Download MendeleyIdentification through structure-based methods of a bacterial NAD(+)-dependent DNA ligase inhibitor that avoids known resistance mutations.
Murphy-Benenato, K., Wang, H., McGuire, H.M., Davis, H.E., Gao, N., Prince, D.B., Jahic, H., Stokes, S.S., Boriack-Sjodin, P.A.(2014) Bioorg Med Chem Lett 24: 360-366
- PubMed: 24287382
- DOI: https://doi.org/10.1016/j.bmcl.2013.11.007
- Primary Citation of Related Structures:
4LH6, 4LH7 - PubMed Abstract:
In an attempt to identify novel inhibitors of NAD(+)-dependent DNA ligase (LigA) that are not affected by a known resistance mutation in the adenosine binding pocket, a detailed analysis of the binding sites of a variety of bacterial ligases was performed. This analysis revealed several similarities to the adenine binding region of kinases, which enabled a virtual screen of known kinase inhibitors. From this screen, a thienopyridine scaffold was identified that was shown to inhibit bacterial ligase. Further characterization through structure and enzymology revealed the compound was not affected by a previously disclosed resistance mutation in Streptococcus pneumoniae LigA, Leu75Phe. A subsequent medicinal chemistry program identified substitutions that resulted in an inhibitor with moderate activity across various Gram-positive bacterial LigA enzymes.
Organizational Affiliation:
Department of Chemistry, Infection Innovative Medicines, AstraZeneca R&D Boston, 35 Gatehouse Dr., Waltham, MA 02451, United States. Electronic address: kerry.benenato@astrazeneca.com.
