Inhibitor specificity via protein dynamics: insights from the design of antibacterial agents targeted against thymidylate synthase

Chem Biol. 2003 Dec;10(12):1183-93. doi: 10.1016/j.chembiol.2003.11.012.


Structure-based drug design of species-specific inhibitors generally exploits structural differences in proteins from different organisms. Here, we demonstrate how achieving specificity can be aided by targeting differences in the dynamics of proteins. Thymidylate synthase (TS) is a good target for anticancer agents and a potential target for antibacterial agents. Most inhibitors are folate-analogs that bind at the folate binding site and are not species specific. In contrast, alpha156 is not a folate-analog and is specific for bacterial TS; it has been shown crystallographically to bind in a nonconserved binding site. Docking calculations and crystal structure-based estimation of the essential dynamics of TSs from five different species show that differences in the dynamics of TSs make the active site more accessible to alpha156 in the prokaryotic than in the eukaryotic TSs and thereby enhance the specificity of alpha156.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / chemistry*
  • Anti-Bacterial Agents / metabolism
  • Anti-Bacterial Agents / pharmacology*
  • Binding Sites
  • Drug Design*
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Models, Molecular
  • Pliability
  • Protein Conformation
  • Protein Structure, Tertiary
  • Software
  • Substrate Specificity
  • Thymidylate Synthase / antagonists & inhibitors*
  • Thymidylate Synthase / metabolism


  • Anti-Bacterial Agents
  • Enzyme Inhibitors
  • Thymidylate Synthase