC-MS is a unique hybrid approach that can be used to increase the efficacy of both hit discovery and optimization efforts in drug discovery and has successfully identified hits, in particular 19a (36% shift, IC(50) = 5.2 microM, K(d) = 3.3 microM), as inhibitors for EphB2, a potential cancer target.
authors.affiliation: Protana Inc., OptiMol Drug Discovery Divison, 251 Attwell Drive, Toronto, Ontario, M9W 7H4, Canada.
authors.forename: Leticia
authors.initials: L
authors.lastname: Toledo-Sherman
authors.forename: Eugen
authors.initials: E
authors.lastname: Deretey
authors.forename: Jacek J
authors.initials: JJ
authors.lastname: Slon-Usakiewicz
authors.forename: William
authors.initials: W
authors.lastname: Ng
authors.forename: Jin-Rui
authors.initials: JR
authors.lastname: Dai
authors.forename: J Estelle
authors.initials: JE
authors.lastname: Foster
authors.forename: Peter R
authors.initials: PR
authors.lastname: Redden
authors.forename: Marni D
authors.initials: MD
authors.lastname: Uger
authors.forename: Linda C
authors.initials: LC
authors.lastname: Liao
authors.forename: Andrew
authors.initials: A
authors.lastname: Pasternak
authors.forename: Neil
authors.initials: N
authors.lastname: Reid
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D002846:Chromatography, Affinity; D016208:Databases, Factual; D004797:Enzyme-Linked Immunosorbent Assay; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D013058:Mass Spectrometry; D008958:Models, Molecular; D008970:Molecular Weight; D009285:Naphthoquinones / Q000737:chemistry / Q000494:pharmacology; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D021281:Quantitative Structure-Activity Relationship; D036183:Receptor, EphB2 / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D013440:Sulfides / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D006571:Heterocyclic Compounds; D009285:Naphthoquinones; D013440:Sulfides; D036183:Receptor, EphB2