A highly potent non-nucleoside adenosine deaminase inhibitor: efficient drug discovery by intentional lead hybridization

J Am Chem Soc. 2004 Jan 14;126(1):34-5. doi: 10.1021/ja038606l.


We disclose herein the rapid discovery of the first highly potent (Ki = 7.7 nM) non-nucleoside adenosine deaminase (ADA) inhibitor based on the rational hybridization of two structurally distinct leads. Two micromolar inhibitors were discovered by a parallel rational design and random screening program, and individual crystal structures of bovine ADA in complexation with these inhibitors revealed several unknown binding sites and distinct binding modes. Using this information as the starting point, highly effective lead hybridization was achieved in only two structure-based drug design iterations. The conceptual approach illustrated by this example promises to be broadly useful in the search for new chemical entities and can contribute greatly to improve the overall efficiency and speed of drug discovery.

MeSH terms

  • Adenosine Deaminase Inhibitors*
  • Benzimidazoles / chemistry
  • Benzimidazoles / pharmacology
  • Binding Sites
  • Drug Design
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Models, Molecular
  • Molecular Conformation
  • Nucleosides / chemistry
  • Nucleosides / pharmacology
  • Structure-Activity Relationship
  • Thiazoles / chemistry
  • Thiazoles / pharmacology


  • Adenosine Deaminase Inhibitors
  • Benzimidazoles
  • Enzyme Inhibitors
  • Nucleosides
  • Thiazoles