Identification of Trypanosoma brucei leucyl-tRNA synthetase inhibitors by pharmacophore- and docking-based virtual screening and synthesis

Bioorg Med Chem. 2012 Feb 1;20(3):1240-50. doi: 10.1016/j.bmc.2011.12.035. Epub 2011 Dec 30.

Abstract

Human African trypanosomiasis (HAT), caused by the protozoan parasite Trypanosoma brucei, is a neglected fatal disease. Leucyl-tRNA synthetase (LeuRS), which has been successfully applied in the development of antifungal agent, represents a potential antiprotozoal drug target. In this study, a 3D model of T. brucei LeuRS (TbLeuRS) synthetic active site was constructed and subjected to virtual screening using a combination of pharmacophore- and docking-based methods. A new 2-pyrrolinone scaffold was discovered and the structure-activity relationship (SAR) studies aided by the docking model and organic synthesis were carried out. Compounds with various substituents on R(1), R(2) and R(3) were synthesized and their SAR was discussed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Antiprotozoal Agents / chemical synthesis
  • Antiprotozoal Agents / chemistry*
  • Antiprotozoal Agents / pharmacology*
  • Catalytic Domain
  • Drug Design*
  • Humans
  • Leucine-tRNA Ligase / antagonists & inhibitors*
  • Leucine-tRNA Ligase / chemistry
  • Leucine-tRNA Ligase / metabolism
  • Models, Molecular
  • Molecular Sequence Data
  • Sequence Alignment
  • Structure-Activity Relationship
  • Trypanosoma brucei brucei / drug effects
  • Trypanosoma brucei brucei / enzymology*
  • Trypanosomiasis, African / drug therapy*
  • Trypanosomiasis, African / enzymology

Substances

  • Antiprotozoal Agents
  • Leucine-tRNA Ligase