Discovery of novel CDK1 inhibitors by combining pharmacophore modeling, QSAR analysis and in silico screening followed by in vitro bioassay

Eur J Med Chem. 2010 Sep;45(9):4316-30. doi: 10.1016/j.ejmech.2010.06.034. Epub 2010 Jun 30.

Abstract

Cyclin-dependent kinase 1 (CDK1) is a valid anticancer target. With this in mind we applied a modeling workflow by combining pharmacophore modeling and QSAR analysis followed by in silico screening towards the discovery of novel inhibitory CDK1 scaffolds. Virtual screening identified 10 low micromolar inhibitory leads: 8 from the National Caner Institute (NCI) list of compounds and 2 from our in house list of established drugs and agrochemicals. The most potent NCI hit illustrated anti-CDK1 IC(50) value of 0.83 microM, while the drug hit isoxsuprine illustrated anti-CDK1 IC(50) value of 2.9 microM and the agrochemical hit foramsulfuran showed IC(50) = 3.6 microM. These results demonstrate that our virtual screening protocol is able to identify novel anti-CDK1 leads for subsequent development into potential anticancer agents.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CDC2 Protein Kinase / antagonists & inhibitors*
  • CDC2 Protein Kinase / chemistry
  • Computational Biology*
  • Databases, Factual
  • Drug Discovery / methods*
  • Humans
  • Models, Molecular*
  • Protein Conformation
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Quantitative Structure-Activity Relationship*
  • ROC Curve
  • Thermodynamics

Substances

  • Protein Kinase Inhibitors
  • CDC2 Protein Kinase