4C28: 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-(4-chlorophenyl)piperazin-1-yl)- 2-fluorobenzamide

Citation:
Abstract
Chagas disease is a chronic infection in humans caused by Trypanosoma cruzi and manifested in progressive cardiomyopathy and/or gastrointestinal dysfunction. Limited therapeutic options to prevent and treat Chagas disease put 8 million people infected with T. cruzi worldwide at risk. CYP51, involved in the biosynthesis of the membrane sterol component in eukaryotes, is a promising drug target in T. cruzi. We report the structure-activity relationships (SAR) of an N-arylpiperazine series of N-indolyloxopyridinyl-4-aminopropanyl-based inhibitors designed to probe the impact of substituents in the terminal N-phenyl ring on binding mode, selectivity and potency. Depending on the substituents at C-4, two distinct ring binding modes, buried and solvent-exposed, have been observed by X-ray structure analysis (resolution of 1.95-2.48 A). The 5-chloro-substituted analogs 9 and 10 with no substituent at C-4 demonstrated improved selectivity and potency, suppressing >/=99.8% parasitemia in mice when administered orally at 25 mg/kg, b.i.d., for 4 days.
PDB ID: 4C28Download
MMDB ID: 122821
PDB Deposition Date: 2013/8/16
Updated in MMDB: 2014/11
Experimental Method:
x-ray diffraction
Resolution: 2.03  Å
Source Organism:
Similar Structures:
Biological Unit for 4C28: monomeric; determined by author and by software (PISA)
Molecular Components in 4C28
Label Count Molecule
Protein (1 molecule)
1
Sterol 14-alpha Demethylase(Gene symbol: Tc00.1047053506297.260)
Molecule annotation
Chemicals (4 molecules)
1
1
2
1
3
1
4
1
* Click molecule labels to explore molecular sequence information.

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