View source for 4ufz


==Synthesis of Novel NAD Dependant DNA Ligase Inhibitors via Negishi Cross-Coupling: Development of SAR and Resistance Studies==
<StructureSection load='4ufz' size='340' side='right'caption='[[4ufz]], [[Resolution|resolution]] 2.33&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4ufz]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Haemophilus_influenzae Haemophilus influenzae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4UFZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4UFZ FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.33&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=IA7:5,7-BIS(AZANYL)-2-TERT-BUTYL-4-(1,3-THIAZOL-2-YL)PYRIDO[2,3-D]PYRIMIDINE-6-CARBONITRILE'>IA7</scene>, <scene name='pdbligand=IWH:1-(2,4-DIMETHYLBENZYL)-6-OXO-1,6-DIHYDROPYRIDINE-3-CARBOXAMIDE'>IWH</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=4ufz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ufz OCA], [https://pdbe.org/4ufz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ufz RCSB], [https://www.ebi.ac.uk/pdbsum/4ufz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ufz ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/DNLJ_HAEIN 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).
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== 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<ref>PMID:26463129</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 4ufz" style="background-color:#fffaf0;"></div>

==See Also==
*[[DNA ligase 3D structures|DNA ligase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Haemophilus influenzae]]
[[Category: Large Structures]]
[[Category: Boriack-Sjodin PA]]
[[Category: Carcanague D]]
[[Category: Gingipali L]]
[[Category: Gowravaram M]]
[[Category: Hale M]]
[[Category: Harang J]]
[[Category: Ioannidis G]]
[[Category: Jahic H]]
[[Category: Johnstone M]]
[[Category: Kutschke A]]
[[Category: Laganas VA]]
[[Category: Loch J]]
[[Category: Martinez-Botella G]]
[[Category: Murphy-Benenato KE]]
[[Category: Oguto H]]
[[Category: Patel SJ]]