4eux - Revision history

OCA at 10:52, 13 August 2026

2026-08-13T10:52:54Z

← Older revision		Revision as of 10:52, 13 August 2026
Line 10:		Line 10:
	== Function ==		== Function ==
	[https://www.uniprot.org/uniprot/NOS1_RAT NOS1_RAT] Produces nitric oxide (NO) which is a messenger molecule with diverse functions throughout the body. In the brain and peripheral nervous system, NO displays many properties of a neurotransmitter. Inhibitory transmitter for non-adrenergic and non-cholinergic nerves in the colorectum. Probably has nitrosylase activity and mediates cysteine S-nitrosylation of cytoplasmic target proteins such SRR. Inhibitory transmitter for non-adrenergic and non-cholinergic nerves in the colorectum.		[https://www.uniprot.org/uniprot/NOS1_RAT NOS1_RAT] Produces nitric oxide (NO) which is a messenger molecule with diverse functions throughout the body. In the brain and peripheral nervous system, NO displays many properties of a neurotransmitter. Inhibitory transmitter for non-adrenergic and non-cholinergic nerves in the colorectum. Probably has nitrosylase activity and mediates cysteine S-nitrosylation of cytoplasmic target proteins such SRR. Inhibitory transmitter for non-adrenergic and non-cholinergic nerves in the colorectum.
			<div style="background-color:#fffaf0;">
			== Publication Abstract from PubMed ==
			The reduction of pathophysiologic levels of nitric oxide through inhibition of neuronal nitric oxide synthase (nNOS) has the potential to be therapeutically beneficial in various neurodegenerative diseases. We have developed a series of pyrrolidine-based nNOS inhibitors that exhibit excellent potencies and isoform selectivities (J. Am. Chem. Soc. 2010, 132, 5437). However, there are still important challenges, such as how to decrease the multiple positive charges derived from basic amino groups, which contribute to poor bioavailability, without losing potency and/or selectivity. Here we present an interdisciplinary study combining molecular docking, crystallography, molecular dynamics simulations, synthesis, and enzymology to explore potential pharmacophoric features of nNOS inhibitors and to design potent and selective monocationic nNOS inhibitors. The simulation results indicate that different hydrogen bond patterns, electrostatic interactions, hydrophobic interactions, and a water molecule bridge are key factors for stabilizing ligands and controlling ligand orientation. We find that a heteroatom in the aromatic head or linker chain of the ligand provides additional stability and blocks the substrate binding pocket. Finally, the computational insights are experimentally validated with double-headed pyridine analogs. The compounds reported here are among the most potent and selective monocationic pyrrolidine-based nNOS inhibitors reported to date, and 10 shows improved membrane permeability.

			Selective Monocationic Inhibitors of Neuronal Nitric Oxide Synthase. Binding Mode Insights from Molecular Dynamics Simulations.,Huang H, Ji H, Li H, Jing Q, Jansen Labby K, Martasek P, Roman LJ, Poulos TL, Silverman RB J Am Chem Soc. 2012 Jun 25. PMID:22731813<ref>PMID:22731813</ref>

			From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
			</div>
			<div class="pdbe-citations 4eux" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==
	*[[Nitric Oxide Synthase 3D structures\|Nitric Oxide Synthase 3D structures]]		*[[Nitric Oxide Synthase 3D structures\|Nitric Oxide Synthase 3D structures]]
			== References ==
			<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>

