4c0c

From Proteopedia

(Difference between revisions)

Revision as of 22:03, 4 August 2016

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.

Structural highlights

4c0c is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , ,
Related:	4bmm, 4uqh
Activity:	Sterol 14-demethylase, with EC number 1.14.13.70
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[CP51_TRYCC] Catalyzes C14-demethylation of lanosterol which is critical for ergosterol biosynthesis. It transforms lanosterol into 4,4'-dimethyl cholesta-8,14,24-triene-3-beta-ol (By similarity). Favors C4 dimethylated substrates, the substrate preference order is 24-methylenedihydrolanosterol > 24,25-dihydrolanosterol > lanosterol > obtusifoliol > norlanosterol.^[1] [UniProtKB:P0A512]

Publication Abstract from PubMed

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.

4-Aminopyridyl-Based CYP51 Inhibitors as Anti-Trypanosoma cruzi Drug Leads with Improved Pharmacokinetic Profile and in Vivo Potency.,Calvet CM, Vieira DF, Choi JY, Kellar D, Cameron MD, Siqueira-Neto JL, Gut J, Johnston JB, Lin L, Khan S, McKerrow JH, Roush WR, Podust LM J Med Chem. 2014 Aug 19. PMID:25101801^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Lepesheva GI, Zaitseva NG, Nes WD, Zhou W, Arase M, Liu J, Hill GC, Waterman MR. CYP51 from Trypanosoma cruzi: a phyla-specific residue in the B' helix defines substrate preferences of sterol 14alpha-demethylase. J Biol Chem. 2006 Feb 10;281(6):3577-85. Epub 2005 Nov 30. PMID:16321980 doi:M510317200
↑ Calvet CM, Vieira DF, Choi JY, Kellar D, Cameron MD, Siqueira-Neto JL, Gut J, Johnston JB, Lin L, Khan S, McKerrow JH, Roush WR, Podust LM. 4-Aminopyridyl-Based CYP51 Inhibitors as Anti-Trypanosoma cruzi Drug Leads with Improved Pharmacokinetic Profile and in Vivo Potency. J Med Chem. 2014 Aug 19. PMID:25101801 doi:http://dx.doi.org/10.1021/jm500448u

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4c0c"

@@ Line 1: / Line 1: @@
 ==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.==
 <StructureSection load='4c0c' size='340' side='right' caption='[[4c0c]], [[Resolution|resolution]] 2.04&Aring;' scene=''>
@@ Line 6: / Line 7: @@
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4bmm|4bmm]], [[4uqh|4uqh]]</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 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=4c0c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4c0c OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4c0c RCSB], [http://www.ebi.ac.uk/pdbsum/4c0c 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=4c0c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4c0c OCA], [http://pdbe.org/4c0c PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4c0c RCSB], [http://www.ebi.ac.uk/pdbsum/4c0c PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4c0c ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 18: / Line 19: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4c0c" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>

4c0c

From Proteopedia

Revision as of 22:03, 4 August 2016

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.

Structural highlights

Function

Publication Abstract from PubMed

References

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