4ufz | pdb_00004ufz

Synthesis of Novel NAD Dependant DNA Ligase Inhibitors via Negishi Cross-Coupling: Development of SAR and Resistance Studies

spinqualitylabelsall models 4ufz, resolution 2.33Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4ufz is a 1 chain structure with sequence from Haemophilus influenzae. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.33Å Ligands: IA7, IWH Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function DNLJ_HAEIN DNA ligase that catalyzes the formation of phosphodiester linkages between 5'-phosphoryl and 3'-hydroxyl groups in double-stranded DNA using NAD as a coenzyme and as the energy source for the reaction. It is essential for DNA replication and repair of damaged DNA (By similarity). Publication Abstract from PubMed Two novel compounds, pyridopyrimidines (1) and naphthyridines (2) were identified as potent inhibitors of bacterial NAD(+)-dependent DNA ligase (Lig) A in a fragment screening. SAR was guided by molecular modeling and X-ray crystallography. It was observed that the diaminonitrile pharmacophore made a key interaction with the ligase enzyme, specifically residues Glu114, Lys291, and Leu117. Synthetic challenges limited opportunities for diversification of the naphthyridine core, therefore most of the SAR was focused on a pyridopyrimidine scaffold. The initial diversification at R(1) improved both enzyme and cell potency. Further SAR developed at the R(2) position using the Negishi cross-coupling reaction provided several compounds, among these compounds 22g showed good enzyme potency and cellular potency. Negishi cross-coupling enabled synthesis of novel NAD(+)-dependent DNA ligase inhibitors and SAR development.,Murphy-Benenato KE, Gingipalli L, Boriack-Sjodin PA, Martinez-Botella G, Carcanague D, Eyermann CJ, Gowravaram M, Harang J, Hale MR, Ioannidis G, Jahic H, Johnstone M, Kutschke A, Laganas VA, Loch JT 3rd, Miller MD, Oguto H, Patel SJ Bioorg Med Chem Lett. 2015 Nov 15;25(22):5172-7. doi: 10.1016/j.bmcl.2015.09.075., Epub 2015 Oct 14. PMID:26463129 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also DNA ligase 3D structures

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