OCA at 15:09, 14 March 2024

2024-03-14T15:09:49Z

← Older revision		Revision as of 15:09, 14 March 2024
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4eux]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4EUX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4EUX FirstGlance]. <br>		<table><tr><td colspan='2'>[[4eux]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4EUX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4EUX FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=H4B:5,6,7,8-TETRAHYDROBIOPTERIN'>H4B</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=HW1:6-[5-({(3R,4R)-4-[(6-AMINO-4-METHYLPYRIDIN-2-YL)METHYL]PYRROLIDIN-3-YL}OXY)PENTYL]-4-METHYLPYRIDIN-2-AMINE'>HW1</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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]] 2.14Å</td></tr>
			<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=H4B:5,6,7,8-TETRAHYDROBIOPTERIN'>H4B</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=HW1:6-[5-({(3R,4R)-4-[(6-AMINO-4-METHYLPYRIDIN-2-YL)METHYL]PYRROLIDIN-3-YL}OXY)PENTYL]-4-METHYLPYRIDIN-2-AMINE'>HW1</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=4eux FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4eux OCA], [https://pdbe.org/4eux PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4eux RCSB], [https://www.ebi.ac.uk/pdbsum/4eux PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4eux 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=4eux FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4eux OCA], [https://pdbe.org/4eux PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4eux RCSB], [https://www.ebi.ac.uk/pdbsum/4eux PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4eux ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
	[https://www.uniprot.org/uniprot/NOS1_RAT NOS1_RAT] Produces nitric oxide (NO) which is a messenger molecule with diverse functions throughout the body. In the brain and peripheral nervous system, NO displays many properties of a neurotransmitter. Inhibitory transmitter for non-adrenergic and non-cholinergic nerves in the colorectum. Probably has nitrosylase activity and mediates cysteine S-nitrosylation of cytoplasmic target proteins such SRR. Inhibitory transmitter for non-adrenergic and non-cholinergic nerves in the colorectum.		[https://www.uniprot.org/uniprot/NOS1_RAT NOS1_RAT] Produces nitric oxide (NO) which is a messenger molecule with diverse functions throughout the body. In the brain and peripheral nervous system, NO displays many properties of a neurotransmitter. Inhibitory transmitter for non-adrenergic and non-cholinergic nerves in the colorectum. Probably has nitrosylase activity and mediates cysteine S-nitrosylation of cytoplasmic target proteins such SRR. Inhibitory transmitter for non-adrenergic and non-cholinergic nerves in the colorectum.
	~~<div style="background-color:#fffaf0;">~~
	~~== Publication Abstract from PubMed ==~~
	The reduction of pathophysiologic levels of nitric oxide through inhibition of neuronal nitric oxide synthase (nNOS) has the potential to be therapeutically beneficial in various neurodegenerative diseases. We have developed a series of pyrrolidine-based nNOS inhibitors that exhibit excellent potencies and isoform selectivities (J. Am. Chem. Soc. 2010, 132, 5437). However, there are still important challenges, such as how to decrease the multiple positive charges derived from basic amino groups, which contribute to poor bioavailability, without losing potency and/or selectivity. Here we present an interdisciplinary study combining molecular docking, crystallography, molecular dynamics simulations, synthesis, and enzymology to explore potential pharmacophoric features of nNOS inhibitors and to design potent and selective monocationic nNOS inhibitors. The simulation results indicate that different hydrogen bond patterns, electrostatic interactions, hydrophobic interactions, and a water molecule bridge are key factors for stabilizing ligands and controlling ligand orientation. We find that a heteroatom in the aromatic head or linker chain of the ligand provides additional stability and blocks the substrate binding pocket. Finally, the computational insights are experimentally validated with double-headed pyridine analogs. The compounds reported here are among the most potent and selective monocationic pyrrolidine-based nNOS inhibitors reported to date, and 10 shows improved membrane permeability.

	Selective Monocationic Inhibitors of Neuronal Nitric Oxide Synthase. Binding Mode Insights from Molecular Dynamics Simulations.,Huang H, Ji H, Li H, Jing Q, Jansen Labby K, Martasek P, Roman LJ, Poulos TL, Silverman RB J Am Chem Soc. 2012 Jun 25. PMID:22731813<ref>PMID:22731813</ref>

	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~
	~~</div>~~
	~~<div class="pdbe-citations 4eux" style="background-color:#fffaf0;"></div>~~

	==See Also==		==See Also==
	*[[Nitric Oxide Synthase 3D structures\|Nitric Oxide Synthase 3D structures]]		*[[Nitric Oxide Synthase 3D structures\|Nitric Oxide Synthase 3D structures]]
	~~== References ==~~
	~~<references/>~~
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>

