4jr5
From Proteopedia
(Difference between revisions)
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4jr5]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4JR5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4JR5 FirstGlance]. <br> | <table><tr><td colspan='2'>[[4jr5]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4JR5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4JR5 FirstGlance]. <br> | ||
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1LS:1-[4-(PIPERIDIN-1-YLSULFONYL)PHENYL]-3-(PYRIDIN-3-YLMETHYL)THIOUREA'>1LS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.906Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1LS:1-[4-(PIPERIDIN-1-YLSULFONYL)PHENYL]-3-(PYRIDIN-3-YLMETHYL)THIOUREA'>1LS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4jr5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jr5 OCA], [https://pdbe.org/4jr5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4jr5 RCSB], [https://www.ebi.ac.uk/pdbsum/4jr5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4jr5 ProSAT]</span></td></tr> | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4jr5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jr5 OCA], [https://pdbe.org/4jr5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4jr5 RCSB], [https://www.ebi.ac.uk/pdbsum/4jr5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4jr5 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
[https://www.uniprot.org/uniprot/NAMPT_HUMAN NAMPT_HUMAN] Catalyzes the condensation of nicotinamide with 5-phosphoribosyl-1-pyrophosphate to yield nicotinamide mononucleotide, an intermediate in the biosynthesis of NAD. It is the rate limiting component in the mammalian NAD biosynthesis pathway (By similarity). | [https://www.uniprot.org/uniprot/NAMPT_HUMAN NAMPT_HUMAN] Catalyzes the condensation of nicotinamide with 5-phosphoribosyl-1-pyrophosphate to yield nicotinamide mononucleotide, an intermediate in the biosynthesis of NAD. It is the rate limiting component in the mammalian NAD biosynthesis pathway (By similarity). | ||
| - | <div style="background-color:#fffaf0;"> | ||
| - | == Publication Abstract from PubMed == | ||
| - | Nicotinamide phosphoribosyltransferase (Nampt) is a promising anticancer target. Virtual screening identified a thiourea analog, compound 5, as a novel highly potent Nampt inhibitor. Guided by the co-crystal structure of 5, SAR exploration revealed that the corresponding urea compound 7 exhibited similar potency with an improved solubility profile. These studies also indicated that a 3-pyridyl group was the preferred substituent at one inhibitor terminus and also identified a urea moiety as the optimal linker to the remainder of the inhibitor structure. Further SAR optimization of the other inhibitor terminus ultimately yielded compound 50 as a urea-containing Nampt inhibitor which exhibited excellent biochemical and cellular potency (enzyme IC50 = 0.007 uM; A2780 IC50 = 0.032 uM). Compound 50 also showed excellent in vivo antitumor efficacy when dosed orally in an A2780 ovarian tumor xenograft model (TGI of 97% was observed on day 17). | ||
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| - | Structure-based Identification of Novel Nicotinamide Phosphoribosyltransferase (Nampt) Inhibitors.,Zheng X, Bauer P, Baumeister T, Buckmelter AJ, Caligiuri M, Clodfelter KH, Han B, Ho YC, Kley N, Lin J, Reynolds DJ, Sharma G, Smith CC, Wang Z, Dragovich PS, Oh A, Wang W, Zak M, Gunzner-Toste J, Zhao G, Yuen PW, Bair KW J Med Chem. 2013 Apr 25. PMID:23617784<ref>PMID:23617784</ref> | ||
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| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| - | </div> | ||
| - | <div class="pdbe-citations 4jr5" style="background-color:#fffaf0;"></div> | ||
==See Also== | ==See Also== | ||
*[[Phosphoribosyltransferase 3D structures|Phosphoribosyltransferase 3D structures]] | *[[Phosphoribosyltransferase 3D structures|Phosphoribosyltransferase 3D structures]] | ||
| - | == References == | ||
| - | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
Current revision
Structure-based Identification of Ureas as Novel Nicotinamide Phosphoribosyltransferase (Nampt) Inhibitors
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Categories: Homo sapiens | Large Structures | Bair KW | Bauer P | Baumeister T | Buckmelter AJ | Caligiuri M | Clodfelter KH | Dragovich PS | Gunzner-Toste J | Han B | Ho Y | Kley N | Lin J | Oh A | Reynolds DJ | Sharma G | Smith CC | Wang W | Wang Z | Yuen P | Zak M | Zhao G | Zheng X
