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.
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 Å 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.
Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD15EH, Scotland.
Alice
A
Dawson
Lindsay B
LB
Tulloch
Keri L
KL
Barrack
William N
WN
Hunter
D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D005971:Glutamates / Q000737:chemistry; D006147:Guanine / Q000031:analogs & derivatives / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D009249:NADP / Q000737:chemistry / Q000378:metabolism; D010088:Oxidoreductases / Q000737:chemistry* / Q000378:metabolism; D000068437:Pemetrexed; D011485:Protein Binding; D014227:Triazines / Q000737:chemistry; D016597:Trimetrexate / Q000737:chemistry; D014346:Trypanosoma brucei brucei / Q000201:enzymology*
D005971:Glutamates; D008024:Ligands; D014227:Triazines; D000068437:Pemetrexed; D009249:NADP; D006147:Guanine; C028704:cyromazine; D010088:Oxidoreductases; C085592:pteridine reductase; D016597:Trimetrexate