Pyrrolopyrimidine inhibitors of DNA gyrase B (GyrB) and topoisomerase IV (ParE). Part I: Structure guided discovery and optimization of dual targeting agents with potent, broad-spectrum enzymatic activity

Leslie W. Tari, Michael Trzoss, Daniel C. Bensen, Xiaoming Li, Zhiyong Chen, Thanh Lam, Junhu Zhang, Christopher J. Creighton, Mark L. Cunningham, Bryan Kwan, Mark Stidham, Karen J. Shaw, Felice C Lightstone, Sergio E. Wong, Toan B. Nguyen, Jay Nix, John Finn

Research output: Contribution to journalArticle

62 Citations (Scopus)

Abstract

The bacterial topoisomerases DNA gyrase (GyrB) and topoisomerase IV (ParE) are essential enzymes that control the topological state of DNA during replication. The high degree of conservation in the ATP-binding pockets of these enzymes make them appealing targets for broad-spectrum inhibitor development. A pyrrolopyrimidine scaffold was identified from a pharmacophore-based fragment screen with optimization potential. Structural characterization of inhibitor complexes conducted using selected GyrB/ParE orthologs aided in the identification of important steric, dynamic and compositional differences in the ATP-binding pockets of the targets, enabling the design of highly potent pyrrolopyrimidine inhibitors with broad enzymatic spectrum and dual targeting activity.

Original languageEnglish (US)
Pages (from-to)1529-1536
Number of pages8
JournalBioorganic and Medicinal Chemistry Letters
Volume23
Issue number5
DOIs
StatePublished - Mar 1 2013
Externally publishedYes

Fingerprint

DNA Topoisomerase IV
Topoisomerase II Inhibitors
Type I DNA Topoisomerase
Adenosine Triphosphate
DNA Gyrase
Bacterial DNA
Enzymes
DNA Replication
Scaffolds
Conservation
DNA
pyrrolopyrimidine

Keywords

  • Bacterial topoisomerases
  • GyrB
  • Inhibitor
  • ParE
  • Pyrrolopyrimidine

ASJC Scopus subject areas

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

Cite this

Pyrrolopyrimidine inhibitors of DNA gyrase B (GyrB) and topoisomerase IV (ParE). Part I : Structure guided discovery and optimization of dual targeting agents with potent, broad-spectrum enzymatic activity. / Tari, Leslie W.; Trzoss, Michael; Bensen, Daniel C.; Li, Xiaoming; Chen, Zhiyong; Lam, Thanh; Zhang, Junhu; Creighton, Christopher J.; Cunningham, Mark L.; Kwan, Bryan; Stidham, Mark; Shaw, Karen J.; Lightstone, Felice C; Wong, Sergio E.; Nguyen, Toan B.; Nix, Jay; Finn, John.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 23, No. 5, 01.03.2013, p. 1529-1536.

Research output: Contribution to journalArticle

Tari, LW, Trzoss, M, Bensen, DC, Li, X, Chen, Z, Lam, T, Zhang, J, Creighton, CJ, Cunningham, ML, Kwan, B, Stidham, M, Shaw, KJ, Lightstone, FC, Wong, SE, Nguyen, TB, Nix, J & Finn, J 2013, 'Pyrrolopyrimidine inhibitors of DNA gyrase B (GyrB) and topoisomerase IV (ParE). Part I: Structure guided discovery and optimization of dual targeting agents with potent, broad-spectrum enzymatic activity', Bioorganic and Medicinal Chemistry Letters, vol. 23, no. 5, pp. 1529-1536. https://doi.org/10.1016/j.bmcl.2012.11.032
Tari, Leslie W. ; Trzoss, Michael ; Bensen, Daniel C. ; Li, Xiaoming ; Chen, Zhiyong ; Lam, Thanh ; Zhang, Junhu ; Creighton, Christopher J. ; Cunningham, Mark L. ; Kwan, Bryan ; Stidham, Mark ; Shaw, Karen J. ; Lightstone, Felice C ; Wong, Sergio E. ; Nguyen, Toan B. ; Nix, Jay ; Finn, John. / Pyrrolopyrimidine inhibitors of DNA gyrase B (GyrB) and topoisomerase IV (ParE). Part I : Structure guided discovery and optimization of dual targeting agents with potent, broad-spectrum enzymatic activity. In: Bioorganic and Medicinal Chemistry Letters. 2013 ; Vol. 23, No. 5. pp. 1529-1536.
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