SNAP output for PDB entry 4glx [SNAP web server]

PDB-id

4glx; SNAP-derived features in text and JSON formats; DNAproDB

Class

ligase-ligase inhibitor-DNA

Method

X-ray (1.9 Å)

Summary

DNA ligase a in complex with inhibitor

Reference

Surivet JP, Lange R, Hubschwerlen C, Keck W, Specklin JL, Ritz D, Bur D, Locher H, Seiler P, Strasser DS, Prade L, Kohl C, Schmitt C, Chapoux G, Ilhan E, Ekambaram N, Athanasiou A, Knezevic A, Sabato D, Chambovey A, Gaertner M, Enderlin M, Boehme M, Sippel V, Wyss P (2012): "Structure-guided design, synthesis and biological evaluation of novel DNA ligase inhibitors with in vitro and in vivo anti-staphylococcal activity." Bioorg.Med.Chem.Lett., 22, 6705-6711. doi: 10.1016/j.bmcl.2012.08.094.

Abstract

A series of 2-amino-[1,8]-naphthyridine-3-carboxamides (ANCs) with potent inhibition of bacterial NAD(+)-dependent DNA ligases (LigAs) evolved from a 2,4-diaminopteridine derivative discovered by HTS. The design was guided by several highly resolved X-ray structures of our inhibitors in complex with either Streptococcus pneumoniae or Escherichia coli LigA. The structure-activity-relationship based on the ANC scaffold is discussed. The in-depth characterization of 2-amino-6-bromo-7-(trifluoromethyl)-[1,8]-naphthyridine-3-carboxamide, which displayed promising in vitro (MIC Staphylococcus aureus 1 mg/L) and in vivo anti-staphylococcal activity, is presented.