High-resolution structures of Trypanosoma brucei pteridine reductase ligand complexes inform on the placement of new molecular entities in the active site of a potential drug target

Alice Dawson, Lindsay B. Tulloch, Keri L. Barrack, William N. Hunter*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

24 Citations (Scopus)

Abstract

Pteridine reductase (PTR1) is a potential target for drug development against parasitic Trypanosoma and Leishmania species. These protozoa cause serious diseases for which current therapies are inadequate. High-resolution structures have been determined, using data between 1.6 and 1.1 A resolution, of T. brucei PTR1 in complex with pemetrexed, trimetrexate, cyromazine and a 2,4-diaminopyrimidine derivative. The structures provide insight into the interactions formed by new molecular entities in the enzyme active site with ligands that represent lead compounds for structure-based inhibitor development and to support early-stage drug discovery.

Original languageEnglish
Pages (from-to)1334-1340
Number of pages7
JournalActa Crystallographica. Section D, Biological crystallography
Volume66
DOIs
Publication statusPublished - Dec 2010

Keywords

  • DESIGN
  • INHIBITORS
  • DIFFRACTION
  • METHOTREXATE
  • Trypanosoma
  • AFRICAN TRYPANOSOMIASIS
  • Leishmania
  • cyromazine
  • pterin
  • PNEUMOCYSTIS-CARINII
  • trimetrexate
  • pemetrexed
  • RESISTANCE
  • METABOLISM
  • antifolates
  • DIHYDROFOLATE-REDUCTASE
  • PARASITE LEISHMANIA-MAJOR

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