Fragment-based lead generation: identification of seed fragments by a highly efficient fragment screening technology

J Comput Aided Mol Des. 2009 Aug;23(8):501-11. doi: 10.1007/s10822-009-9288-x. Epub 2009 Jun 17.


For the detection of the precise and unambiguous binding of fragments to a specific binding site on the target protein, we have developed a novel reporter displacement binding assay technology. The application of this technology for the fragment screening as well as the fragment evolution process with a specific modelling based design strategy is demonstrated for inhibitors of the protein kinase p38alpha. In a fragment screening approach seed fragments were identified which were then used to build compounds from the deep-pocket towards the hinge binding area of the protein kinase p38alpha based on a modelling approach. BIRB796 was used as a blueprint for the alignment of the fragments. The fragment evolution of these deep-pocket binding fragments towards the fully optimized inhibitor BIRB796 included the modulation of the residence time as well as the affinity. The goal of our study was to evaluate the robustness and efficiency of our novel fragment screening technology at high fragment concentrations, compare the screening data with biochemical activity data and to demonstrate the evolution of the hit fragments with fast kinetics, into slow kinetic inhibitors in an in silico approach.

MeSH terms

  • Binding Sites
  • Drug Discovery*
  • Enzyme Inhibitors / chemistry
  • Humans
  • Kinetics
  • Ligands*
  • Models, Molecular
  • Molecular Targeted Therapy*
  • Protein Binding
  • Protein Conformation
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / therapeutic use
  • Structure-Activity Relationship
  • p38 Mitogen-Activated Protein Kinases* / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases* / chemistry


  • Enzyme Inhibitors
  • Ligands
  • Small Molecule Libraries
  • p38 Mitogen-Activated Protein Kinases