PRO_SELECT: combining structure-based drug design and array-based chemistry for rapid lead discovery. 2. The development of a series of highly potent and selective factor Xa inhibitors

J Med Chem. 2002 Mar 14;45(6):1221-32. doi: 10.1021/jm010944e.

Abstract

In silico screening of combinatorial libraries prior to synthesis promises to be a valuable aid to lead discovery. PRO_SELECT, a tool for the virtual screening of libraries for fit to a protein active site, has been used to find novel leads against the serine protease factor Xa. A small seed template was built upon using three iterations of library design, virtual screening, synthesis, and biological testing. Highly potent molecules with selectivity for factor Xa over other serine proteases were rapidly obtained.

MeSH terms

  • Animals
  • Benzamidines / chemical synthesis*
  • Benzamidines / pharmacology
  • Combinatorial Chemistry Techniques / methods*
  • Drug Design*
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology
  • Factor Xa Inhibitors*
  • Humans
  • Models, Molecular
  • Protein Conformation
  • Rats
  • Structure-Activity Relationship

Substances

  • Benzamidines
  • Enzyme Inhibitors
  • Factor Xa Inhibitors