Improving specificity vs bacterial thymidylate synthases through N-dansyl modulation of didansyltyrosine

J Med Chem. 2005 Feb 24;48(4):913-6. doi: 10.1021/jm0491445.

Abstract

N,O-Didansyl-L-tyrosine (DDT) represented the starting lead for further development of novel non-substrate-like inhibitors of bacterial thymidylate synthase. The N-dansyl structure modulation led to a submicromolar inhibitor of Lactobacillus casei TS (LcTS), which is highly specific with respect to human TS (hTS). Using molecular dynamics simulation, a binding mode for DDT vs LcTS was predicted, explaining activity and species-specificity along the series.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bacteria / enzymology*
  • Dansyl Compounds / chemical synthesis
  • Dansyl Compounds / chemistry*
  • Humans
  • Lacticaseibacillus casei / enzymology
  • Models, Molecular
  • Molecular Conformation
  • Protein Binding
  • Structure-Activity Relationship
  • Substrate Specificity
  • Thymidylate Synthase / antagonists & inhibitors*
  • Thymidylate Synthase / chemistry*
  • Tyrosine / analogs & derivatives*
  • Tyrosine / chemical synthesis
  • Tyrosine / chemistry*

Substances

  • Dansyl Compounds
  • N,O-didansyl-L-tyrosine
  • Tyrosine
  • Thymidylate Synthase