4BMM: 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)- 2',3,5'-trifluoro-(1,1'-biphenyl)-4-carboxamide

Citation:
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.
PDB ID: 4BMMDownload
MMDB ID: 120565
PDB Deposition Date: 2013/5/9
Updated in MMDB: 2014/09
Experimental Method:
x-ray diffraction
Resolution: 2.84  Å
Source Organism:
Similar Structures:
Biological Unit for 4BMM: dimeric; determined by author and by software (PISA)
Molecular Components in 4BMM
Label Count Molecule
Proteins (2 molecules)
2
Sterol 14-alpha Demethylase(Gene symbol: Tc00.1047053506297.260)
Molecule annotation
Chemicals (4 molecules)
1
2
2
2
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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