5ta4 - Revision history

OCA at 14:20, 6 March 2024

OCA — Wed, 06 Mar 2024 14:20:05 GMT

←Older revision		Revision as of 14:20, 6 March 2024
Line 1:		Line 1:

	==Discovery of a Potent Cyclophilin Inhibitor (Compound 8) based on Structural Simplification of Sanglifehrin A==		==Discovery of a Potent Cyclophilin Inhibitor (Compound 8) based on Structural Simplification of Sanglifehrin A==
-	<StructureSection load='5ta4' size='340' side='right' caption='[[5ta4]], [[Resolution\|resolution]] 1.50Å' scene=''>	+	<StructureSection load='5ta4' size='340' side='right'caption='[[5ta4]], [[Resolution\|resolution]] 1.50Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5ta4]] is a 1 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~Human Human~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5TA4 OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5TA4 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5ta4]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5TA4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5TA4 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=838:18-METHOXY-2,11,17-TRIMETHYL-14-(PROPAN-2-YL)-3-OXA-9,12,15,28-TETRAAZATRICYCLO[21.3.1.1~5,9~]OCTACOSA-1(27),21,23,25-TETRAENE-4,10,13,16-TETRONE'>838</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 1.5Å</td></tr>
-	~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[5t9u\|5t9u]], [[5t9w\|5t9w]], [[5t9z\|5t9z]], [[5ta2\|5ta2]]</td></tr>~~	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=838:18-METHOXY-2,11,17-TRIMETHYL-14-(PROPAN-2-YL)-3-OXA-9,12,15,28-TETRAAZATRICYCLO[21.3.1.1~5,9~]OCTACOSA-1(27),21,23,25-TETRAENE-4,10,13,16-TETRONE'>838</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
-	~~<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PPIA, CYPA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=5ta4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ta4 OCA], [https://pdbe.org/5ta4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ta4 RCSB], [https://www.ebi.ac.uk/pdbsum/5ta4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ta4 ProSAT]</span></td></tr>
-	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Peptidylprolyl_isomerase Peptidylprolyl isomerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.2.1.8 5.2.1.8] </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=5ta4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ta4 OCA], [~~http~~://pdbe.org/5ta4 PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=5ta4 RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/5ta4 PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=5ta4 ProSAT]</span></td></tr>	+
	</table>		</table>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/PPIA_HUMAN PPIA_HUMAN]] PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides.	+	[https://www.uniprot.org/uniprot/PPIA_HUMAN PPIA_HUMAN] PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides.
-	~~<div style="background-color:#fffaf0;">~~	+
-	~~== Publication Abstract from PubMed ==~~	+
-	Cyclophilin inhibition has been a target for the treatment of hepatitis C and other diseases, but the generation of potent, drug-like molecules through chemical synthesis has been challenging. In this study, a set of macrocyclic cyclophilin inhibitors was synthesized based on the core structure of the natural product sanglifehrin A. Initial compound optimization identified the valine-m-tyrosine-piperazic acid tripeptide (Val-m-Tyr-Pip) in the sanglifehrin core, stereocenters at C14 and C15, and the hydroxyl group of the m-tyrosine (m-Tyr) residue as key contributors to compound potency. Replacing the C18-C21 diene unit of sanglifehrin with a styryl group led to potent compounds that displayed a novel binding mode in which the styrene moiety engaged in a pi-stacking interaction with Arg55 of cyclophilin A (Cyp A), and the m-Tyr residue was displaced into solvent. This observation allowed further simplifications of the scaffold, to generate new lead compounds in the search for orally bioavailable cyclophilin inhibitors.	+

-	Discovery of Potent Cyclophilin Inhibitors based on Structural Simplification of Sanglifehrin A.,Steadman VA, Pettit SB, Poullennec KG, Lazarides L, Keats AJ, Dean DK, Stanway SJ, Austin CA, Sanvoisin JA, Watt GM, Fliri HG, Liclican AC, Jin D, Wong MH, Leavitt SA, Lee YJ, Tian Y, Frey CR, Appleby TC, Schmitz U, Jansa P, Mackman RL, Schultz BE J Med Chem. 2017 Jan 11. doi: 10.1021/acs.jmedchem.6b01329. PMID:28075591<ref>PMID:28075591</ref>	+	==See Also==
-		+	*[[Cyclophilin 3D structures\|Cyclophilin 3D structures]]
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class~~=~~"pdbe-citations 5ta4" style~~=~~"background-color:#fffaf0;"></div>~~	+
-	~~== References~~ ==	+
-	~~<references/>~~	+
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
-	[[Category: ~~Peptidylprolyl isomerase~~]]	+	[[Category: Large Structures]]
-	[[Category: Appleby~~, T C~~]]	+	[[Category: Appleby TC]]
-	[[Category: Mackman~~, R L~~]]	+	[[Category: Mackman RL]]
-	[[Category: Pettit, S]]	+	[[Category: Pettit S]]
-	[[Category: Schmitz, U]]	+	[[Category: Schmitz U]]
-	[[Category: Schultz, B]]	+	[[Category: Schultz B]]
-	[[Category: Steadman, V]]	+	[[Category: Steadman V]]
-	~~[[Category: Cyclophilin inhibitor antiviral hcv]]~~	+
-	~~[[Category: Isomerase-isomerase inhibitor complex~~]]	+

