6HAW

Crystal structure of bovine cytochrome bc1 in complex with 2-pyrazolyl quinolone inhibitor WDH2G7

6HAW の概要

• エントリーDOI: 10.2210/pdb6haw/pdb
• 分子名称: Cytochrome b-c1 complex subunit 1, mitochondrial, Cytochrome b-c1 complex subunit 9, 1,2-DIHEXANOYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE, ... (24 entities in total)
• 機能のキーワード: cytochrome bc1, malaria, electron transport
• 由来する生物種: Bos taurus (cattle); 詳細
• タンパク質・核酸の鎖数: 10
• 化学式量合計: 238530.04

構造登録者

Amporndanai, K.,Hong, W.D.,O'Neill, P.M.,Hasnain, S.S.,Antonyuk, S.V. (登録日: 2018-08-08, 公開日: 2019-01-16, 最終更新日: 2024-01-17)

主引用文献

David Hong, W.,Leung, S.C.,Amporndanai, K.,Davies, J.,Priestley, R.S.,Nixon, G.L.,Berry, N.G.,Samar Hasnain, S.,Antonyuk, S.,Ward, S.A.,Biagini, G.A.,O'Neill, P.M.
Potent Antimalarial 2-Pyrazolyl Quinolonebc1(Qi) Inhibitors with Improved Drug-like Properties.
ACS Med Chem Lett, 9:1205-1210, 2018

PubMed Abstract: A series of 2-pyrazolyl quinolones has been designed and synthesized in 5-7 steps to optimize for both antimalarial potency and various drug metabolism and pharmacokinetics (DMPK) features. The most potent compounds display no cross-resistance with multidrug resistant parasite strains (W2) compared to drug sensitive strains (3D7), with IC (concentration of drug required to achieve half maximal growth suppression) values in the range of 15-33 nM. Furthermore, members of the series retain moderate activity against the atovaquone-resistant parasite isolate (TM90C2B). The described 2-pyrazoyl series displays improved DMPK properties, including improved aqueous solubility compared to previously reported quinolone series and acceptable safety margin through cytotoxicity assessment. The 2-pyrazolyl quinolones are believed to bind to the ubiquinone-reducing Q site of the parasite complex, which is supported by crystallographic studies of bovine cytochrome complex.

PubMed: 30613327
DOI: 10.1021/acsmedchemlett.8b00371

実験手法

X-RAY DIFFRACTION (3.45 Å)