SHAFTS: a hybrid approach for 3D molecular similarity calculation. 2. Prospective case study in the discovery of diverse p90 ribosomal S6 protein kinase 2 inhibitors to suppress cell migration

J Med Chem. 2011 May 26;54(10):3564-74. doi: 10.1021/jm200139j. Epub 2011 Apr 22.


We described a prospective application of ligand-based virtual screening program SHAFTS to discover novel inhibitors for p90 ribosomal S6 protein kinase 2 (RSK2). Taking the putative 3D conformations of two weakly binding RSK2 NTKD inhibitors as query templates, SHAFTS was used to perform 3D similarity based virtual screening because of a lack of crystal structure of RSK2 protein, thus leading to the identification of several novel scaffolds that would have been missed by conventional 2D fingerprint methods. The most potent hit compounds show low micromolar inhibitory activities against RSK2. In particular, one of the hit compounds exhibits potent antimigration activity against the MDA-MB-231 tumor cell. The results exemplified SHAFTS' application in active enrichment and scaffold hopping, which is of general interest for lead identification in drug discovery endeavors and also provides novel scaffolds that lay the foundation for uncovering new RSK2 regulatory mechanisms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Chemistry, Pharmaceutical / instrumentation*
  • Chemistry, Pharmaceutical / methods
  • Computational Biology / methods
  • Drug Design
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Humans
  • Inhibitory Concentration 50
  • Ligands
  • Models, Chemical
  • Molecular Conformation
  • Prospective Studies
  • Protein Structure, Tertiary
  • Ribosomal Protein S6 Kinases, 90-kDa / chemistry*


  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Ligands
  • Ribosomal Protein S6 Kinases, 90-kDa
  • ribosomal protein S6 kinase, 90kDa, polypeptide 3