4b1f | pdb_00004b1f

Design of Inhibitors of Helicobacter pylori Glutamate Racemase as Selective Antibacterial Agents: Incorporation of Imidazoles onto a Core Pyrazolopyrimidinedione Scaffold to Improve Bioavailabilty

spinqualitylabelsall models 4b1f, resolution 2.05Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4b1f is a 2 chain structure with sequence from Helicobacter pylori. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.05Å Ligands: DGL, KRH Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function MURI_HELPJ Provides the (R)-glutamate required for cell wall biosynthesis (By similarity). Publication Abstract from PubMed Structure-activity relationships are presented around a series of pyrazolopyrimidinediones that inhibit the growth of Helicobacter pylori by targeting glutamate racemase, an enzyme that provides d-glutamate for the construction of N-acetylglucosamine-N-acetylmuramic acid peptidoglycan subunits assimilated into the bacterial cell wall. Substituents on the inhibitor scaffold were varied to optimize target potency, antibacterial activity and in vivo pharmacokinetic stability. By incorporating an imidazole ring at the 7-position of scaffold, high target potency was achieved due to a hydrogen bonding network that occurs between the 3-position nitrogen atom, a bridging water molecule and the side chains Ser152 and Trp244 of the enzyme. The lipophilicity of the scaffold series proved important for expression of antibacterial activity. Clearances in vitro and in vivo were monitored to identify compounds with improved plasma stability. The basicity of the imidazole may contribute to increased aqueous solubility at lower pH allowing for improved oral bioavailability. Design of inhibitors of Helicobacter pylori glutamate racemase as selective antibacterial agents: Incorporation of imidazoles onto a core pyrazolopyrimidinedione scaffold to improve bioavailabilty.,Basarab GS, Hill P, Eyermann CJ, Gowravaram M, Kack H, Osimoni E Bioorg Med Chem Lett. 2012 Sep 1;22(17):5600-7. Epub 2012 Jul 20. PMID:22877632 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Glutamate racemase 3D structures

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