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| | <StructureSection load='6mo4' size='340' side='right'caption='[[6mo4]], [[Resolution|resolution]] 1.84Å' scene=''> | | <StructureSection load='6mo4' size='340' side='right'caption='[[6mo4]], [[Resolution|resolution]] 1.84Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6mo4]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Pseae Pseae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6MO4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6MO4 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6mo4]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Pseudomonas_aeruginosa_PAO1 Pseudomonas aeruginosa PAO1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6MO4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6MO4 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=JWM:N-[(2R)-1-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-1-oxobutan-2-yl]-4-(6-hydroxyhexa-1,3-diyn-1-yl)benzamide'>JWM</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.844Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">lpxC, envA, PA4406 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=208964 PSEAE])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=JWM:N-[(2R)-1-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-1-oxobutan-2-yl]-4-(6-hydroxyhexa-1,3-diyn-1-yl)benzamide'>JWM</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/UDP-3-O-acyl-N-acetylglucosamine_deacetylase UDP-3-O-acyl-N-acetylglucosamine deacetylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.1.108 3.5.1.108] </span></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=6mo4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6mo4 OCA], [https://pdbe.org/6mo4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6mo4 RCSB], [https://www.ebi.ac.uk/pdbsum/6mo4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6mo4 ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6mo4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6mo4 OCA], [http://pdbe.org/6mo4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6mo4 RCSB], [http://www.ebi.ac.uk/pdbsum/6mo4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6mo4 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/LPXC_PSEAE LPXC_PSEAE]] Involved in the biosynthesis of lipid A, a phosphorylated glycolipid that anchors the lipopolysaccharide to the outer membrane of the cell. | + | [https://www.uniprot.org/uniprot/LPXC_PSEAE LPXC_PSEAE] Involved in the biosynthesis of lipid A, a phosphorylated glycolipid that anchors the lipopolysaccharide to the outer membrane of the cell. |
| - | <div style="background-color:#fffaf0;">
| + | |
| - | == Publication Abstract from PubMed ==
| + | |
| - | LpxC is a Zn2+ deacetylase that is essential for the survival of most pathogenic Gram(-) bacteria. ACHN-975 (N-((S)-3-amino-1-(hydroxyamino)-3-methyl-1-oxobutan-2-yl)-4-(((1R,2R)-2-(hydroxy methyl)cyclopropyl)buta-1,3-diyn-1-yl)benzamide) was the first LpxC inhibitor to reach human clinical testing and was discovered to have a dose-limiting cardiovascular toxicity of transient hypotension without compensatory tachycardia. We report here the effort beyond ACHN-975 to discover LpxC inhibitors optimized for enzyme potency, antibacterial activity, pharmacokinetics, and cardiovascular safety. Based on overall profile, 26 (LPXC-516, (S)-N-(2-(hydroxyamino)-1-(3-methoxy-1,1-dioxidothietan-3-yl)-2-oxoethyl)-4-(6-hy droxyhexa-1,3-diyn-1-yl)benzamide) was chosen for further development. A phosphate prodrug of 26 was developed that provided solubility of >30 mg/mL for parenteral administration and conversion to the active drug with a T1/2 of approximately 2 minutes. Unexpectedly, and despite our optimization efforts, the prodrug of 26 still possesses a therapeutic window insufficient to support further clinical development.
| + | |
| | | | |
| - | -Optimization of LpxC Inhibitors for Antibacterial Activity and Cardiovascular Safety.,Cohen F, Aggen JB, Andrews LD, Assar Z, Boggs J, Choi T, Dozzo P, Easterday AN, Haglund CM, Hildebrandt DJ, Holt MC, Joly K, Jubb A, Kamal Z, Kane TR, Konradi AW, Krause KM, Linsell MS, Machajewski TD, Miroshnikova O, Moser HE, Nieto V, Phan T, Plato C, Serio AW, Seroogy J, Shakhmin A, Stein AJ, Sun AD, Sviridov S, Wang Z, Wlasichuk K, Yang W, Zhou X, Zhu H, Cirz RT ChemMedChem. 2019 Jul 8. doi: 10.1002/cmdc.201900287. PMID:31283109<ref>PMID:31283109</ref>
| + | ==See Also== |
| - | | + | *[[UDP-3-O-acyl-N-acetylglucosamine deacetylase|UDP-3-O-acyl-N-acetylglucosamine deacetylase]] |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
| + | |
| - | </div>
| + | |
| - | <div class="pdbe-citations 6mo4" style="background-color:#fffaf0;"></div>
| + | |
| - | == References ==
| + | |
| - | <references/>
| + | |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Pseae]] | + | [[Category: Pseudomonas aeruginosa PAO1]] |
| - | [[Category: UDP-3-O-acyl-N-acetylglucosamine deacetylase]]
| + | [[Category: Andrews L]] |
| - | [[Category: Andrews, L]] | + | [[Category: Assar Z]] |
| - | [[Category: Assar, Z]] | + | [[Category: Cirz R]] |
| - | [[Category: Cirz, R]] | + | [[Category: Cohen F]] |
| - | [[Category: Cohen, F]] | + | [[Category: Holt MC]] |
| - | [[Category: Holt, M C]] | + | [[Category: Stein AJ]] |
| - | [[Category: Stein, A J]] | + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Hydrolase lpxc pseudomonas aeruginosa]]
| + | |
| - | [[Category: Hydrolase-inhibitor complex]]
| + | |
