4UVR: Binding Mode, Selectivity And Potency Of N-indolyl- Oxopyridinyl-4-amino-propanyl-based Inhibitors Targeting Trypanosoma Cruzi Cyp51

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: 4UVRDownload
MMDB ID: 125120
PDB Deposition Date: 2014/8/8
Updated in MMDB: 2014/11
Experimental Method:
x-ray diffraction
Resolution: 2.48  Å
Source Organism:
Similar Structures:
Biological Unit for 4UVR: dimeric; determined by author and by software (PISA)
Molecular Components in 4UVR
Label Count Molecule
Proteins (2 molecules)
Sterol 14-demethylase, Cyp51
Molecule annotation
Chemicals (11 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB