6mo5: Difference between revisions
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<StructureSection load='6mo5' size='340' side='right'caption='[[6mo5]], [[Resolution|resolution]] 1.85Å' scene=''> | <StructureSection load='6mo5' size='340' side='right'caption='[[6mo5]], [[Resolution|resolution]] 1.85Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6mo5]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6MO5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6MO5 FirstGlance]. <br> | <table><tr><td colspan='2'>[[6mo5]] 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=6MO5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6MO5 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=JWP:N-[(2S)-1-(hydroxyamino)-3-methyl-3-{[(oxetan-3-yl)methyl]sulfonyl}-1-oxobutan-2-yl]-4-(6-hydroxyhexa-1,3-diyn-1-yl)benzamide'>JWP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=JWP:N-[(2S)-1-(hydroxyamino)-3-methyl-3-{[(oxetan-3-yl)methyl]sulfonyl}-1-oxobutan-2-yl]-4-(6-hydroxyhexa-1,3-diyn-1-yl)benzamide'>JWP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></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='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='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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6mo5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6mo5 OCA], [http://pdbe.org/6mo5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6mo5 RCSB], [http://www.ebi.ac.uk/pdbsum/6mo5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6mo5 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=6mo5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6mo5 OCA], [http://pdbe.org/6mo5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6mo5 RCSB], [http://www.ebi.ac.uk/pdbsum/6mo5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6mo5 ProSAT]</span></td></tr> | ||
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== 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. | [[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. | ||
<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> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6mo5" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Pseae]] | |||
[[Category: UDP-3-O-acyl-N-acetylglucosamine deacetylase]] | [[Category: UDP-3-O-acyl-N-acetylglucosamine deacetylase]] | ||
[[Category: Andrews, L]] | [[Category: Andrews, L]] | ||
Revision as of 11:38, 24 July 2019
Co-Crystal structure of P. aeruginosa LpxC-50228 complexCo-Crystal structure of P. aeruginosa LpxC-50228 complex
Structural highlights
Function[LPXC_PSEAE] Involved in the biosynthesis of lipid A, a phosphorylated glycolipid that anchors the lipopolysaccharide to the outer membrane of the cell. Publication Abstract from PubMedLpxC 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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