Article ID Journal Published Year Pages File Type
1395984 European Journal of Medicinal Chemistry 2012 8 Pages PDF
Abstract

The in silico identification, optimization and crystallographic characterization of a 6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]isoquinolin-1-amine scaffold as an inhibitor for the EPHA4 receptor tyrosine kinase is described. A database containing commercially available compounds was subjected to an in silico screening procedure which was focused on finding novel, EPHA4 hinge binding fragments. This resulted in the identification of 6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]isoquinolin-1-amine derivatives as EPHA4 inhibitors. Hit exploration yielded a compound with 2 μM (IC50) affinity for the EPHA4 receptor tyrosine kinase domain. Soaking experiments into a crystal of the EPHA4 kinase domain gave a 2.11Å X-ray structure of the EPHA4 – inhibitor complex, which confirmed the binding mode of the scaffold as proposed by the initial in silico work. The results underscore the strength of fragment based in silico screening as a tool for the discovery of novel lead compounds as small molecule kinase inhibitors.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► In silico screening used to identify hinge binding fragments. ► Characterization of novel EPHA4 inhibitors. ► Hit exploration yielded a compound with 2 μM (IC50) affinity for EPHA4. ► Soaking into a crystal of EPHA4 confirmed the binding mode.

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Physical Sciences and Engineering Chemistry Organic Chemistry
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