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 (IC 50) affinity for the EPHA4 receptor tyrosine kinase domain. Soaking experiments into a crystal of the EPHA4 kinase domain gave a 2.11 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.
Original language | English |
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Pages (from-to) | 493-500 |
Number of pages | 8 |
Journal | European Journal of Medicinal Chemistry |
Volume | 47 |
Issue number | 1 |
DOIs | |
Publication status | Published - Jan 2012 |
Externally published | Yes |
Keywords
- Cancer
- Crystallization
- Docking
- EPH receptor
- EPHA4
- Ephrin
- Fragment
- In silico
- Inhibition
- Kinase
- Pharmacophore
- Screening