4BY0

Crystal structure of Trypanosoma cruzi CYP51 bound to the inhibitor (R)-N-(3-(1H-indol-3-yl)-1-oxo-1-(pyridin-4-ylamino)propan-2-yl)-3,3'- difluoro-(1,1'-biphenyl)-4-carboxamide

4BY0 の概要

• エントリーDOI: 10.2210/pdb4by0/pdb
• 分子名称: STEROL 14-ALPHA DEMETHYLASE, PROTOPORPHYRIN IX CONTAINING FE, (R)-N-(3-(1H-indol-3-yl)-1-oxo-1-(pyridin-4-ylamino)propan-2-yl)-3,3'-difluoro-(1,1'-biphenyl)-4-carboxamide, ... (4 entities in total)
• 機能のキーワード: oxidoreductase, sterol 14-demethylase, sterol biosynthesis, chagas disease
• 由来する生物種: TRYPANOSOMA CRUZI
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 108799.63

構造登録者

Choi, J.Y.,Calvet, C.M.,Vierira, D.F.,Gunatilleke, S.S.,Cameron, M.D.,McKerrow, J.H.,Podust, L.M.,Roush, W.R. (登録日: 2013-07-16, 公開日: 2014-01-22, 最終更新日: 2023-12-20)

主引用文献

Choi, J.Y.,Calvet, C.M.,Vieira, D.F.,Gunatilleke, S.S.,Cameron, M.D.,Mckerrow, J.H.,Podust, L.M.,Roush, W.R.
R-Configuration of 4-Aminopyridyl-Based Inhibitors of Cyp51 Confers Superior Efficacy Against Trypanosoma Cruzi
Acs Med.Chem.Lett., 5:434-, 2014

PubMed Abstract: Sterol 14α-demethylase (CYP51) is an important therapeutic target for fungal and parasitic infections due to its key role in the biosynthesis of ergosterol, an essential component of the cell membranes of these pathogenic organisms. We report the development of potent and selective d-tryptophan-derived inhibitors of T. cruzi CYP51. Structural information obtained from the cocrystal structure of CYP51 and (R)-2, which is >1000-fold more potent than its enantiomer (S)-1, was used to guide design of additional analogues. The in vitro efficacy data presented here for (R)-2-(R)-8, together with preliminary in vitro pharmacokinetic data suggest that this new CYP51 inhibitor scaffold series has potential to deliver drug candidates for treatment of T. cruzi infections.

PubMed: 24900854
DOI: 10.1021/ML500010M

実験手法

X-RAY DIFFRACTION (3.1 Å)