8dsr - Revision history

OCA at 09:34, 17 October 2024

2024-10-17T09:34:04Z

← Older revision		Revision as of 09:34, 17 October 2024
Line 5:		Line 5:
	<table><tr><td colspan='2'>[[8dsr]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Plasmodium_falciparum_3D7 Plasmodium falciparum 3D7]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8DSR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8DSR FirstGlance]. <br>		<table><tr><td colspan='2'>[[8dsr]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Plasmodium_falciparum_3D7 Plasmodium falciparum 3D7]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8DSR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8DSR FirstGlance]. <br>
	</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 2.85Å</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]] 2.85Å</td></tr>
	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=TWU:(~~2E,6S~~)-6-{2-~~chloro~~-3-[(2-cyclopropylpyrimidin-5-yl)amino]phenyl~~}-2-imino~~-6-methyl-3-[(2S,4S)-2-methyloxan-4-yl]-1,3-diazinan-4-one'>TWU</scene></td></tr>		<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=TWU:(6~{S})-2-azanylidene-6-[2-chloranyl-3-[(2-cyclopropylpyrimidin-5-yl)amino]phenyl]-6-methyl-3-[(2~{S},4~{S})-2-methyloxan-4-yl]-1,3-diazinan-4-one'>TWU</scene></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=8dsr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8dsr OCA], [https://pdbe.org/8dsr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8dsr RCSB], [https://www.ebi.ac.uk/pdbsum/8dsr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8dsr ProSAT]</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=8dsr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8dsr OCA], [https://pdbe.org/8dsr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8dsr RCSB], [https://www.ebi.ac.uk/pdbsum/8dsr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8dsr ProSAT]</span></td></tr>
	</table>		</table>
	~~== Function ==~~
	[https://www.uniprot.org/uniprot/PLM10_PLAF7 PLM10_PLAF7] During the asexual blood stage, processes key proteins essential for merozoite egress and invasion of host erythrocytes (PubMed:29074775, PubMed:32109369). Cleaves and activates proteases SUB1 and SUB2 (PubMed:29074775, PubMed:32109369). May process members of the EBL and Rh protein families (PubMed:32109369). Also cleaves apical membrane protein AMA1 (PubMed:29074775). During the mosquito vector stage and probably in ookinetes, cleaves CelTOS (PubMed:29074775).<ref>PMID:29074775</ref> <ref>PMID:32109369</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
	Plasmepsin X (PMX) is an essential aspartyl protease controlling malaria parasite egress and invasion of erythrocytes, development of functional liver merozoites (prophylactic activity), and blocking transmission to mosquitoes, making it a potential multistage drug target. We report the optimization of an aspartyl protease binding scaffold and the discovery of potent, orally active PMX inhibitors with in vivo antimalarial efficacy. Incorporation of safety evaluation early in the characterization of PMX inhibitors precluded compounds with a long human half-life (t1/2) to be developed. Optimization focused on improving the off-target safety profile led to the identification of UCB7362 that had an improved in vitro and in vivo safety profile but a shorter predicted human t1/2. UCB7362 is estimated to achieve ~~9log10~~ unit reduction in asexual blood-stage parasites with once-daily dosing of 50 mg for 7 days. This work demonstrates the potential to deliver PMX inhibitors with in vivo efficacy to treat malaria.		Plasmepsin X (PMX) is an essential aspartyl protease controlling malaria parasite egress and invasion of erythrocytes, development of functional liver merozoites (prophylactic activity), and blocking transmission to mosquitoes, making it a potential multistage drug target. We report the optimization of an aspartyl protease binding scaffold and the discovery of potent, orally active PMX inhibitors with in vivo antimalarial efficacy. Incorporation of safety evaluation early in the characterization of PMX inhibitors precluded compounds with a long human half-life (t(1/2)) to be developed. Optimization focused on improving the off-target safety profile led to the identification of UCB7362 that had an improved in vitro and in vivo safety profile but a shorter predicted human t(1/2). UCB7362 is estimated to achieve 9â¯logâ¯10 unit reduction in asexual blood-stage parasites with once-daily dosing of 50 mg for 7 days. This work demonstrates the potential to deliver PMX inhibitors with in vivo efficacy to treat malaria.

