4dai

Crystal structure of B. anthracis DHPS with compound 23

spinqualitylabelsall models 4dai, resolution 2.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4dai is a 2 chain structure with sequence from Bacillus anthracis str. A2012. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 0J5, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [Q81VW8_BACAN] Publication Abstract from PubMed Dihydropteroate synthase (DHPS) is the validated drug target for sulfonamide antimicrobial therapy. However, due to widespread drug resistance and poor tolerance, the use of sulfonamide antibiotics is now limited. The pterin binding pocket in DHPS is highly conserved and is distinct from the sulfonamide binding site. It therefore represents an attractive alternative target for the design of novel antibacterial agents. We previously carried out the structural characterization of a known pyridazine inhibitor in the Bacillus anthracis DHPS pterin site and identified a number of unfavorable interactions that appear to compromise binding. With this structural information, a series of 4,5-dioxo-1,4,5,6-tetrahydropyrimido[4,5-c]pyridazines were designed to improve binding affinity. Most importantly, the N-methyl ring substitution was removed to improve binding within the pterin pocket, and the length of the side chain carboxylic acid was optimized to fully engage the pyrophosphate binding site. These inhibitors were synthesized and evaluated by an enzyme activity assay, X-ray crystallography, isothermal calorimetry, and surface plasmon resonance to obtain a comprehensive understanding of the binding interactions from structural, kinetic, and thermodynamic perspectives. This study clearly demonstrates that compounds lacking the N-methyl substitution exhibit increased inhibition of DHPS, but the beneficial effects of optimizing the side chain length are less apparent. Structure-Based Design of Novel Pyrimido[4,5-c]pyridazine Derivatives as Dihydropteroate Synthase Inhibitors with Increased Affinity.,Zhao Y, Hammoudeh D, Yun MK, Qi J, White SW, Lee RE ChemMedChem. 2012 Mar 13. doi: 10.1002/cmdc.201200049. PMID:22416048 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Dihydropteroate synthase 3D structures

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