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==Fragment-based Design of 3-Aminopyridine-derived Amides as Potent Inhibitors of Human Nicotinamide Phosphoribosyltransferase (NAMPT)== | ==Fragment-based Design of 3-Aminopyridine-derived Amides as Potent Inhibitors of Human Nicotinamide Phosphoribosyltransferase (NAMPT)== | ||
<StructureSection load='4n9d' size='340' side='right' caption='[[4n9d]], [[Resolution|resolution]] 1.70Å' scene=''> | <StructureSection load='4n9d' size='340' side='right'caption='[[4n9d]], [[Resolution|resolution]] 1.70Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4n9d]] is a 2 chain structure with sequence from [ | <table><tr><td colspan='2'>[[4n9d]] 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=4N9D OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4N9D FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2HJ:4-({[(4-TERT-BUTYLPHENYL)SULFONYL]AMINO}METHYL)-N-(PYRIDIN-3-YL)BENZAMIDE'>2HJ</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2HJ:4-({[(4-TERT-BUTYLPHENYL)SULFONYL]AMINO}METHYL)-N-(PYRIDIN-3-YL)BENZAMIDE'>2HJ</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=4n9d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4n9d OCA], [https://pdbe.org/4n9d PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4n9d RCSB], [https://www.ebi.ac.uk/pdbsum/4n9d PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4n9d ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</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). | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
| Line 23: | Line 20: | ||
==See Also== | ==See Also== | ||
*[[Phosphoribosyltransferase|Phosphoribosyltransferase]] | *[[Phosphoribosyltransferase 3D structures|Phosphoribosyltransferase 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Baumeister | [[Category: Baumeister T]] | ||
[[Category: Bravo | [[Category: Bravo B]] | ||
[[Category: Dragovich PS]] | |||
[[Category: Dragovich | [[Category: Giannetti AM]] | ||
[[Category: Giannetti | [[Category: Ho Y]] | ||
[[Category: Ho | [[Category: Hua R]] | ||
[[Category: Hua | [[Category: Li G]] | ||
[[Category: Li | [[Category: Liang X]] | ||
[[Category: Liang | [[Category: O'Brien T]] | ||
[[Category: Oh | [[Category: Oh A]] | ||
[[Category: Skelton | [[Category: Skelton NJ]] | ||
[[Category: Wang | [[Category: Wang C]] | ||
[[Category: Wang | [[Category: Wang W]] | ||
[[Category: Wang | [[Category: Wang Y]] | ||
[[Category: Xiao | [[Category: Xiao Y]] | ||
[[Category: Yuen | [[Category: Yuen P]] | ||
[[Category: Zak | [[Category: Zak M]] | ||
[[Category: Zhao | [[Category: Zhao G]] | ||
[[Category: Zhao | [[Category: Zhao Q]] | ||
[[Category: Zheng | [[Category: Zheng X]] | ||
Revision as of 11:15, 11 January 2023
Fragment-based Design of 3-Aminopyridine-derived Amides as Potent Inhibitors of Human Nicotinamide Phosphoribosyltransferase (NAMPT)Fragment-based Design of 3-Aminopyridine-derived Amides as Potent Inhibitors of Human Nicotinamide Phosphoribosyltransferase (NAMPT)
Structural highlights
FunctionNAMPT_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). Publication Abstract from PubMedThe fragment-based identification of two novel and potent biochemical inhibitors of the nicotinamide phosphoribosyltransferase (NAMPT) enzyme is described. These compounds (51 and 63) incorporate an amide moiety derived from 3-aminopyridine, and are thus structurally distinct from other known anti-NAMPT agents. Each exhibits potent inhibition of NAMPT biochemical activity (IC50=19 and 15nM, respectively) as well as robust antiproliferative properties in A2780 cell culture experiments (IC50=121 and 99nM, respectively). However, additional biological studies indicate that only inhibitor 51 exerts its A2780 cell culture effects via a NAMPT-mediated mechanism. The crystal structures of both 51 and 63 in complex with NAMPT are also independently described. Fragment-based design of 3-aminopyridine-derived amides as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT).,Dragovich PS, Zhao G, Baumeister T, Bravo B, Giannetti AM, Ho YC, Hua R, Li G, Liang X, Ma X, O'Brien T, Oh A, Skelton NJ, Wang C, Wang W, Wang Y, Xiao Y, Yuen PW, Zak M, Zhao Q, Zheng X Bioorg Med Chem Lett. 2014 Feb 1;24(3):954-62. doi: 10.1016/j.bmcl.2013.12.062., Epub 2013 Dec 21. PMID:24433859[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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