6mod - Revision history

OCA at 14:44, 13 March 2024

2024-03-13T14:44:15Z

← Older revision		Revision as of 14:44, 13 March 2024
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	<StructureSection load='6mod' size='340' side='right'caption='[[6mod]], [[Resolution\|resolution]] 1.85Å' scene=''>		<StructureSection load='6mod' size='340' side='right'caption='[[6mod]], [[Resolution\|resolution]] 1.85Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[6mod]] is a 1 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~"bacillus_aeruginosus"_(schroeter_1872)_trevisan_1885 "bacillus aeruginosus" (schroeter 1872) trevisan 1885~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6MOD OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=6MOD FirstGlance]. <br>		<table><tr><td colspan='2'>[[6mod]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Pseudomonas_aeruginosa Pseudomonas aeruginosa]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6MOD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6MOD FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=JWV:N-[(1S)-2-(hydroxyamino)-1-(3-methoxy-1,1-dioxo-1lambda~6~-thietan-3-yl)-2-oxoethyl]-4-(6-hydroxyhexa-1,3-diyn-1-yl)benzamide'>JWV</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]] 1.85Å</td></tr>
	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">lpxC, PLES_47851 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=287 "Bacillus aeruginosus" (Schroeter 1872) Trevisan 1885])</td></tr>		<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=JWV:N-[(1S)-2-(hydroxyamino)-1-(3-methoxy-1,1-dioxo-1lambda~6~-thietan-3-yl)-2-oxoethyl]-4-(6-hydroxyhexa-1,3-diyn-1-yl)benzamide'>JWV</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=6mod FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6mod OCA], [https://pdbe.org/6mod PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6mod RCSB], [https://www.ebi.ac.uk/pdbsum/6mod PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6mod 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=6mod FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6mod OCA], [~~http~~://pdbe.org/6mod PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6mod RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6mod PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6mod ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
	[~~[http~~://www.uniprot.org/uniprot/~~LPXC_PSEA8 LPXC_PSEA8~~]~~] Catalyzes~~ the ~~hydrolysis~~ of ~~UDP-3-O-myristoyl-N-acetylglucosamine to form UDP-3-O-myristoylglucosamine and acetate, the committed step in~~ lipid A ~~biosynthesis.~~		[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 6mod" style="background-color:#fffaf0;"></div>~~
	== ~~References~~ ==
	~~<references/>~~
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: Large Structures]]		[[Category: Large Structures]]
	[[Category: ~~UDP-3-O-acyl-N-acetylglucosamine deacetylase~~]]		[[Category: Pseudomonas aeruginosa]]
	[[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~~, M C~~]]		[[Category: Holt MC]]
	[[Category: Stein~~, A J]]~~		[[Category: Stein AJ]]
	~~[[Category: Hydrolase]]~~
	~~[[Category: Hydrolase lpxc pseudomonas aeruginosa]]~~
	~~[[Category: Hydrolase-inhibitor complex~~]]

OCA at 08:38, 24 July 2019

2019-07-24T08:38:24Z

← Older revision		Revision as of 08:38, 24 July 2019
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	<StructureSection load='6mod' size='340' side='right'caption='[[6mod]], [[Resolution\|resolution]] 1.85Å' scene=''>		<StructureSection load='6mod' size='340' side='right'caption='[[6mod]], [[Resolution\|resolution]] 1.85Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[6mod]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6MOD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6MOD FirstGlance]. <br>		<table><tr><td colspan='2'>[[6mod]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_aeruginosus"_(schroeter_1872)_trevisan_1885 "bacillus aeruginosus" (schroeter 1872) trevisan 1885]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6MOD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6MOD FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=JWV:N-[(1S)-2-(hydroxyamino)-1-(3-methoxy-1,1-dioxo-1lambda~6~-thietan-3-yl)-2-oxoethyl]-4-(6-hydroxyhexa-1,3-diyn-1-yl)benzamide'>JWV</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=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=JWV:N-[(1S)-2-(hydroxyamino)-1-(3-methoxy-1,1-dioxo-1lambda~6~-thietan-3-yl)-2-oxoethyl]-4-(6-hydroxyhexa-1,3-diyn-1-yl)benzamide'>JWV</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, PLES_47851 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=287 "Bacillus aeruginosus" (Schroeter 1872) Trevisan 1885])</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=6mod FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6mod OCA], [http://pdbe.org/6mod PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6mod RCSB], [http://www.ebi.ac.uk/pdbsum/6mod PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6mod 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=6mod FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6mod OCA], [http://pdbe.org/6mod PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6mod RCSB], [http://www.ebi.ac.uk/pdbsum/6mod PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6mod ProSAT]</span></td></tr>
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	== Function ==		== Function ==
	[[http://www.uniprot.org/uniprot/LPXC_PSEA8 LPXC_PSEA8]] Catalyzes the hydrolysis of UDP-3-O-myristoyl-N-acetylglucosamine to form UDP-3-O-myristoylglucosamine and acetate, the committed step in lipid A biosynthesis.		[[http://www.uniprot.org/uniprot/LPXC_PSEA8 LPXC_PSEA8]] Catalyzes the hydrolysis of UDP-3-O-myristoyl-N-acetylglucosamine to form UDP-3-O-myristoylglucosamine and acetate, the committed step in lipid A biosynthesis.
			<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 6mod" style="background-color:#fffaf0;"></div>
			== References ==
			<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>

OCA at 10:44, 17 July 2019

2019-07-17T10:44:41Z

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

	~~The entry~~ 6mod ~~is ON HOLD until Paper Publication~~		==Co-Crystal structure of P. aeruginosa LpxC-50432 complex==
			<StructureSection load='6mod' size='340' side='right'caption='[[6mod]], [[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'>[[6mod]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6MOD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6MOD FirstGlance]. <br>
	~~Description~~: Co-~~Crystal structure of P. aeruginosa LpxC~~-~~50432 complex~~		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=JWV:N-[(1S)-2-(hydroxyamino)-1-(3-methoxy-1,1-dioxo-1lambda~6~-thietan-3-yl)-2-oxoethyl]-4-(6-hydroxyhexa-1,3-diyn-1-yl)benzamide'>JWV</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=6mod FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6mod OCA], [http://pdbe.org/6mod PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6mod RCSB], [http://www.ebi.ac.uk/pdbsum/6mod PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6mod ProSAT]</span></td></tr>
			</table>
			== Function ==
			[[http://www.uniprot.org/uniprot/LPXC_PSEA8 LPXC_PSEA8]] Catalyzes the hydrolysis of UDP-3-O-myristoyl-N-acetylglucosamine to form UDP-3-O-myristoylglucosamine and acetate, the committed step in lipid A biosynthesis.
			__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

2019-01-16T10:30:43Z

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

	The entry 6mod is ON HOLD		The entry 6mod 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: Assar, Z]]
	[[Category: Holt, M.C]]		[[Category: Holt, M.C]]
	~~[[Category: Andrews, L]]~~
	~~[[Category: Assar, Z]]~~

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

2018-10-10T06:37:32Z

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

← Older revision	Revision as of 06:37, 10 October 2018
(No difference)

OCA: New page: '''Unreleased structure''' The entry 6mod 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...

2018-10-10T06:37:30Z

New page: '''Unreleased structure''' The entry 6mod 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 6mod 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-50432 complex
[[Category: Unreleased Structures]]
[[Category: Cirz, R]]
[[Category: Stein, A.J]]
[[Category: Cohen, F]]
[[Category: Holt, M.C]]
[[Category: Andrews, L]]
[[Category: Assar, Z]]