4p8o

S. aureus gyrase bound to an aminobenzimidazole urea inhibitor

spinqualitylabelsall models 4p8o, resolution 2.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4p8o is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 883 Activity: DNA topoisomerase (ATP-hydrolyzing), with EC number 5.99.1.3 Resources: FirstGlance, OCA, RCSB, PDBsum Function [GYRB_STAAR] DNA gyrase negatively supercoils closed circular double-stranded DNA in an ATP-dependent manner and also catalyzes the interconversion of other topological isomers of double-stranded DNA rings, including catenanes and knotted rings.[HAMAP-Rule:MF_01898] Publication Abstract from PubMed Compound 3 is a potent aminobenzimidazole urea with broad-spectrum Gram-positive antibacterial activity resulting from dual inhibition of bacterial gyrase (GyrB) and topoisomerase IV (ParE), and it demonstrates efficacy in rodent models of bacterial infection. Preclinical in vitro and in vivo studies showed that compound 3 covalently labels liver proteins, presumably via formation of a reactive metabolite, and hence presented a potential safety liability. The urea moiety in compound 3 was identified as being potentially responsible for reactive metabolite formation, but its replacement resulted in loss of antibacterial activity and/or oral exposure due to poor physicochemical parameters. To identify second-generation aminobenzimidazole ureas devoid of reactive metabolite formation potential, we implemented a metabolic shift strategy, which focused on shifting metabolism away from the urea moiety by introducing metabolic soft spots elsewhere in the molecule. Aminobenzimidazole urea 34, identified through this strategy, exhibits similar antibacterial activity as that of 3 and did not label liver proteins in vivo, indicating reduced/no potential for reactive metabolite formation. Second-Generation Antibacterial Benzimidazole Ureas: Discovery of a Preclinical Candidate with Reduced Metabolic Liability.,Grillot AL, Tiran AL, Shannon D, Krueger E, Liao Y, O'Dowd H, Tang Q, Ronkin S, Wang T, Waal N, Li P, Lauffer D, Sizensky E, Tanoury J, Perola E, Grossman TH, Doyle T, Hanzelka B, Jones S, Dixit V, Ewing N, Liao S, Boucher B, Jacobs M, Bennani Y, Charifson PS J Med Chem. 2014 Oct 28. PMID:25317480 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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