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

Summary for 4BY0

• Entry DOI: 10.2210/pdb4by0/pdb
• Descriptor: 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)
• Functional Keywords: oxidoreductase, sterol 14-demethylase, sterol biosynthesis, chagas disease
• Biological source: TRYPANOSOMA CRUZI
• Total number of polymer chains: 2
• Total formula weight: 108799.63

Authors

Choi, J.Y.,Calvet, C.M.,Vierira, D.F.,Gunatilleke, S.S.,Cameron, M.D.,McKerrow, J.H.,Podust, L.M.,Roush, W.R. (deposition date: 2013-07-16, release date: 2014-01-22, Last modification date: 2023-12-20)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (3.1 Å)