7OPJ

Trypanosoma brucei PTR1 (TbPTR1) in complex with pyrimethamine

7OPJ の概要

• エントリーDOI: 10.2210/pdb7opj/pdb
• 分子名称: Pteridine reductase, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 5-(4-CHLORO-PHENYL)-6-ETHYL-PYRIMIDINE-2,4-DIAMINE, ... (6 entities in total)
• 機能のキーワード: trypanosoma brucei, ptr1, tbptr1, pyrimethamine, oxidoreductase
• 由来する生物種: Trypanosoma brucei brucei
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 126975.90

構造登録者

Tassone, G.,Landi, G.,Pozzi, C.,Mangani, S. (登録日: 2021-05-31, 公開日: 2021-07-14, 最終更新日: 2024-01-31)

主引用文献

Tassone, G.,Landi, G.,Linciano, P.,Francesconi, V.,Tonelli, M.,Tagliazucchi, L.,Costi, M.P.,Mangani, S.,Pozzi, C.
Evidence of Pyrimethamine and Cycloguanil Analogues as Dual Inhibitors of Trypanosoma brucei Pteridine Reductase and Dihydrofolate Reductase.
Pharmaceuticals, 14:-, 2021

PubMed Abstract: and parasites are the etiological agents of various threatening neglected tropical diseases (NTDs), including human African trypanosomiasis (HAT), Chagas disease, and various types of leishmaniasis. Recently, meaningful progresses in the treatment of HAT, due to (), have been achieved by the introduction of fexinidazole and the combination therapy eflornithine-nifurtimox. Nevertheless, due to drug resistance issues and the exitance of animal reservoirs, the development of new NTD treatments is still required. For this purpose, we explored the combined targeting of two key folate enzymes, dihydrofolate reductase (DHFR) and pteridine reductase 1 (PTR1). We formerly showed that the DHFR inhibitor cycloguanil (CYC) also targets PTR1, although with reduced affinity. Here, we explored a small library of CYC analogues to understand how their substitution pattern affects the inhibition of both PTR1 and DHFR. Some novel structural features responsible for an improved, but preferential, ability of CYC analogues to target PTR1 were disclosed. Furthermore, we showed that the known drug pyrimethamine (PYR) effectively targets both enzymes, also unveiling its binding mode to PTR1. The structural comparison between PYR and CYC binding modes to PTR1 and DHFR provided key insights for the future design of dual inhibitors for HAT therapy.

PubMed: 34209148
DOI: 10.3390/ph14070636

実験手法

X-RAY DIFFRACTION (1.34 Å)