Bacterial Sliding Clamp Inhibitors that Mimic the Sequential Binding Mechanism of Endogenous Linear Motifs

Zhou Yin, Louise R. Whittell, Yao Wang, Slobodan Jergic, Cong Ma, Peter J. Lewis, Nicholas E. Dixon, Jennifer L. Beck, Michael J. Kelso, Aaron J. Oakley

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

The bacterial DNA replication machinery presents new targets for the development of antibiotics acting via novel mechanisms. One such target is the protein-protein interaction between the DNA sliding clamp and the conserved peptide linear motifs in DNA polymerases. We previously established that binding of linear motifs to the Escherichia coli sliding clamp occurs via a sequential mechanism that involves two subsites (I and II). Here, we report the development of small-molecule inhibitors that mimic this mechanism. The compounds contain tetrahydrocarbazole moieties as "anchors" to occupy subsite I. Functional groups appended at the tetrahydrocarbazole nitrogen bind to a channel gated by the side chain of M362 and lie at the edge of subsite II. One derivative induced the formation of a new binding pocket, termed subsite III, by rearrangement of a loop adjacent to subsite I. Discovery of the extended binding area will guide further inhibitor development. (Figure Presented).

Original languageEnglish (US)
Pages (from-to)4693-4702
Number of pages10
JournalJournal of medicinal chemistry
Volume58
Issue number11
DOIs
StatePublished - Jun 11 2015

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Yin, Z., Whittell, L. R., Wang, Y., Jergic, S., Ma, C., Lewis, P. J., Dixon, N. E., Beck, J. L., Kelso, M. J., & Oakley, A. J. (2015). Bacterial Sliding Clamp Inhibitors that Mimic the Sequential Binding Mechanism of Endogenous Linear Motifs. Journal of medicinal chemistry, 58(11), 4693-4702. https://doi.org/10.1021/acs.jmedchem.5b00232