4C0C

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)-4-(4-(2,4-difluorophenyl)piperazin-1-yl)-2-fluorobenzamide.

Summary for 4C0C

• Entry DOI: 10.2210/pdb4c0c/pdb
• Related: 4BMM 4UQH
• Descriptor: STEROL 14-ALPHA DEMETHYLASE, PROTOPORPHYRIN IX CONTAINING FE, 4-[4-[2,4-bis(fluoranyl)phenyl]piperazin-1-yl]-2-fluoranyl-N-[(2R)-3-(1H-indol-3-yl)-1-oxidanylidene-1-(pyridin-4-ylamino)propan-2-yl]benzamide, ... (6 entities in total)
• Functional Keywords: oxidoreductase, sterol biosynthesis, chagas disease
• Biological source: TRYPANOSOMA CRUZI
• Total number of polymer chains: 1
• Total formula weight: 55934.93

Authors

Calvet, C.M.,Vieira, D.F.,Choi, J.Y.,Cameron, M.D.,Gut, J.,Kellar, D.,Siqueira-Neto, J.L.,McKerrow, J.H.,Roush, W.R.,Podust, L.M. (deposition date: 2013-08-01, release date: 2014-08-20, Last modification date: 2023-12-20)

Primary citation

Calvet, C.M.,Vieira, D.F.,Choi, J.Y.,Kellar, D.,Cameron, M.D.,Siqueira-Neto, J.L.,Gut, J.,Johnston, J.B.,Lin, L.,Khan, S.,Mckerrow, J.H.,Roush, W.R.,Podust, L.M.
4-Aminopyridyl-Based Cyp51 Inhibitors as Anti-Trypanosoma Cruzi Drug Leads with Improved Pharmacokinetic Profile and in Vivo Potency.
J.Med.Chem., 57:6989-, 2014

PubMed Abstract: CYP51 is a P450 enzyme involved in the biosynthesis of the sterol components of eukaryotic cell membranes. CYP51 inhibitors have been developed to treat infections caused by fungi, and more recently the protozoan parasite Trypanosoma cruzi, the causative agent of Chagas disease. To specifically optimize drug candidates for T. cruzi CYP51 (TcCYP51), we explored the structure-activity relationship (SAR) of a N-indolyl-oxopyridinyl-4-aminopropanyl-based scaffold originally identified in a target-based screen. This scaffold evolved via medicinal chemistry to yield orally bioavailable leads with potent anti-T. cruzi activity in vivo. Using an animal model of infection with a transgenic T. cruzi Y luc strain expressing firefly luciferase, we prioritized the biaryl and N-arylpiperazine analogues by oral bioavailability and potency. The drug-target complexes for both scaffold variants were characterized by X-ray structure analysis. Optimization of both binding mode and pharmacokinetic properties of these compounds led to potent inhibitors against experimental T. cruzi infection.

PubMed: 25101801
DOI: 10.1021/JM500448U

Experimental method

X-RAY DIFFRACTION (2.04 Å)