Abstract
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.
Original language | English (US) |
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Pages (from-to) | 6097-6105 |
Number of pages | 9 |
Journal | Bioorganic and Medicinal Chemistry |
Volume | 14 |
Issue number | 17 |
DOIs | |
State | Published - Sep 1 2006 |
Externally published | Yes |
Keywords
- ATP-binding site
- Homology model
- Ligand docking
- Pharmacophore
- Ribosomal S6 kinase 2
- Virtual screening
ASJC Scopus subject areas
- Biochemistry
- Molecular Medicine
- Molecular Biology
- Pharmaceutical Science
- Drug Discovery
- Clinical Biochemistry
- Organic Chemistry