OCA at 10:14, 22 November 2017

OCA — Wed, 22 Nov 2017 10:14:05 GMT

←Older revision		Revision as of 10:14, 22 November 2017
Line 3:		Line 3:
	<StructureSection load='5ta4' size='340' side='right' caption='[[5ta4]], [[Resolution\|resolution]] 1.50Å' scene=''>		<StructureSection load='5ta4' size='340' side='right' caption='[[5ta4]], [[Resolution\|resolution]] 1.50Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5ta4]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5TA4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5TA4 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5ta4]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5TA4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5TA4 FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=838:18-METHOXY-2,11,17-TRIMETHYL-14-(PROPAN-2-YL)-3-OXA-9,12,15,28-TETRAAZATRICYCLO[21.3.1.1~5,9~]OCTACOSA-1(27),21,23,25-TETRAENE-4,10,13,16-TETRONE'>838</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=838:18-METHOXY-2,11,17-TRIMETHYL-14-(PROPAN-2-YL)-3-OXA-9,12,15,28-TETRAAZATRICYCLO[21.3.1.1~5,9~]OCTACOSA-1(27),21,23,25-TETRAENE-4,10,13,16-TETRONE'>838</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[5t9u\|5t9u]], [[5t9w\|5t9w]], [[5t9z\|5t9z]], [[5ta2\|5ta2]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[5t9u\|5t9u]], [[5t9w\|5t9w]], [[5t9z\|5t9z]], [[5ta2\|5ta2]]</td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PPIA, CYPA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Peptidylprolyl_isomerase Peptidylprolyl isomerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.2.1.8 5.2.1.8] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Peptidylprolyl_isomerase Peptidylprolyl isomerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.2.1.8 5.2.1.8] </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=5ta4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ta4 OCA], [http://pdbe.org/5ta4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ta4 RCSB], [http://www.ebi.ac.uk/pdbsum/5ta4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ta4 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=5ta4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ta4 OCA], [http://pdbe.org/5ta4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ta4 RCSB], [http://www.ebi.ac.uk/pdbsum/5ta4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ta4 ProSAT]</span></td></tr>
Line 24:		Line 25:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Peptidylprolyl isomerase]]		[[Category: Peptidylprolyl isomerase]]
	[[Category: Appleby, T C]]		[[Category: Appleby, T C]]

OCA at 07:00, 29 March 2017

OCA — Wed, 29 Mar 2017 07:00:28 GMT

←Older revision		Revision as of 07:00, 29 March 2017
Line 1:		Line 1:

-	==Discovery of a Potent Cyclophilin Inhibitor (Compound 7) based on Structural Simplification of Sanglifehrin A==	+	==Discovery of a Potent Cyclophilin Inhibitor (Compound 8) based on Structural Simplification of Sanglifehrin A==
	<StructureSection load='5ta4' size='340' side='right' caption='[[5ta4]], [[Resolution\|resolution]] 1.50Å' scene=''>		<StructureSection load='5ta4' size='340' side='right' caption='[[5ta4]], [[Resolution\|resolution]] 1.50Å' scene=''>
	== Structural highlights ==		== Structural highlights ==

OCA at 23:33, 25 January 2017

OCA — Wed, 25 Jan 2017 23:33:24 GMT

←Older revision		Revision as of 23:33, 25 January 2017
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 5ta4 is ~~ON HOLD until Paper~~ Publication	+	==Discovery of a Potent Cyclophilin Inhibitor (Compound 7) based on Structural Simplification of Sanglifehrin A==
		+	<StructureSection load='5ta4' size='340' side='right' caption='[[5ta4]], [[Resolution\|resolution]] 1.50Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[5ta4]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5TA4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5TA4 FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=838:18-METHOXY-2,11,17-TRIMETHYL-14-(PROPAN-2-YL)-3-OXA-9,12,15,28-TETRAAZATRICYCLO[21.3.1.1~5,9~]OCTACOSA-1(27),21,23,25-TETRAENE-4,10,13,16-TETRONE'>838</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[5t9u\|5t9u]], [[5t9w\|5t9w]], [[5t9z\|5t9z]], [[5ta2\|5ta2]]</td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Peptidylprolyl_isomerase Peptidylprolyl isomerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.2.1.8 5.2.1.8] </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=5ta4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ta4 OCA], [http://pdbe.org/5ta4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ta4 RCSB], [http://www.ebi.ac.uk/pdbsum/5ta4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ta4 ProSAT]</span></td></tr>
		+	</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/PPIA_HUMAN PPIA_HUMAN]] PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides.
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Cyclophilin inhibition has been a target for the treatment of hepatitis C and other diseases, but the generation of potent, drug-like molecules through chemical synthesis has been challenging. In this study, a set of macrocyclic cyclophilin inhibitors was synthesized based on the core structure of the natural product sanglifehrin A. Initial compound optimization identified the valine-m-tyrosine-piperazic acid tripeptide (Val-m-Tyr-Pip) in the sanglifehrin core, stereocenters at C14 and C15, and the hydroxyl group of the m-tyrosine (m-Tyr) residue as key contributors to compound potency. Replacing the C18-C21 diene unit of sanglifehrin with a styryl group led to potent compounds that displayed a novel binding mode in which the styrene moiety engaged in a pi-stacking interaction with Arg55 of cyclophilin A (Cyp A), and the m-Tyr residue was displaced into solvent. This observation allowed further simplifications of the scaffold, to generate new lead compounds in the search for orally bioavailable cyclophilin inhibitors.

