6HOW

Trypanosoma brucei PTR1 in complex with the triazine inhibitor 2a (F219).

Summary for 6HOW

• Entry DOI: 10.2210/pdb6how/pdb
• Related: 6HNC 6HNR
• Descriptor: Pteridine reductase, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, (2~{R})-1-(3,4-dichlorophenyl)-2-(4-nitrophenyl)-2~{H}-1,3,5-triazine-4,6-diamine, ... (5 entities in total)
• Functional Keywords: trypanosoma brucei, pteridine reductase, ptr1, tbptr1, triazine inhibitors, oxidoreductase
• Biological source: Trypanosoma brucei brucei; More
• Total number of polymer chains: 4
• Total formula weight: 126806.38

Authors

Landi, G.,Pozzi, C.,Mangani, S. (deposition date: 2018-09-18, release date: 2019-05-08, Last modification date: 2024-01-24)

Primary citation

Landi, G.,Linciano, P.,Borsari, C.,Bertolacini, C.P.,Moraes, C.B.,Cordeiro-da-Silva, A.,Gul, S.,Witt, G.,Kuzikov, M.,Costi, M.P.,Pozzi, C.,Mangani, S.
Structural Insights into the Development of Cycloguanil Derivatives asTrypanosoma bruceiPteridine-Reductase-1 Inhibitors.
Acs Infect Dis., 5:1105-1114, 2019

PubMed Abstract: Cycloguanil is a known dihydrofolate-reductase (DHFR) inhibitor, but there is no evidence of its activity on pteridine reductase (PTR), the main metabolic bypass to DHFR inhibition in trypanosomatid parasites. Here, we provide experimental evidence of cycloguanil as an inhibitor of PTR1 (PTR1). A small library of cycloguanil derivatives was developed, resulting in and having IC values of 692 and 186 nM, respectively, toward PTR1. Structural analysis revealed that the increased potency of and is due to the combined contributions of hydrophobic interactions, H-bonds, and halogen bonds. Moreover, cell-growth-inhibition tests indicated that is also effective on . The simultaneous inhibition of DHFR and PTR1 activity in is a promising new strategy for the treatment of human African trypanosomiasis. For this purpose, 1,6-dihydrotriazines represent new molecular tools to develop potent dual PTR and DHFR inhibitors.

PubMed: 31012301
DOI: 10.1021/acsinfecdis.8b00358

Experimental method

X-RAY DIFFRACTION (1.92 Å)