	Discovery and Characterization of Potent, Efficacious, Orally Available Antimalarial Plasmepsin X Inhibitors and Preclinical Safety Assessment of UCB7362.,Lowe MA, Cardenas A, Valentin JP, Zhu Z, Abendroth J, Castro JL, Class R, Delaunois A, Fleurance R, Gerets H, Gryshkova V, King L, Lorimer DD, MacCoss M, Rowley JH, Rosseels ML, Royer L, Taylor RD, Wong M, Zaccheo O, Chavan VP, Ghule GA, Tapkir BK, Burrows JN, Duffey M, Rottmann M, Wittlin S, Angulo-Barturen I, Jimenez-Diaz MB, Striepen J, Fairhurst KJ, Yeo T, Fidock DA, Cowman AF, Favuzza P, Crespo-Fernandez B, Gamo FJ, Goldberg DE, Soldati-Favre D, Laleu B, de Haro T J Med Chem. 2022 Oct 10. doi: 10.1021/acs.jmedchem.2c01336. PMID:36216349<ref>PMID:36216349</ref>		Discovery and Characterization of Potent, Efficacious, Orally Available Antimalarial Plasmepsin X Inhibitors and Preclinical Safety Assessment of UCB7362.,Lowe MA, Cardenas A, Valentin JP, Zhu Z, Abendroth J, Castro JL, Class R, Delaunois A, Fleurance R, Gerets H, Gryshkova V, King L, Lorimer DD, MacCoss M, Rowley JH, Rosseels ML, Royer L, Taylor RD, Wong M, Zaccheo O, Chavan VP, Ghule GA, Tapkir BK, Burrows JN, Duffey M, Rottmann M, Wittlin S, Angulo-Barturen I, Jimenez-Diaz MB, Striepen J, Fairhurst KJ, Yeo T, Fidock DA, Cowman AF, Favuzza P, Crespo-Fernandez B, Gamo FJ, Goldberg DE, Soldati-Favre D, Laleu B, de Haro T J Med Chem. 2022 Oct 27;65(20):14121-14143. doi: 10.1021/acs.jmedchem.2c01336. , Epub 2022 Oct 10. PMID:36216349<ref>PMID:36216349</ref>

	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>

OCA at 10:14, 25 October 2023

2023-10-25T10:14:05Z

← Older revision		Revision as of 10:14, 25 October 2023
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[8dsr]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Plasmodium_falciparum_3D7 Plasmodium falciparum 3D7]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8DSR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8DSR FirstGlance]. <br>		<table><tr><td colspan='2'>[[8dsr]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Plasmodium_falciparum_3D7 Plasmodium falciparum 3D7]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8DSR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8DSR FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=TWU:(2E,6S)-6-{2-chloro-3-[(2-cyclopropylpyrimidin-5-yl)amino]phenyl}-2-imino-6-methyl-3-[(2S,4S)-2-methyloxan-4-yl]-1,3-diazinan-4-one'>TWU</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]] 2.85Å</td></tr>
			<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=TWU:(2E,6S)-6-{2-chloro-3-[(2-cyclopropylpyrimidin-5-yl)amino]phenyl}-2-imino-6-methyl-3-[(2S,4S)-2-methyloxan-4-yl]-1,3-diazinan-4-one'>TWU</scene></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=8dsr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8dsr OCA], [https://pdbe.org/8dsr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8dsr RCSB], [https://www.ebi.ac.uk/pdbsum/8dsr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8dsr ProSAT]</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=8dsr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8dsr OCA], [https://pdbe.org/8dsr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8dsr RCSB], [https://www.ebi.ac.uk/pdbsum/8dsr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8dsr ProSAT]</span></td></tr>
	</table>		</table>
Line 18:		Line 19:
	</div>		</div>
	<div class="pdbe-citations 8dsr" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 8dsr" style="background-color:#fffaf0;"></div>

