4CLX

Crystal structure of pteridine reductase 1 (PTR1) from Trypanosoma brucei in ternary complex with cofactor and inhibitor

Summary for 4CLX

• Entry DOI: 10.2210/pdb4clx/pdb
• Related: 4CL8 4CLD 4CLE 4CLH 4CLO 4CLR 4CM1 4CM3 4CM4 4CM5 4CM6 4CM7 4CM8 4CM9 4CMA 4CMB 4CMC 4CME 4CMG 4CMI 4CMJ 4CMK
• Descriptor: PTERIDINE REDUCTASE 1, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 2-amino-5-(p-tolyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one, ... (5 entities in total)
• Functional Keywords: oxidoreductase, short-chain dehydrogenase/reductase
• Biological source: TRYPANOSOMA BRUCEI BRUCEI
• Total number of polymer chains: 4
• Total formula weight: 126672.87

Authors

Barrack, K.L.,Hunter, W.N. (deposition date: 2014-01-15, release date: 2015-01-21, Last modification date: 2024-05-08)

Primary citation

Khalaf, A.I.,Huggan, J.K.,Suckling, C.J.,Gibson, C.L.,Stewart, K.,Giordani, F.,Barrett, M.P.,Wong, P.E.,Barrack, K.L.,Hunter, W.N.
Structure-Based Design and Synthesis of Antiparasitic Pyrrolopyrimidines Targeting Pteridine Reductase 1.
J.Med.Chem., 57:6479-, 2014

PubMed Abstract: The treatment of Human African trypanosomiasis remains a major unmet health need in sub-Saharan Africa. Approaches involving new molecular targets are important; pteridine reductase 1 (PTR1), an enzyme that reduces dihydrobiopterin in Trypanosoma spp., has been identified as a candidate target, and it has been shown previously that substituted pyrrolo[2,3-d]pyrimidines are inhibitors of PTR1 from Trypanosoma brucei (J. Med. Chem. 2010, 53, 221-229). In this study, 61 new pyrrolo[2,3-d]pyrimidines have been prepared, designed with input from new crystal structures of 23 of these compounds complexed with PTR1, and evaluated in screens for enzyme inhibitory activity against PTR1 and in vitro antitrypanosomal activity. Eight compounds were sufficiently active in both screens to take forward to in vivo evaluation. Thus, although evidence for trypanocidal activity in a stage I disease model in mice was obtained, the compounds were too toxic to mice for further development.

PubMed: 25007262
DOI: 10.1021/JM500483B

Experimental method

X-RAY DIFFRACTION (1.85 Å)