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==Fragment-based Identification of Amides Derived From trans-2-(Pyridin-3-yl)cyclopropanecarboxylic Acid as Potent Inhibitors of Human Nicotinamide Phosphoribosyltransferase (NAMPT)==
==Fragment-based Identification of Amides Derived From trans-2-(Pyridin-3-yl)cyclopropanecarboxylic Acid as Potent Inhibitors of Human Nicotinamide Phosphoribosyltransferase (NAMPT)==
<StructureSection load='4lva' size='340' side='right' caption='[[4lva]], [[Resolution|resolution]] 1.55&Aring;' scene=''>
<StructureSection load='4lva' size='340' side='right'caption='[[4lva]], [[Resolution|resolution]] 1.55&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4lva]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4LVA OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4LVA FirstGlance]. <br>
<table><tr><td colspan='2'>[[4lva]] 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=4LVA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4LVA FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=20M:N-(4-{[4-(PYRROLIDIN-1-YL)PIPERIDIN-1-YL]SULFONYL}BENZYL)-2H-PYRIDO[4,3-E][1,2,4]THIADIAZIN-3-AMINE+1,1-DIOXIDE'>20M</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]] 1.55&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4lv9|4lv9]], [[4lvb|4lvb]], [[4lvd|4lvd]], [[4lvf|4lvf]], [[4lvg|4lvg]], [[4m6p|4m6p]], [[4m6q|4m6q]]</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=20M:N-(4-{[4-(PYRROLIDIN-1-YL)PIPERIDIN-1-YL]SULFONYL}BENZYL)-2H-PYRIDO[4,3-E][1,2,4]THIADIAZIN-3-AMINE+1,1-DIOXIDE'>20M</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NAMPT, PBEF, PBEF1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4lva FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4lva OCA], [https://pdbe.org/4lva PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4lva RCSB], [https://www.ebi.ac.uk/pdbsum/4lva PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4lva ProSAT]</span></td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Nicotinamide_phosphoribosyltransferase Nicotinamide phosphoribosyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.4.2.12 2.4.2.12] </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=4lva FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4lva OCA], [http://pdbe.org/4lva PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4lva RCSB], [http://www.ebi.ac.uk/pdbsum/4lva PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4lva ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[http://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 ==
Potent, 1H-pyrazolo[3,4-b]pyridine-containing inhibitors of the human nicotinamide phosphoribosyltransferase (NAMPT) enzyme were identified using structure-based design techniques. Many of these compounds exhibited nanomolar antiproliferation activities against human tumor lines in in vitro cell culture experiments, and a representative example (compound 26) demonstrated encouraging in vivo efficacy in a mouse xenograft tumor model derived from the A2780 cell line. This molecule also exhibited reduced rat retinal exposures relative to a previously studied imidazo-pyridine-containing NAMPT inhibitor. Somewhat surprisingly, compound 26 was only weakly active in vitro against mouse and monkey tumor cell lines even though it was a potent inhibitor of NAMPT enzymes derived from these species. The compound also exhibited only minimal effects on in vivo NAD levels in mice, and these changes were considerably less profound than those produced by an imidazo-pyridine-containing NAMPT inhibitor. The crystal structures of compound 26 and the corresponding PRPP-derived ribose adduct in complex with NAMPT were also obtained.
 
Identification of amides derived from 1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT).,Zheng X, Bair KW, Bauer P, Baumeister T, Bowman KK, Buckmelter AJ, Caligiuri M, Clodfelter KH, Feng Y, Han B, Ho YC, Kley N, Li H, Liang X, Liederer BM, Lin J, Ly J, O'Brien T, Oeh J, Oh A, Reynolds DJ, Sampath D, Sharma G, Skelton N, Smith CC, Tremayne J, Wang L, Wang W, Wang Z, Wu H, Wu J, Xiao Y, Yang G, Yuen PW, Zak M, Dragovich PS Bioorg Med Chem Lett. 2013 Oct 15;23(20):5488-97. doi:, 10.1016/j.bmcl.2013.08.074. Epub 2013 Aug 22. PMID:24021463<ref>PMID:24021463</ref>
 
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4lva" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==
*[[Phosphoribosyltransferase|Phosphoribosyltransferase]]
*[[Phosphoribosyltransferase 3D structures|Phosphoribosyltransferase 3D structures]]
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Homo sapiens]]
[[Category: Nicotinamide phosphoribosyltransferase]]
[[Category: Large Structures]]
[[Category: Bravo, B]]
[[Category: Bravo B]]
[[Category: Brien, T O]]
[[Category: Dragovich PS]]
[[Category: Dragovich, P S]]
[[Category: Feng Y]]
[[Category: Feng, Y]]
[[Category: Giannetti AM]]
[[Category: Giannetti, A M]]
[[Category: Gunzner-Toste J]]
[[Category: Gunzner-Toste, J]]
[[Category: Ho Y]]
[[Category: Ho, Y]]
[[Category: Hua R]]
[[Category: Hua, R]]
[[Category: Liederer BM]]
[[Category: Liederer, B M]]
[[Category: Liu Y]]
[[Category: Liu, Y]]
[[Category: O'Brien T]]
[[Category: Oeh, J]]
[[Category: Oeh J]]
[[Category: Sampath, D]]
[[Category: Sampath D]]
[[Category: Shen, Y]]
[[Category: Shen Y]]
[[Category: Skelton, N]]
[[Category: Skelton N]]
[[Category: Wang, C]]
[[Category: Wang C]]
[[Category: Wang, L]]
[[Category: Wang L]]
[[Category: Wang, W]]
[[Category: Wang W]]
[[Category: Wu, H]]
[[Category: Wu H]]
[[Category: Xiao, Y]]
[[Category: Xiao Y]]
[[Category: Yuen, P]]
[[Category: Yuen P]]
[[Category: Zak, M]]
[[Category: Zak M]]
[[Category: Zhao, G]]
[[Category: Zhao G]]
[[Category: Zhao, Q]]
[[Category: Zhao Q]]
[[Category: Zheng, X]]
[[Category: Zheng X]]
[[Category: Transferase]]
[[Category: Transferase-transferase inhibitor complex]]

Latest revision as of 15:21, 1 March 2024

Fragment-based Identification of Amides Derived From trans-2-(Pyridin-3-yl)cyclopropanecarboxylic Acid as Potent Inhibitors of Human Nicotinamide Phosphoribosyltransferase (NAMPT)Fragment-based Identification of Amides Derived From trans-2-(Pyridin-3-yl)cyclopropanecarboxylic Acid as Potent Inhibitors of Human Nicotinamide Phosphoribosyltransferase (NAMPT)

Structural highlights

4lva is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.55Å
Ligands:, ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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).

See Also

4lva, resolution 1.55Å

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