OCA at 04:17, 7 October 2022

2022-10-07T04:17:39Z

← Older revision		Revision as of 04:17, 7 October 2022
Line 1:		Line 1:

	==Structure of neuronal nitric oxide synthase heme domain in complex with 6-(5-(((3R,4R)-4-((6-amino-4-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)oxy)pentyl)-4-methylpyridin-2-amine==		==Structure of neuronal nitric oxide synthase heme domain in complex with 6-(5-(((3R,4R)-4-((6-amino-4-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)oxy)pentyl)-4-methylpyridin-2-amine==
	<StructureSection load='4eux' size='340' side='right' caption='[[4eux]], [[Resolution\|resolution]] 2.14Å' scene=''>		<StructureSection load='4eux' size='340' side='right'caption='[[4eux]], [[Resolution\|resolution]] 2.14Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4eux]] is a 2 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~Buffalo_rat Buffalo rat~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4EUX OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4EUX FirstGlance]. <br>		<table><tr><td colspan='2'>[[4eux]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4EUX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4EUX FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=H4B:5,6,7,8-TETRAHYDROBIOPTERIN'>H4B</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=HW1:6-[5-({(3R,4R)-4-[(6-AMINO-4-METHYLPYRIDIN-2-YL)METHYL]PYRROLIDIN-3-YL}OXY)PENTYL]-4-METHYLPYRIDIN-2-AMINE'>HW1</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene~~></td></tr>~~		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=H4B:5,6,7,8-TETRAHYDROBIOPTERIN'>H4B</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=HW1:6-[5-({(3R,4R)-4-[(6-AMINO-4-METHYLPYRIDIN-2-YL)METHYL]PYRROLIDIN-3-YL}OXY)PENTYL]-4-METHYLPYRIDIN-2-AMINE'>HW1</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">Nos1, Bnos ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10116 Buffalo rat])</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=4eux FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4eux OCA], [https://pdbe.org/4eux PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4eux RCSB], [https://www.ebi.ac.uk/pdbsum/4eux PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4eux 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/Nitric-oxide_synthase_(NADPH_dependent) Nitric-oxide synthase (NADPH dependent)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.13.39 1.14.13.39] </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=4eux FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4eux OCA], [~~http~~://pdbe.org/4eux PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4eux RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4eux PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4eux ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
	[~~[http~~://www.uniprot.org/uniprot/NOS1_RAT NOS1_RAT]] Produces nitric oxide (NO) which is a messenger molecule with diverse functions throughout the body. In the brain and peripheral nervous system, NO displays many properties of a neurotransmitter. Inhibitory transmitter for non-adrenergic and non-cholinergic nerves in the colorectum. Probably has nitrosylase activity and mediates cysteine S-nitrosylation of cytoplasmic target proteins such SRR. Inhibitory transmitter for non-adrenergic and non-cholinergic nerves in the colorectum.		[https://www.uniprot.org/uniprot/NOS1_RAT NOS1_RAT] Produces nitric oxide (NO) which is a messenger molecule with diverse functions throughout the body. In the brain and peripheral nervous system, NO displays many properties of a neurotransmitter. Inhibitory transmitter for non-adrenergic and non-cholinergic nerves in the colorectum. Probably has nitrosylase activity and mediates cysteine S-nitrosylation of cytoplasmic target proteins such SRR. Inhibitory transmitter for non-adrenergic and non-cholinergic nerves in the colorectum.
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 20:		Line 18:
	</div>		</div>
	<div class="pdbe-citations 4eux" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 4eux" style="background-color:#fffaf0;"></div>

