Frontal Affinity Chromatography with MS Detection of EphB2 Tyrosine Kinase Receptor. 2. Identification of Small-Molecule Inhibitors via Coupling with Virtual Screening

• Published in: Journal of medicinal chemistry Vol. 48; no. 9; pp. 3221 - 3230
• Main Authors: Toledo-Sherman, Leticia, Deretey, Eugen, Slon-Usakiewicz, Jacek J, Ng, William, Dai, Jin-Rui, Foster, J. Estelle, Redden, Peter R, Uger, Marni D, Liao, Linda C, Pasternak, Andrew, Reid, Neil
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 05.05.2005
• Subjects: Analytical chemistry; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Binding Sites; Biological and medical sciences; Cell Line, Tumor; Chemistry; Chromatographic methods and physical methods associated with chromatography; Chromatography, Affinity; Databases, Factual; Enzyme-Linked Immunosorbent Assay; Exact sciences and technology; Heterocyclic Compounds - chemistry; Heterocyclic Compounds - pharmacology; Humans; Mass Spectrometry; Medical sciences; Miscellaneous; Models, Molecular; Molecular Weight; Naphthoquinones - chemistry; Naphthoquinones - pharmacology; Other chromatographic methods; Pharmacology. Drug treatments; Phosphorylation; Protein Structure, Tertiary; Quantitative Structure-Activity Relationship; Receptor, EphB2 - antagonists & inhibitors; Receptor, EphB2 - chemistry; Receptor, EphB2 - metabolism; Sulfides - chemistry; Sulfides - pharmacology; Frontal chromatography; Enzyme; Transferases; Virtual screening; Data mining; Modeling; Signal transduction; Structure activity relation; Affinity chromatography; Chemical compound library; Molecular model; Inhibitor; Detection; Protein-tyrosine kinase; Mass spectrometry; Biological receptor
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0492204

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, IC50 = 5.2 μM, K d = 3.3 μM), as inhibitors for EphB2, a potential cancer target.