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 |
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Authors: | 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 |
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Institution: | 1. Trius Therapeutics, 6310 Nancy Ridge Dr., San Diego, CA 92121, USA;2. Lawrence Livermore National Laboratory, Physical and Life Sciences Directorate, Livermore, CA 94550, USA;3. Advanced Light Source, Beamline 4.2.2, 1 Cyclotron Rd., Berkeley, CA 94720, USA |
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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. |
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