			==See Also==
			*[[Nitric Oxide Synthase 3D structures\|Nitric Oxide Synthase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: ~~Buffalo rat~~]]		[[Category: Large Structures]]
	[[Category: ~~Li, H~~]]		[[Category: Rattus norvegicus]]
	[[Category: ~~Poulos, T L~~]]		[[Category: Li H]]
	[[Category: ~~Inhibitor binding]]~~		[[Category: Poulos TL]]
	~~[[Category: Nitric oxide synthase]]~~
	~~[[Category: Oxidoreductase-oxidoreductase inhibitor complex~~]]

OCA at 08:10, 15 November 2017

2017-11-15T08:10:12Z

← Older revision		Revision as of 08:10, 15 November 2017
Line 20:		Line 20:
	</div>		</div>
	<div class="pdbe-citations 4eux" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 4eux" style="background-color:#fffaf0;"></div>

	~~==See Also==~~
	*[[Nitric Oxide Synthase\|Nitric Oxide Synthase]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 16:38, 4 August 2016

2016-08-04T16:38:05Z

← Older revision		Revision as of 16:38, 4 August 2016
Line 1:		Line 1:

	==Structure of neuronal nitric oxide synthase heme domain in complex with 6-(5-(((3R,4R)-4-((6-amino-4-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)oxy)pentyl)-4-methylpyridin-2-amine==		==Structure of neuronal nitric oxide synthase heme domain in complex with 6-(5-(((3R,4R)-4-((6-amino-4-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)oxy)pentyl)-4-methylpyridin-2-amine==
	<StructureSection load='4eux' size='340' side='right' caption='[[4eux]], [[Resolution\|resolution]] 2.14Å' scene=''>		<StructureSection load='4eux' size='340' side='right' caption='[[4eux]], [[Resolution\|resolution]] 2.14Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4eux]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/~~Rattus_norvegicus Rattus norvegicus~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4EUX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4EUX FirstGlance]. <br>		<table><tr><td colspan='2'>[[4eux]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Buffalo_rat Buffalo rat]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4EUX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4EUX FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=H4B:5,6,7,8-TETRAHYDROBIOPTERIN'>H4B</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=HW1:6-[5-({(3R,4R)-4-[(6-AMINO-4-METHYLPYRIDIN-2-YL)METHYL]PYRROLIDIN-3-YL}OXY)PENTYL]-4-METHYLPYRIDIN-2-AMINE'>HW1</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=H4B:5,6,7,8-TETRAHYDROBIOPTERIN'>H4B</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=HW1:6-[5-({(3R,4R)-4-[(6-AMINO-4-METHYLPYRIDIN-2-YL)METHYL]PYRROLIDIN-3-YL}OXY)PENTYL]-4-METHYLPYRIDIN-2-AMINE'>HW1</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">Nos1, Bnos ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10116 ~~Rattus norvegicus~~])</td></tr>		<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">Nos1, Bnos ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10116 Buffalo rat])</td></tr>
	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Nitric-~~oxide_synthase~~ Nitric-oxide synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.13.39 1.14.13.39] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Nitric-oxide_synthase_(NADPH_dependent) Nitric-oxide synthase (NADPH dependent)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.13.39 1.14.13.39] </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=4eux FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4eux OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4eux RCSB], [http://www.ebi.ac.uk/pdbsum/4eux PDBsum]</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=4eux FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4eux OCA], [http://pdbe.org/4eux PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4eux RCSB], [http://www.ebi.ac.uk/pdbsum/4eux PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4eux ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
Line 18:		Line 19:
	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>
	</div>		</div>
			<div class="pdbe-citations 4eux" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==
Line 25:		Line 27:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: ~~Nitric-oxide synthase]]~~		[[Category: Buffalo rat]]
	~~[[Category: Rattus norvegicus~~]]
	[[Category: Li, H]]		[[Category: Li, H]]
	[[Category: Poulos, T L]]		[[Category: Poulos, T L]]

