4c27
From Proteopedia
(Difference between revisions)
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4c27]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4C27 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4C27 FirstGlance]. <br> | <table><tr><td colspan='2'>[[4c27]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4C27 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4C27 FirstGlance]. <br> | ||
| - | </td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=26N:NALPHA-(2-FLUORO-4-{4-[4-(TRIFLUOROMETHYL)PHENYL]PIPERAZIN-1-YL}BENZOYL)-N-PYRIDIN-4-YL-D-TRYPTOPHANAMIDE'>26N</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>< | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=26N:NALPHA-(2-FLUORO-4-{4-[4-(TRIFLUOROMETHYL)PHENYL]PIPERAZIN-1-YL}BENZOYL)-N-PYRIDIN-4-YL-D-TRYPTOPHANAMIDE'>26N</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene></td></tr> |
| - | <tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4c28|4c28]]</td></tr> | + | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4c28|4c28]]</td></tr> |
| - | <tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Sterol_14-demethylase Sterol 14-demethylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.13.70 1.14.13.70] </span></td></tr> | + | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Sterol_14-demethylase Sterol 14-demethylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.13.70 1.14.13.70] </span></td></tr> |
| - | <tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4c27 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4c27 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4c27 RCSB], [http://www.ebi.ac.uk/pdbsum/4c27 PDBsum]</span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4c27 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4c27 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4c27 RCSB], [http://www.ebi.ac.uk/pdbsum/4c27 PDBsum]</span></td></tr> |
| - | <table> | + | </table> |
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | 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. | ||
| + | |||
| + | Binding Mode and Potency of N-Indolyloxopyridinyl-4-aminopropanyl-Based Inhibitors Targeting Trypanosoma cruzi CYP51.,Vieira DF, Choi JY, Calvet CM, Siqueira-Neto JL, Johnston JB, Kellar D, Gut J, Cameron MD, McKerrow JH, Roush WR, Podust LM J Med Chem. 2014 Nov 25. PMID:25393646<ref>PMID:25393646</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Sterol 14-demethylase]] | [[Category: Sterol 14-demethylase]] | ||
| - | [[Category: Calvet, C M | + | [[Category: Calvet, C M]] |
| - | [[Category: Cameron, M D | + | [[Category: Cameron, M D]] |
| - | [[Category: Choi, J Y | + | [[Category: Choi, J Y]] |
| - | [[Category: Gut, J | + | [[Category: Gut, J]] |
| - | [[Category: Kellar, D | + | [[Category: Kellar, D]] |
| - | [[Category: McKerrow, J H | + | [[Category: McKerrow, J H]] |
| - | [[Category: Podust, L M | + | [[Category: Podust, L M]] |
| - | [[Category: Roush, W R | + | [[Category: Roush, W R]] |
| - | [[Category: Siqueira-Neto, J L | + | [[Category: Siqueira-Neto, J L]] |
| - | [[Category: Vieira, D F | + | [[Category: Vieira, D F]] |
[[Category: Chagas disease]] | [[Category: Chagas disease]] | ||
[[Category: Oxidoreductase]] | [[Category: Oxidoreductase]] | ||
[[Category: Sterol biosynthesis]] | [[Category: Sterol biosynthesis]] | ||
Revision as of 05:48, 26 November 2014
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-fluoro-4-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)benzamide
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