Frontal Affinity Chromatography with MS Detection of EphB2 Tyrosine Kinase Receptor. 2. Identification of Small-Molecule Inhibitors via Coupling with Virtual Screening
| Autor: | Leticia Toledo-Sherman, J. Estelle Foster, Neil Reid, and Andrew Pasternak, Jacek J. Slon-Usakiewicz, Peter R. Redden, William Ng, Eugen Deretey, Linda C. Liao, Marni D. Uger, Jin-Rui Dai |
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| Rok vydání: | 2005 |
| Předmět: |
Models
Molecular Databases Factual Molecular model Receptor EphB2 Quantitative Structure-Activity Relationship Antineoplastic Agents Enzyme-Linked Immunosorbent Assay Sulfides Mass spectrometry Chromatography Affinity Mass Spectrometry Affinity chromatography Heterocyclic Compounds Cell Line Tumor Drug Discovery Humans Phosphorylation Receptor chemistry.chemical_classification Virtual screening Binding Sites Chromatography Small molecule Protein Structure Tertiary Molecular Weight Enzyme chemistry Biochemistry Molecular Medicine Signal transduction Naphthoquinones |
| Zdroj: | Journal of Medicinal Chemistry. 48:3221-3230 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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