Identification and validation of small molecule modulators of the NusB-NusE interaction

Peter J. Cossar, Cong Ma, Christopher P. Gordon, Joseph I. Ambrus, Peter J. Lewis, Adam McCluskey

Research output: Journal article publicationJournal articleAcademic researchpeer-review

6 Citations (Scopus)

Abstract

� 2016 Formation of highly possessive antitermination complexes is crucial for the efficient transcription of stable RNA in all bacteria. A key step in the formation of these complexes is the protein-protein interaction (PPI) between N-utilisation substances (Nus) B and E and thus this PPI offers a novel target for a new antibiotic class. A pharmacophore developed via a secondary structure epitope approach was utilised to perform an in silico screen of the mini-Maybridge library (56,000 compounds) which identified 25 hits of which five compounds were synthetically tractable leads. Here we report the synthesis of these five leads and their biological evaluation as potential inhibitors of the NusB-NusE PPI. Two chemically diverse scaffolds were identified to be low micro molar potent PPI inhibitors, with compound (4,6-bis(2′,4′,3.4 tetramethoxyphenyl))pyrimidine-2-sulphonamido-N-4-acetamide 1 and N,N′-[1,4-butanediylbis(oxy-4,1-phenylene)]bis(N-ethyl)urea 3 exhibiting IC50values of 6.1�μM and 19.8�μM, respectively. These inhibitors were also shown to be moderate inhibitors of Gram-positive Bacillus subtilis and Gram-negative Escherichia coli growth.
Original languageEnglish
Pages (from-to)162-167
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume27
Issue number2
DOIs
Publication statusPublished - 1 Jan 2017

Keywords

  • Antibiotic
  • In silico screening
  • NusB-NusE
  • Pharmacophore
  • Protein-protein interaction

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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