4b1f: Difference between revisions
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==Design of Inhibitors of Helicobacter pylori Glutamate Racemase as Selective Antibacterial Agents: Incorporation of Imidazoles onto a Core Pyrazolopyrimidinedione Scaffold to Improve Bioavailabilty== | |||
<StructureSection load='4b1f' size='340' side='right'caption='[[4b1f]], [[Resolution|resolution]] 2.05Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4b1f]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Helicobacter_pylori Helicobacter pylori]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4B1F OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4B1F FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.05Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DGL:D-GLUTAMIC+ACID'>DGL</scene>, <scene name='pdbligand=KRH:5-METHYL-3-(1-METHYL-1H-IMIDAZOL-5-YL)-7-(2-METHYLPROPYL)-2-(NAPHTHALEN-1-YLMETHYL)-2H-PYRAZOLO[3,4-D]PYRIMIDINE-4,6(5H,7H)-DIONE'>KRH</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4b1f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4b1f OCA], [https://pdbe.org/4b1f PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4b1f RCSB], [https://www.ebi.ac.uk/pdbsum/4b1f PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4b1f ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/MURI_HELPJ MURI_HELPJ] Provides the (R)-glutamate required for cell wall biosynthesis (By similarity). | |||
<div style="background-color:#fffaf0;"> | |||
== 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<ref>PMID:22877632</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4b1f" style="background-color:#fffaf0;"></div> | |||
== | ==See Also== | ||
[[ | *[[Glutamate racemase 3D structures|Glutamate racemase 3D structures]] | ||
[[Category: | == References == | ||
[[Category: Basarab | <references/> | ||
[[Category: | __TOC__ | ||
[[Category: | </StructureSection> | ||
[[Category: | [[Category: Helicobacter pylori]] | ||
[[Category: Kack | [[Category: Large Structures]] | ||
[[Category: | [[Category: Basarab GS]] | ||
[[Category: Eyermann CJ]] | |||
[[Category: Gowravaram M]] | |||
[[Category: Hill P]] | |||
[[Category: Kack H]] | |||
[[Category: Osimoni E]] | |||
Latest revision as of 13:55, 9 May 2024
Design of Inhibitors of Helicobacter pylori Glutamate Racemase as Selective Antibacterial Agents: Incorporation of Imidazoles onto a Core Pyrazolopyrimidinedione Scaffold to Improve BioavailabiltyDesign of Inhibitors of Helicobacter pylori Glutamate Racemase as Selective Antibacterial Agents: Incorporation of Imidazoles onto a Core Pyrazolopyrimidinedione Scaffold to Improve Bioavailabilty
Structural highlights
FunctionMURI_HELPJ Provides the (R)-glutamate required for cell wall biosynthesis (By similarity). Publication Abstract from PubMedStructure-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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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