4wq6 | pdb_00004wq6

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)

spinqualitylabelsall models 4wq6, resolution 1.72Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4wq6 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 1.72Å Ligands: 3TQ, EDO, PO4 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). 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Glycosyltransferase 3D structures Phosphoribosyltransferase 3D structures

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