			==See Also==
			*[[Plasmepsin\|Plasmepsin]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 19:27, 19 October 2022

2022-10-19T19:27:17Z

← Older revision		Revision as of 19:27, 19 October 2022
Line 1:		Line 1:
	~~'''Unreleased structure'''~~

	~~The entry~~ 8dsr is ~~ON HOLD until Paper~~ Publication		==Structure of Plasmepsin X (PM10, PMX) from Plasmodium falciparum 3D7 in complex with UCB7362==
			<StructureSection load='8dsr' size='340' side='right'caption='[[8dsr]], [[Resolution\|resolution]] 2.85Å' scene=''>
			== Structural highlights ==
			<table><tr><td colspan='2'>[[8dsr]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Plasmodium_falciparum_3D7 Plasmodium falciparum 3D7]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8DSR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8DSR FirstGlance]. <br>
			</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=TWU:(2E,6S)-6-{2-chloro-3-[(2-cyclopropylpyrimidin-5-yl)amino]phenyl}-2-imino-6-methyl-3-[(2S,4S)-2-methyloxan-4-yl]-1,3-diazinan-4-one'>TWU</scene></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=8dsr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8dsr OCA], [https://pdbe.org/8dsr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8dsr RCSB], [https://www.ebi.ac.uk/pdbsum/8dsr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8dsr ProSAT]</span></td></tr>
			</table>
			== Function ==
			[https://www.uniprot.org/uniprot/PLM10_PLAF7 PLM10_PLAF7] During the asexual blood stage, processes key proteins essential for merozoite egress and invasion of host erythrocytes (PubMed:29074775, PubMed:32109369). Cleaves and activates proteases SUB1 and SUB2 (PubMed:29074775, PubMed:32109369). May process members of the EBL and Rh protein families (PubMed:32109369). Also cleaves apical membrane protein AMA1 (PubMed:29074775). During the mosquito vector stage and probably in ookinetes, cleaves CelTOS (PubMed:29074775).<ref>PMID:29074775</ref> <ref>PMID:32109369</ref>
			<div style="background-color:#fffaf0;">
			== Publication Abstract from PubMed ==
			Plasmepsin X (PMX) is an essential aspartyl protease controlling malaria parasite egress and invasion of erythrocytes, development of functional liver merozoites (prophylactic activity), and blocking transmission to mosquitoes, making it a potential multistage drug target. We report the optimization of an aspartyl protease binding scaffold and the discovery of potent, orally active PMX inhibitors with in vivo antimalarial efficacy. Incorporation of safety evaluation early in the characterization of PMX inhibitors precluded compounds with a long human half-life (t1/2) to be developed. Optimization focused on improving the off-target safety profile led to the identification of UCB7362 that had an improved in vitro and in vivo safety profile but a shorter predicted human t1/2. UCB7362 is estimated to achieve 9log10 unit reduction in asexual blood-stage parasites with once-daily dosing of 50 mg for 7 days. This work demonstrates the potential to deliver PMX inhibitors with in vivo efficacy to treat malaria.

	~~Authors:~~ Abendroth, J., ~~Lorimer~~, D.D.~~, Seattle Structural Genomics Center for Infectious Disease (SSGCID)~~		Discovery and Characterization of Potent, Efficacious, Orally Available Antimalarial Plasmepsin X Inhibitors and Preclinical Safety Assessment of UCB7362.,Lowe MA, Cardenas A, Valentin JP, Zhu Z, Abendroth J, Castro JL, Class R, Delaunois A, Fleurance R, Gerets H, Gryshkova V, King L, Lorimer DD, MacCoss M, Rowley JH, Rosseels ML, Royer L, Taylor RD, Wong M, Zaccheo O, Chavan VP, Ghule GA, Tapkir BK, Burrows JN, Duffey M, Rottmann M, Wittlin S, Angulo-Barturen I, Jimenez-Diaz MB, Striepen J, Fairhurst KJ, Yeo T, Fidock DA, Cowman AF, Favuzza P, Crespo-Fernandez B, Gamo FJ, Goldberg DE, Soldati-Favre D, Laleu B, de Haro T J Med Chem. 2022 Oct 10. doi: 10.1021/acs.jmedchem.2c01336. PMID:36216349<ref>PMID:36216349</ref>

