4wq6
From Proteopedia
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| - | ''' | + | ==The crystal structure of human Nicotinamide phosphoribosyltransferase (NAMPT) in complex with N-(4-{(S)-[1-(2-methylpropyl)piperidin-4-yl]sulfinyl}benzyl)furo[2,3-c]pyridine-2-carboxamide inhibitor (compound 21)== |
| + | <StructureSection load='4wq6' size='340' side='right' caption='[[4wq6]], [[Resolution|resolution]] 1.72Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[4wq6]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4WQ6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4WQ6 FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3TQ:N-(4-{(S)-[1-(2-METHYLPROPYL)PIPERIDIN-4-YL]SULFINYL}BENZYL)FURO[2,3-C]PYRIDINE-2-CARBOXAMIDE'>3TQ</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></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=4wq6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4wq6 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4wq6 RCSB], [http://www.ebi.ac.uk/pdbsum/4wq6 PDBsum]</span></td></tr> | ||
| + | </table> | ||
| + | == 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). | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Herein we report the optimization efforts to ameliorate the potent CYP3A4 time-dependent inhibition (TDI) and low aqueous solubility exhibited by a previously identified lead compound from our NAMPT inhibitor program (1, GNE-617). Metabolite identification studies pinpointed the imidazopyridine moiety present in 1 as the likely source of the TDI signal, and replacement with other bicyclic systems was found to reduce or eliminate the TDI finding. A strategy of reducing the number of aromatic rings and/or lowering cLogD7.4 was then employed to significantly improve aqueous solubility. These efforts culminated in the discovery of 42, a compound with no evidence of TDI, improved aqueous solubility, and robust efficacy in tumor xenograft studies. | ||
| - | + | Identification of nicotinamide phosphoribosyltransferase (NAMPT) inhibitors with no evidence of CYP3A4 time-dependent inhibition and improved aqueous solubility.,Zak M, Liederer BM, Sampath D, Yuen PW, Bair KW, Baumeister T, Buckmelter AJ, Clodfelter KH, Cheng E, Crocker L, Fu B, Han B, Li G, Ho YC, Lin J, Liu X, Ly J, O'Brien T, Reynolds DJ, Skelton N, Smith CC, Tay S, Wang W, Wang Z, Xiao Y, Zhang L, Zhao G, Zheng X, Dragovich PS Bioorg Med Chem Lett. 2015 Feb 1;25(3):529-41. doi: 10.1016/j.bmcl.2014.12.026., Epub 2014 Dec 17. PMID:25556090<ref>PMID:25556090</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| - | + | == References == | |
| - | [[Category: | + | <references/> |
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Nicotinamide phosphoribosyltransferase]] | ||
[[Category: Li, D]] | [[Category: Li, D]] | ||
[[Category: Wang, W]] | [[Category: Wang, W]] | ||
| + | [[Category: Transferase-transferase inhibitor complex]] | ||
Revision as of 11:45, 12 February 2015
The crystal structure of human Nicotinamide phosphoribosyltransferase (NAMPT) in complex with N-(4-{(S)-[1-(2-methylpropyl)piperidin-4-yl]sulfinyl}benzyl)furo[2,3-c]pyridine-2-carboxamide inhibitor (compound 21)
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