-	~~Authors: Appleby, T.C~~., Steadman~~, V.~~, Pettit, S., ~~Schmitz~~, U., Mackman, R.L.~~, Schultz, B~~.	+	Discovery of Potent Cyclophilin Inhibitors based on Structural Simplification of Sanglifehrin A.,Steadman VA, Pettit SB, Poullennec KG, Lazarides L, Keats AJ, Dean DK, Stanway SJ, Austin CA, Sanvoisin JA, Watt GM, Fliri HG, Liclican AC, Jin D, Wong MH, Leavitt SA, Lee YJ, Tian Y, Frey CR, Appleby TC, Schmitz U, Jansa P, Mackman RL, Schultz BE J Med Chem. 2017 Jan 11. doi: 10.1021/acs.jmedchem.6b01329. PMID:28075591<ref>PMID:28075591</ref>

-	~~Description: Discovery of~~ a ~~Potent Cyclophilin Inhibitor (Compound 7) based on Structural Simplification~~ of ~~Sanglifehrin A~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased Structures~~]]	+	</div>
		+	<div class="pdbe-citations 5ta4" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Peptidylprolyl isomerase]]
		+	[[Category: Appleby, T C]]
		+	[[Category: Mackman, R L]]
	[[Category: Pettit, S]]		[[Category: Pettit, S]]
-	[[Category: Mackman, R.L]]
	[[Category: Schmitz, U]]		[[Category: Schmitz, U]]
-	[[Category: Appleby, T.C]]
	[[Category: Schultz, B]]		[[Category: Schultz, B]]
	[[Category: Steadman, V]]		[[Category: Steadman, V]]
		+	[[Category: Cyclophilin inhibitor antiviral hcv]]
		+	[[Category: Isomerase-isomerase inhibitor complex]]

OCA at 19:50, 5 October 2016

OCA — Wed, 05 Oct 2016 19:50:32 GMT

←Older revision		Revision as of 19:50, 5 October 2016
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 5ta4 is ON HOLD	+	The entry 5ta4 is ON HOLD until Paper Publication

	Authors: Appleby, T.C., Steadman, V., Pettit, S., Schmitz, U., Mackman, R.L., Schultz, B.		Authors: Appleby, T.C., Steadman, V., Pettit, S., Schmitz, U., Mackman, R.L., Schultz, B.

OCA: Protected "5ta4" [edit=sysop:move=sysop]

OCA — Wed, 21 Sep 2016 12:24:50 GMT

Protected "5ta4" [edit=sysop:move=sysop]

←Older revision

Revision as of 12:24, 21 September 2016

OCA: New page: '''Unreleased structure''' The entry 5ta4 is ON HOLD Authors: Appleby, T.C., Steadman, V., Pettit, S., Schmitz, U., Mackman, R.L., Schultz, B. Description: Discovery of a Potent Cyclop...

OCA — Wed, 21 Sep 2016 12:24:49 GMT

New page: '''Unreleased structure''' The entry 5ta4 is ON HOLD Authors: Appleby, T.C., Steadman, V., Pettit, S., Schmitz, U., Mackman, R.L., Schultz, B. Description: Discovery of a Potent Cyclop...

New page

'''Unreleased structure'''

The entry 5ta4 is ON HOLD

Authors: Appleby, T.C., Steadman, V., Pettit, S., Schmitz, U., Mackman, R.L., Schultz, B.

Description: Discovery of a Potent Cyclophilin Inhibitor (Compound 7) based on Structural Simplification of Sanglifehrin A
[[Category: Unreleased Structures]]
[[Category: Pettit, S]]
[[Category: Mackman, R.L]]
[[Category: Schmitz, U]]
[[Category: Appleby, T.C]]
[[Category: Schultz, B]]
[[Category: Steadman, V]]