	~~Description~~: ~~Structure of Plasmepsin X (PM10, PMX) from Plasmodium falciparum 3D7 in complex with UCB7362~~		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	[[Category: ~~Unreleased~~ Structures]]		</div>
	[[Category: ~~Seattle Structural Genomics Center For Infectious Disease (Ssgcid)~~]]		<div class="pdbe-citations 8dsr" style="background-color:#fffaf0;"></div>
	[[Category: ~~Lorimer, D.D~~]]		== References ==
	[[Category: ~~Abendroth, J~~]]		<references/>
			__TOC__
			</StructureSection>
			[[Category: Large Structures]]
			[[Category: Plasmodium falciparum 3D7]]
			[[Category: Abendroth J]]
			[[Category: Lorimer DD]]

OCA at 04:04, 18 August 2022

2022-08-18T04:04:14Z

← Older revision		Revision as of 04:04, 18 August 2022
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

	The entry 8dsr is ON HOLD		The entry 8dsr is ON HOLD until Paper Publication

	Authors: Abendroth, J., Lorimer, D.D., Seattle Structural Genomics Center for Infectious Disease (SSGCID)		Authors: Abendroth, J., Lorimer, D.D., Seattle Structural Genomics Center for Infectious Disease (SSGCID)
Line 8:		Line 8:
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
	[[Category: Seattle Structural Genomics Center For Infectious Disease (Ssgcid)]]		[[Category: Seattle Structural Genomics Center For Infectious Disease (Ssgcid)]]
			[[Category: Lorimer, D.D]]
	[[Category: Abendroth, J]]		[[Category: Abendroth, J]]
	~~[[Category: Lorimer, D.D]]~~

OCA at 04:02, 10 August 2022

2022-08-10T04:02:30Z

← Older revision		Revision as of 04:02, 10 August 2022
Line 3:		Line 3:
	The entry 8dsr is ON HOLD		The entry 8dsr is ON HOLD

	Authors: Abendroth, J., Lorimer, D.D.		Authors: Abendroth, J., Lorimer, D.D., Seattle Structural Genomics Center for Infectious Disease (SSGCID)

	Description: Structure of Plasmepsin X (PM10, PMX) from Plasmodium falciparum 3D7 in complex with UCB7362		Description: Structure of Plasmepsin X (PM10, PMX) from Plasmodium falciparum 3D7 in complex with UCB7362
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
			[[Category: Seattle Structural Genomics Center For Infectious Disease (Ssgcid)]]
	[[Category: Abendroth, J]]		[[Category: Abendroth, J]]
	[[Category: Lorimer, D.D]]		[[Category: Lorimer, D.D]]

OCA: Protected "8dsr" [edit=sysop:move=sysop]

2022-08-03T03:55:31Z

Protected "8dsr" [edit=sysop:move=sysop]

← Older revision	Revision as of 03:55, 3 August 2022
(No difference)

OCA: New page: '''Unreleased structure''' The entry 8dsr is ON HOLD Authors: Abendroth, J., Lorimer, D.D. Description: Structure of Plasmepsin X (PM10, PMX) from Plasmodium falciparum 3D7 in complex ...

2022-08-03T03:55:30Z

New page: '''Unreleased structure''' The entry 8dsr is ON HOLD Authors: Abendroth, J., Lorimer, D.D. Description: Structure of Plasmepsin X (PM10, PMX) from Plasmodium falciparum 3D7 in complex ...

New page

'''Unreleased structure'''

The entry 8dsr is ON HOLD

Authors: Abendroth, J., Lorimer, D.D.

Description: Structure of Plasmepsin X (PM10, PMX) from Plasmodium falciparum 3D7 in complex with UCB7362
[[Category: Unreleased Structures]]
[[Category: Abendroth, J]]
[[Category: Lorimer, D.D]]