OCA at 17:07, 24 December 2014

2014-12-24T17:07:23Z

← Older revision		Revision as of 17:07, 24 December 2014
Line 8:		Line 8:
	<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=4eux FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4eux OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4eux RCSB], [http://www.ebi.ac.uk/pdbsum/4eux PDBsum]</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=4eux FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4eux OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4eux RCSB], [http://www.ebi.ac.uk/pdbsum/4eux PDBsum]</span></td></tr>
	</table>		</table>
			== Function ==
			[[http://www.uniprot.org/uniprot/NOS1_RAT NOS1_RAT]] Produces nitric oxide (NO) which is a messenger molecule with diverse functions throughout the body. In the brain and peripheral nervous system, NO displays many properties of a neurotransmitter. Inhibitory transmitter for non-adrenergic and non-cholinergic nerves in the colorectum. Probably has nitrosylase activity and mediates cysteine S-nitrosylation of cytoplasmic target proteins such SRR. Inhibitory transmitter for non-adrenergic and non-cholinergic nerves in the colorectum.
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==

OCA at 17:42, 9 December 2014

2014-12-09T17:42:44Z

← Older revision		Revision as of 17:42, 9 December 2014
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	[[~~Image~~:~~4eux~~.~~png~~\|~~left~~\|~~200px~~]]		==Structure of neuronal nitric oxide synthase heme domain in complex with 6-(5-(((3R,4R)-4-((6-amino-4-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)oxy)pentyl)-4-methylpyridin-2-amine==
			<StructureSection load='4eux' size='340' side='right' caption='[[4eux]], [[Resolution\|resolution]] 2.14Å' scene=''>
			== Structural highlights ==
			<table><tr><td colspan='2'>[[4eux]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4EUX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4EUX FirstGlance]. <br>
			</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=H4B:5,6,7,8-TETRAHYDROBIOPTERIN'>H4B</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=HW1:6-[5-({(3R,4R)-4-[(6-AMINO-4-METHYLPYRIDIN-2-YL)METHYL]PYRROLIDIN-3-YL}OXY)PENTYL]-4-METHYLPYRIDIN-2-AMINE'>HW1</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
			<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">Nos1, Bnos ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10116 Rattus norvegicus])</td></tr>
			<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Nitric-oxide_synthase Nitric-oxide synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.13.39 1.14.13.39] </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=4eux FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4eux OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4eux RCSB], [http://www.ebi.ac.uk/pdbsum/4eux PDBsum]</span></td></tr>
			</table>
			<div style="background-color:#fffaf0;">
			== Publication Abstract from PubMed ==
			The reduction of pathophysiologic levels of nitric oxide through inhibition of neuronal nitric oxide synthase (nNOS) has the potential to be therapeutically beneficial in various neurodegenerative diseases. We have developed a series of pyrrolidine-based nNOS inhibitors that exhibit excellent potencies and isoform selectivities (J. Am. Chem. Soc. 2010, 132, 5437). However, there are still important challenges, such as how to decrease the multiple positive charges derived from basic amino groups, which contribute to poor bioavailability, without losing potency and/or selectivity. Here we present an interdisciplinary study combining molecular docking, crystallography, molecular dynamics simulations, synthesis, and enzymology to explore potential pharmacophoric features of nNOS inhibitors and to design potent and selective monocationic nNOS inhibitors. The simulation results indicate that different hydrogen bond patterns, electrostatic interactions, hydrophobic interactions, and a water molecule bridge are key factors for stabilizing ligands and controlling ligand orientation. We find that a heteroatom in the aromatic head or linker chain of the ligand provides additional stability and blocks the substrate binding pocket. Finally, the computational insights are experimentally validated with double-headed pyridine analogs. The compounds reported here are among the most potent and selective monocationic pyrrolidine-based nNOS inhibitors reported to date, and 10 shows improved membrane permeability.

