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 language | English (US) |
|---|---|
| Pages (from-to) | 1529-1536 |
| Number of pages | 8 |
| Journal | Bioorganic and Medicinal Chemistry Letters |
| Volume | 23 |
| Issue number | 5 |
| DOIs | |
| State | Published - Mar 1 2013 |
| Externally published | Yes |
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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 journal › Article
}
TY - JOUR
T1 - Pyrrolopyrimidine inhibitors of DNA gyrase B (GyrB) and topoisomerase IV (ParE). Part I
T2 - Structure guided discovery and optimization of dual targeting agents with potent, broad-spectrum enzymatic activity
AU - Tari, Leslie W.
AU - Trzoss, Michael
AU - Bensen, Daniel C.
AU - Li, Xiaoming
AU - Chen, Zhiyong
AU - Lam, Thanh
AU - Zhang, Junhu
AU - Creighton, Christopher J.
AU - Cunningham, Mark L.
AU - Kwan, Bryan
AU - Stidham, Mark
AU - Shaw, Karen J.
AU - Lightstone, Felice C
AU - Wong, Sergio E.
AU - Nguyen, Toan B.
AU - Nix, Jay
AU - Finn, John
PY - 2013/3/1
Y1 - 2013/3/1
N2 - 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.
AB - 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.
KW - Bacterial topoisomerases
KW - GyrB
KW - Inhibitor
KW - ParE
KW - Pyrrolopyrimidine
UR - http://www.scopus.com/inward/record.url?scp=84873734502&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84873734502&partnerID=8YFLogxK
U2 - 10.1016/j.bmcl.2012.11.032
DO - 10.1016/j.bmcl.2012.11.032
M3 - Article
C2 - 23352267
AN - SCOPUS:84873734502
VL - 23
SP - 1529
EP - 1536
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
SN - 0960-894X
IS - 5
ER -