6mo5 - Revision history

OCA at 14:44, 13 March 2024

OCA — Wed, 13 Mar 2024 14:44:09 GMT

←Older revision		Revision as of 14:44, 13 March 2024
Line 3:		Line 3:
	<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 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>	+	<table><tr><td colspan='2'>[[6mo5]] 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=6MO5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/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='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 1.851Å</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=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='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=6mo5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6mo5 OCA], [https://pdbe.org/6mo5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6mo5 RCSB], [https://www.ebi.ac.uk/pdbsum/6mo5 PDBsum], [https://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>	+
	</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 6mo5" 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~~]]	+

OCA at 08:38, 24 July 2019

OCA — Wed, 24 Jul 2019 08:38:24 GMT

←Older revision		Revision as of 08:38, 24 July 2019
Line 3:		Line 3:
	<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>
Line 10:		Line 11:
	== 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]]

OCA at 10:44, 17 July 2019

OCA — Wed, 17 Jul 2019 10:44:29 GMT

←Older revision		Revision as of 10:44, 17 July 2019
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 6mo5 ~~is ON HOLD until Paper Publication~~	+	==Co-Crystal structure of P. aeruginosa LpxC-50228 complex==
-		+	<StructureSection load='6mo5' size='340' side='right'caption='[[6mo5]], [[Resolution\|resolution]] 1.85Å' scene=''>
-	~~Authors~~: ~~Stein, A~~.J., ~~Holt~~, M.C., ~~Assar~~, Z., ~~Cohen~~, F., ~~Andrews, L~~., ~~Cirz, R~~.	+	== 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>
-	~~Description~~: ~~Co-Crystal structure~~ of P. ~~aeruginosa LpxC-50228 complex~~	+	</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>
-	[[Category: ~~Unreleased~~ Structures]]	+	<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>
		+	</table>
		+	== 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.
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: UDP-3-O-acyl-N-acetylglucosamine deacetylase]]
		+	[[Category: Andrews, L]]
		+	[[Category: Assar, Z]]
	[[Category: Cirz, R]]		[[Category: Cirz, R]]
-	[[Category: Andrews, L]]
-	[[Category: Stein, A.J]]
	[[Category: Cohen, F]]		[[Category: Cohen, F]]
-	[[Category: ~~Assar~~, Z]]	+	[[Category: Holt, M C]]
-	[[Category: ~~Holt~~, ~~M.C~~]]	+	[[Category: Stein, A J]]
		+	[[Category: Hydrolase]]
		+	[[Category: Hydrolase lpxc pseudomonas aeruginosa]]
		+	[[Category: Hydrolase-inhibitor complex]]

OCA at 10:30, 16 January 2019

OCA — Wed, 16 Jan 2019 10:30:37 GMT

←Older revision		Revision as of 10:30, 16 January 2019
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6mo5 is ON HOLD	+	The entry 6mo5 is ON HOLD until Paper Publication

	Authors: Stein, A.J., Holt, M.C., Assar, Z., Cohen, F., Andrews, L., Cirz, R.		Authors: Stein, A.J., Holt, M.C., Assar, Z., Cohen, F., Andrews, L., Cirz, R.
Line 8:		Line 8:
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
	[[Category: Cirz, R]]		[[Category: Cirz, R]]
		+	[[Category: Andrews, L]]
	[[Category: Stein, A.J]]		[[Category: Stein, A.J]]
	[[Category: Cohen, F]]		[[Category: Cohen, F]]
-	[[Category: Holt, M.C]]
-	[[Category: Andrews, L]]
	[[Category: Assar, Z]]		[[Category: Assar, Z]]
		+	[[Category: Holt, M.C]]

OCA: Protected "6mo5" [edit=sysop:move=sysop]

OCA — Wed, 10 Oct 2018 06:36:41 GMT

Protected "6mo5" [edit=sysop:move=sysop]

←Older revision

Revision as of 06:36, 10 October 2018

OCA: New page: '''Unreleased structure''' The entry 6mo5 is ON HOLD Authors: Stein, A.J., Holt, M.C., Assar, Z., Cohen, F., Andrews, L., Cirz, R. Description: Co-Crystal structure of P. aeruginosa Lp...

OCA — Wed, 10 Oct 2018 06:36:40 GMT

New page: '''Unreleased structure''' The entry 6mo5 is ON HOLD Authors: Stein, A.J., Holt, M.C., Assar, Z., Cohen, F., Andrews, L., Cirz, R. Description: Co-Crystal structure of P. aeruginosa Lp...

New page

'''Unreleased structure'''

The entry 6mo5 is ON HOLD

Authors: Stein, A.J., Holt, M.C., Assar, Z., Cohen, F., Andrews, L., Cirz, R.

Description: Co-Crystal structure of P. aeruginosa LpxC-50228 complex
[[Category: Unreleased Structures]]
[[Category: Cirz, R]]
[[Category: Stein, A.J]]
[[Category: Cohen, F]]
[[Category: Holt, M.C]]
[[Category: Andrews, L]]
[[Category: Assar, Z]]