8PF4

Crystal structure of Trypanosoma brucei trypanothione reductase in complex with 4-(((5-((4-fluorophenethyl)carbamoyl)furan-2-yl)methyl)(4-fluorophenyl)carbamoyl)-1-methyl-1-(3-phenylpropyl)piperazin-1-ium

8PF4 の概要

• エントリーDOI: 10.2210/pdb8pf4/pdb
• 関連するPDBエントリー: 8PF3
• 分子名称: Trypanothione reductase, FLAVIN-ADENINE DINUCLEOTIDE, ~{N}-(4-fluorophenyl)-~{N}-[[5-[2-(4-fluorophenyl)ethylcarbamoyl]furan-2-yl]methyl]-4-methyl-4-(3-phenylpropyl)-1,4$l^{4}-diazinane-1-carboxamide, ... (7 entities in total)
• 機能のキーワード: oxidoreductase activity, nucleotide binding, flavoenzyme, inhibitor binding, oxidoreductase
• 由来する生物種: Trypanosoma brucei
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 223519.78

構造登録者

Exertier, C.,Ilari, A.,Fiorillo, A.,Antonelli, L. (登録日: 2023-06-15, 公開日: 2024-04-03, 最終更新日: 2025-10-01)

主引用文献

Exertier, C.,Salerno, A.,Antonelli, L.,Fiorillo, A.,Ocello, R.,Seghetti, F.,Caciolla, J.,Uliassi, E.,Masetti, M.,Fiorentino, E.,Orsini, S.,Di Muccio, T.,Ilari, A.,Bolognesi, M.L.
Fragment Merging, Growing, and Linking Identify New Trypanothione Reductase Inhibitors for Leishmaniasis.
J.Med.Chem., 67:402-419, 2024

PubMed Abstract: Trypanothione reductase (TR) is a suitable target for drug discovery approaches against leishmaniasis, although the identification of potent inhibitors is still challenging. Herein, we harnessed a fragment-based drug discovery (FBDD) strategy to develop new TR inhibitors. Previous crystallographic screening identified fragments -, which provided ideal starting points for a medicinal chemistry campaign. investigations revealed critical hotspots in the TR binding site, guiding our structure- and ligand-based structure-actvity relationship (SAR) exploration that yielded fragment-derived compounds -. A trend of improvement in TR inhibition was detected along the optimization and confirmed by the crystal structures of , , and in complex with TR. Compound showed the best TR inhibitory profile ( = 0.2 μM), whereas was the best one in terms of and activity. Although further fine-tuning is needed to improve selectivity, we demonstrated the potentiality of FBDD on a classic but difficult target for leishmaniasis.

PubMed: 38164929
DOI: 10.1021/acs.jmedchem.3c01439

実験手法

X-RAY DIFFRACTION (1.84 Å)