Fragment-based lead discovery using X-ray crystallography

J Med Chem. 2005 Jan 27;48(2):403-13. doi: 10.1021/jm0495778.


Fragment screening offers an alternative to traditional screening for discovering new leads in drug discovery programs. This paper describes a fragment screening methodology based on high throughput X-ray crystallography. The method is illustrated against five proteins (p38 MAP kinase, CDK2, thrombin, ribonuclease A, and PTP1B). The fragments identified have weak potency (>100 microM) but are efficient binders relative to their size and may therefore represent suitable starting points for evolution to good quality lead compounds. The examples illustrate that a range of molecular interactions (i.e., lipophilic, charge-charge, neutral hydrogen bonds) can drive fragment binding and also that fragments can induce protein movement. We believe that the method has great potential for the discovery of novel lead compounds against a range of targets, and the companion paper illustrates how lead compounds have been identified for p38 MAP kinase starting from fragments such as those described in this paper.

MeSH terms

  • CDC2-CDC28 Kinases / antagonists & inhibitors
  • CDC2-CDC28 Kinases / chemistry
  • Crystallography, X-Ray*
  • Cyclin-Dependent Kinase 2
  • Data Interpretation, Statistical
  • Databases, Factual
  • Drug Design*
  • Enzyme Inhibitors / chemistry
  • Ligands*
  • Models, Molecular
  • Molecular Structure*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Protein Tyrosine Phosphatases / antagonists & inhibitors
  • Protein Tyrosine Phosphatases / chemistry
  • Proteins / chemistry*
  • Quantitative Structure-Activity Relationship
  • Ribonuclease, Pancreatic / antagonists & inhibitors
  • Ribonuclease, Pancreatic / chemistry
  • Thrombin / antagonists & inhibitors
  • Thrombin / chemistry
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / chemistry


  • Enzyme Inhibitors
  • Ligands
  • Proteins
  • CDC2-CDC28 Kinases
  • Cyclin-Dependent Kinase 2
  • p38 Mitogen-Activated Protein Kinases
  • Ribonuclease, Pancreatic
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Protein Tyrosine Phosphatases
  • Thrombin