3BMN

Structure of Pteridine Reductase 1 (PTR1) from Trypanosoma brucei in ternary complex with cofactor (NADP+) and inhibitor (Compound AX3)

3BMN の概要

• エントリーDOI: 10.2210/pdb3bmn/pdb
• 関連するPDBエントリー: 2C7V 3BMC 3BMD 3BME 3BMF 3BMG 3BMH 3BMI 3BMJ 3BMK 3BML 3BMM 3BMO 3BMQ 3BMR 3BMS 3BMT
• 分子名称: Pteridine reductase, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, N~2~-cyclopropyl-1,3,5-triazine-2,4,6-triamine, ... (8 entities in total)
• 機能のキーワード: pteridine reductase, ptr1, trypanosoma brucei, short chain dehydrogenase, inhibitor, 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: 127131.33

構造登録者

Martini, V.P.,Iulek, J.,Tulloch, L.B.,Hunter, W.N. (登録日: 2007-12-13, 公開日: 2008-12-16, 最終更新日: 2011-07-13)

主引用文献

Tulloch, L.B.,Martini, V.P.,Iulek, J.,Huggan, J.K.,Lee, J.H.,Gibson, C.L.,Smith, T.K.,Suckling, C.J.,Hunter, W.N.
Structure-based design of pteridine reductase inhibitors targeting african sleeping sickness and the leishmaniases.
J.Med.Chem., 53:221-229, 2010

PubMed Abstract: Pteridine reductase (PTR1) is a target for drug development against Trypanosoma and Leishmania species, parasites that cause serious tropical diseases and for which therapies are inadequate. We adopted a structure-based approach to the design of novel PTR1 inhibitors based on three molecular scaffolds. A series of compounds, most newly synthesized, were identified as inhibitors with PTR1-species specific properties explained by structural differences between the T. brucei and L. major enzymes. The most potent inhibitors target T. brucei PTR1, and two compounds displayed antiparasite activity against the bloodstream form of the parasite. PTR1 contributes to antifolate drug resistance by providing a molecular bypass of dihydrofolate reductase (DHFR) inhibition. Therefore, combining PTR1 and DHFR inhibitors might improve therapeutic efficacy. We tested two new compounds with known DHFR inhibitors. A synergistic effect was observed for one particular combination highlighting the potential of such an approach for treatment of African sleeping sickness.

PubMed: 19916554
DOI: 10.1021/jm901059x

実験手法

X-RAY DIFFRACTION (1.98 Å)