6HOW

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

6HOW の概要

• エントリーDOI: 10.2210/pdb6how/pdb
• 関連するPDBエントリー: 6HNC 6HNR
• 分子名称: 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)
• 機能のキーワード: trypanosoma brucei, pteridine reductase, ptr1, tbptr1, triazine inhibitors, oxidoreductase
• 由来する生物種: Trypanosoma brucei brucei; 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 126806.38

構造登録者

Landi, G.,Pozzi, C.,Mangani, S. (登録日: 2018-09-18, 公開日: 2019-05-08, 最終更新日: 2024-01-24)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.92 Å)