6nd2 - Revision history

OCA at 06:49, 11 October 2023

2023-10-11T06:49:47Z

←Older revision		Revision as of 06:49, 11 October 2023
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	<StructureSection load='6nd2' size='340' side='right'caption='[[6nd2]], [[Resolution\|resolution]] 2.24Å' scene=''>		<StructureSection load='6nd2' size='340' side='right'caption='[[6nd2]], [[Resolution\|resolution]] 2.24Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6nd2]] is a 1 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~"micrococcus_aureus"_(rosenbach_1884)_zopf_1885 "micrococcus~~ aureus~~" (rosenbach 1884) zopf 1885~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ND2 OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=6ND2 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6nd2]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Staphylococcus_aureus Staphylococcus aureus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ND2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6ND2 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=G8J:6-ethyl-5-{(3S)-3-[2-methoxy-5-(pyridin-4-yl)phenyl]but-1-yn-1-yl}pyrimidine-2,4-diamine'>G8J</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=XNP:TRICYCLIC+NADPH'>XNP</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]] 2.243Å</td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">folA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1280 "Micrococcus aureus" (Rosenbach 1884) Zopf 1885])</td></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=G8J:6-ethyl-5-{(3S)-3-[2-methoxy-5-(pyridin-4-yl)phenyl]but-1-yn-1-yl}pyrimidine-2,4-diamine'>G8J</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=XNP:TRICYCLIC+NADPH'>XNP</scene></td></tr>
-	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Dihydrofolate_reductase Dihydrofolate reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.5.1.3 1.5.1.3] </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=6nd2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nd2 OCA], [https://pdbe.org/6nd2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6nd2 RCSB], [https://www.ebi.ac.uk/pdbsum/6nd2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6nd2 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=6nd2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nd2 OCA], [~~http~~://pdbe.org/6nd2 PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6nd2 RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6nd2 PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6nd2 ProSAT]</span></td></tr>	+
	</table>		</table>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/DYR_STAAU DYR_STAAU]] Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis.	+	[https://www.uniprot.org/uniprot/DYR_STAAU DYR_STAAU] Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis.
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
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	</div>		</div>
	<div class="pdbe-citations 6nd2" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 6nd2" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Dihydrofolate reductase 3D structures\|Dihydrofolate reductase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: Dihydrofolate reductase]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: ~~Reeve, S M~~]]	+	[[Category: Staphylococcus aureus]]
-	[[Category: ~~Wright, D L~~]]	+	[[Category: Reeve SM]]
-	[[Category: ~~Antibiotic]]~~	+	[[Category: Wright DL]]
-	~~[[Category: Antifolate]]~~	+
-	~~[[Category: Dhfr]]~~	+
-	~~[[Category: Oxidoreductase]]~~	+
-	~~[[Category: Propargyl-linked antifolate~~]]	+

OCA at 11:25, 18 December 2019

2019-12-18T11:25:59Z

←Older revision		Revision as of 11:25, 18 December 2019
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 6nd2 is ~~ON HOLD~~	+	==Staphylococcus aureus Dihydrofolate Reductase complexed with NADPH and 6-ETHYL-5-[(3R)-3-[2-METHOXY-5-(PYRIDIN-4-YL)PHENYL]BUT-1-YN-1-YL]PYRIMIDINE-2,4-DIAMINE (UCP1063)==
		+	<StructureSection load='6nd2' size='340' side='right'caption='[[6nd2]], [[Resolution\|resolution]] 2.24Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[6nd2]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/"micrococcus_aureus"_(rosenbach_1884)_zopf_1885 "micrococcus aureus" (rosenbach 1884) zopf 1885]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ND2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6ND2 FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=G8J:6-ethyl-5-{(3S)-3-[2-methoxy-5-(pyridin-4-yl)phenyl]but-1-yn-1-yl}pyrimidine-2,4-diamine'>G8J</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=XNP:TRICYCLIC+NADPH'>XNP</scene></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">folA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1280 "Micrococcus aureus" (Rosenbach 1884) Zopf 1885])</td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Dihydrofolate_reductase Dihydrofolate reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.5.1.3 1.5.1.3] </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=6nd2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nd2 OCA], [http://pdbe.org/6nd2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6nd2 RCSB], [http://www.ebi.ac.uk/pdbsum/6nd2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6nd2 ProSAT]</span></td></tr>
		+	</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/DYR_STAAU DYR_STAAU]] Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis.
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Pharmacokinetic/pharmacodynamic properties are strongly correlated with the in vivo efficacy of antibiotics. Propargyl-linked antifolates, a novel class of antibiotics, demonstrate potent antibacterial activity against both Gram-positive and Gram-negative pathogenic bacteria, including multidrug-resistant Staphylococcus aureus Here, we report our efforts to optimize the pharmacokinetic profile of this class to best match the established pharmacodynamic properties. High-resolution crystal structures were used in combination with in vitro pharmacokinetic models to design compounds that not only are metabolically stable in vivo but also retain potent antibacterial activity. The initial lead compound was prone to both N-oxidation and demethylation, which resulted in an abbreviated in vivo half-life ( approximately 20 minutes) in mice. Stability of leads toward mouse liver microsomes was primarily used to guide medicinal chemistry efforts so robust efficacy could be demonstrated in a mouse disease model. Structure-based drug design guided mitigation of N-oxide formation through substitutions of sterically demanding groups adjacent to the pyridyl nitrogen. Additionally, deuterium and fluorine substitutions were evaluated for their effect on the rate of oxidative demethylation. The resulting compound was characterized and demonstrated to have a low projected clearance in humans with limited potential for drug-drug interactions as predicted by cytochrome P450 inhibition as well as an in vivo exposure profile that optimizes the potential for bactericidal activity, highlighting how structural data, merged with substitutions to introduce metabolic stability, are a powerful approach to drug design.

-	~~Authors~~:	+	Structure-Guided In Vitro to In Vivo Pharmacokinetic Optimization of Propargyl-Linked Antifolates.,Lombardo MN, G-Dayanandan N, Keshipeddy S, Zhou W, Si D, Reeve SM, Alverson J, Barney P, Walker L, Hoody J, Priestley ND, Obach RS, Wright DL Drug Metab Dispos. 2019 Sep;47(9):995-1003. doi: 10.1124/dmd.119.086504. Epub, 2019 Jun 14. PMID:31201212<ref>PMID:31201212</ref>

-	~~Description~~:	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased~~ Structures]]	+	</div>
		+	<div class="pdbe-citations 6nd2" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Dihydrofolate reductase]]
		+	[[Category: Large Structures]]
		+	[[Category: Reeve, S M]]
		+	[[Category: Wright, D L]]
		+	[[Category: Antibiotic]]
		+	[[Category: Antifolate]]
		+	[[Category: Dhfr]]
		+	[[Category: Oxidoreductase]]
		+	[[Category: Propargyl-linked antifolate]]

OCA: Protected "6nd2" [edit=sysop:move=sysop]

2018-12-19T06:39:21Z

Protected "6nd2" [edit=sysop:move=sysop]

←Older revision

Revision as of 06:39, 19 December 2018

OCA: New page: '''Unreleased structure''' The entry 6nd2 is ON HOLD Authors: Description: Category: Unreleased Structures

2018-12-19T06:39:20Z

New page: '''Unreleased structure''' The entry 6nd2 is ON HOLD Authors: Description: Category: Unreleased Structures

New page

'''Unreleased structure'''

The entry 6nd2 is ON HOLD

Authors:

Description:
[[Category: Unreleased Structures]]