6i46

Structure of P. aeruginosa LpxC with compound 8: (2RS)-4-(5-(2-Fluoro-4-methoxyphenyl)-2-oxooxazol-3(2H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

spinqualitylabelsall models 6i46, resolution 1.75Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6i46 is a 1 chain structure with sequence from Pseudomonas aeruginosa LESB58. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.75Å Ligands: GOL, H2N, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function LPXC_PSEA8 Catalyzes the hydrolysis of UDP-3-O-myristoyl-N-acetylglucosamine to form UDP-3-O-myristoylglucosamine and acetate, the committed step in lipid A biosynthesis. Publication Abstract from PubMed UDP-3-O-((R)-3-hydroxymyristoyl)-N-glucosamine deacetylase (LpxC) is as an attractive target for the discovery and development of novel antibacterial drugs to address the critical medical need created by multi-drug resistant Gram-negative bacteria. Using a scaffold hopping approach on a known family of methylsulfone hydroxamate LpxC inhibitors, several hit series eliciting potent antibacterial activities against Enterobacteriaceae and Pseudomonas aeruginosa were identified. Subsequent hit-to-lead optimization, using co-crystal structures of inhibitors bound to Pseudomonas aeruginosa LpxC as guides, resulted in the discovery of multiple chemical series based on i) isoindolin-1-ones, ii) 4,5-dihydro-6H-thieno[2,3-c]pyrrol-6-ones and iii) 1,2-dihydro-3H-pyrrolo[1,2-c]imidazole-3-ones. Synthetic methods, antibacterial activities and relative binding affinities, as well as physico-chemical properties that allowed compound prioritization are presented. Finally, in vivo properties of lead molecules which belong to the most promising pyrrolo-imidazolone series such as 18d, are discussed. Discovery of Novel Inhibitors of LpxC Displaying Potent In Vitro Activity against Gram-Negative Bacteria.,Surivet JP, Panchaud P, Specklin JL, Diethelm S, Blumstein AC, Gauvin JC, Jacob L, Masse F, Mathieu G, Mirre A, Schmitt C, Lange R, Tidten-Luksch N, Gnerre C, Seeland S, Herrmann C, Seiler P, Enderlin-Paput M, Mac Sweeney A, Wicki M, Hubschwerlen C, Ritz D, Rueedi G J Med Chem. 2019 Dec 5. doi: 10.1021/acs.jmedchem.9b01604. PMID:31804826 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also UDP-3-O-acyl-N-acetylglucosamine deacetylase

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