4HZ5

Pyrrolopyrimidine inhibitors of dna gyrase b and topoisomerase iv, part i: structure guided discovery and optimization of dual targeting agents with potent, broad-spectrum enzymatic activity

Summary for 4HZ5

• Entry DOI: 10.2210/pdb4hz5/pdb
• Related: 4GEE 4GFN 4GGL 4HXW 4HXZ 4HY1 4HYM 4HYP 4HZ0
• Descriptor: DNA topoisomerase IV, B subunit, 6-ethyl-4-methoxy-2-(pyridin-3-ylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde (3 entities in total)
• Functional Keywords: atp-binding, nucleotide-binding, topoisomerase, atp-binding domain, isomerase-isomerase inhibitor complex, isomerase/isomerase inhibitor
• Biological source: Enterococcus faecalis
• Total number of polymer chains: 9
• Total formula weight: 216551.22

Authors

Bensen, D.C.,Creighton, C.J.,Tari, L.W. (deposition date: 2012-11-14, release date: 2013-02-13, Last modification date: 2024-02-28)

Primary citation

Tari, L.W.,Trzoss, M.,Bensen, D.C.,Li, X.,Chen, Z.,Lam, T.,Zhang, J.,Creighton, C.J.,Cunningham, M.L.,Kwan, B.,Stidham, M.,Shaw, K.J.,Lightstone, F.C.,Wong, S.E.,Nguyen, T.B.,Nix, J.,Finn, J.
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.
Bioorg.Med.Chem.Lett., 23:1529-1536, 2013

PubMed 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.

PubMed: 23352267
DOI: 10.1016/j.bmcl.2012.11.032

Experimental method

X-RAY DIFFRACTION (2.7 Å)