Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 14, Issue 17, Pages 6097-6105Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2006.05.001
Keywords
ribosomal S6 kinase 2; homology model; ATP-binding site; virtual screening; ligand docking; pharmacophore
Funding
- Intramural NIH HHS Funding Source: Medline
- NCI NIH HHS [N01-CO-12400] Funding Source: Medline
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Ribosomal S6 kinase 2 (RSK2) is a serine/threonine kinase that plays a role in human cancer and Coffin-Lowry syndrome and is comprised of two nonidentical kinase domains, each domain with its own ATP-binding site. RSK2 can be inactivated by different types of small organic molecules. Potent RSK2 inhibitors include the two classic bisindole maleimide PKC inhibitors, Ro31-8220 and GF109203X, and the natural product SL0101 that was shown to bind specifically to the ATP pocket of the N-terminal domain (NTD). In this paper, we present an atomic model of the RSK2 NTD (residues 68-323), which was built to simultaneously bind the distinctive molecular scaffolds of SL0101, Ro31-8220, and GF109203X. The RSK2 NTD model was used to identify two novel RSK2 inhibitors from the National Cancer Institute open chemical repository and to develop a preliminary structure-based pharmacophore model. Published by Elsevier Ltd.
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