| Autor: |
Raimundo, B. C., Oslob, J. D., Braisted, A. C., Hyde, J., McDowell, R. S., Randal, M., Waal, N. D., Wilkinson, J., Yu, C. H., Arkin, M. R. |
| Zdroj: |
Journal of Medicinal Chemistry; June 2004, Vol. 47 Issue: 12 p3111-3130, 20p |
| Abstrakt: |
Fragment assembly has shown promise for discovering small-molecule antagonists for difficult targets, including protein−protein interactions. Here, we describe a process for identifying a 60 nM inhibitor of the interleukin-2 (IL-2)/IL-2 receptor (IL-2Rα) interaction. By use of fragment-based approaches, a compound with millimolar affinity was evolved to a hit series with low micromolar activity, and these compounds were optimized into a lead series with nanomolar affinity. Fragment assembly was useful not only for hit identification, but also for lead optimization. Throughout the discovery process, biophysical methods and structural biology demonstrated that compounds bound reversibly to IL-2 at the IL-2 receptor binding site. |
| Databáze: |
Supplemental Index |
| Externí odkaz: |
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