	~~{{STRUCTURE_4eux\| PDB=4eux \| SCENE= }}~~		Selective Monocationic Inhibitors of Neuronal Nitric Oxide Synthase. Binding Mode Insights from Molecular Dynamics Simulations.,Huang H, Ji H, Li H, Jing Q, Jansen Labby K, Martasek P, Roman LJ, Poulos TL, Silverman RB J Am Chem Soc. 2012 Jun 25. PMID:22731813<ref>PMID:22731813</ref>

	~~===Structure~~ of ~~neuronal nitric oxide synthase heme domain in complex with 6-(5-(((3R,4R)-4-((6-amino-4-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)oxy)pentyl)-4-methylpyridin-2-amine===~~		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
			</div>

			==See Also==
	==~~About this Structure~~==		*[[Nitric Oxide Synthase\|Nitric Oxide Synthase]]
	[[~~4eux~~]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4EUX OCA].		== References ==
			<references/>
	==~~Reference~~==		__TOC__
	<~~ref group="xtra">PMID:022731813<~~/~~ref~~><~~references group="xtra"~~/>		</StructureSection>
	[[Category: Nitric-oxide synthase]]		[[Category: Nitric-oxide synthase]]
	[[Category: Rattus norvegicus]]		[[Category: Rattus norvegicus]]
	[[Category: Li, H.]]		[[Category: Li, H]]
	[[Category: Poulos, T L.]]		[[Category: Poulos, T L]]
	[[Category: Inhibitor binding]]		[[Category: Inhibitor binding]]
	[[Category: Nitric oxide synthase]]		[[Category: Nitric oxide synthase]]
	[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]		[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]

OCA at 07:11, 14 November 2012

2012-11-14T07:11:06Z

← Older revision		Revision as of 07:11, 14 November 2012
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	[[Image:4eux.~~jpg~~\|left\|200px]]		[[Image:4eux.png\|left\|200px]]

	{{STRUCTURE_4eux\| PDB=4eux \| SCENE= }}		{{STRUCTURE_4eux\| PDB=4eux \| SCENE= }}
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	===Structure of neuronal nitric oxide synthase heme domain in complex with 6-(5-(((3R,4R)-4-((6-amino-4-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)oxy)pentyl)-4-methylpyridin-2-amine===		===Structure of neuronal nitric oxide synthase heme domain in complex with 6-(5-(((3R,4R)-4-((6-amino-4-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)oxy)pentyl)-4-methylpyridin-2-amine===

	~~{{ABSTRACT_PUBMED_22731813}}~~

	==About this Structure==		==About this Structure==

OCA at 08:10, 11 July 2012

2012-07-11T08:10:44Z

← Older revision		Revision as of 08:10, 11 July 2012
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	~~'''Unreleased structure'''~~		[[Image:4eux.jpg\|left\|200px]]

	~~The entry~~ 4eux ~~is ON HOLD~~ ~~until Paper Publication~~		{{STRUCTURE_4eux\| PDB=4eux \| SCENE= }}

	~~Authors: Li~~, ~~H., Poulos, T.L.~~		===Structure of neuronal nitric oxide synthase heme domain in complex with 6-(5-(((3R,4R)-4-((6-amino-4-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)oxy)pentyl)-4-methylpyridin-2-amine===

	~~Description:~~ Structure ~~of neuronal nitric oxide synthase heme domain in complex~~ with 6-(5-~~(((3R~~,~~4R)~~-~~4-((6-amino-4-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)oxy)pentyl)-4-methylpyridin-2-amine~~		{{ABSTRACT_PUBMED_22731813}}

			==About this Structure==
			[[4eux]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4EUX OCA].

			==Reference==
			<ref group="xtra">PMID:022731813</ref><references group="xtra"/>
			[[Category: Nitric-oxide synthase]]
			[[Category: Rattus norvegicus]]
			[[Category: Li, H.]]
			[[Category: Poulos, T L.]]
			[[Category: Inhibitor binding]]
			[[Category: Nitric oxide synthase]]
			[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]

OCA at 07:17, 6 June 2012

2012-06-06T07:17:40Z

← Older revision		Revision as of 07:17, 6 June 2012
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	'''Unreleased structure'''		'''Unreleased structure'''

	The entry 4eux is ON HOLD		The entry 4eux is ON HOLD until Paper Publication

	Authors: Li, H., Poulos, T.L.		Authors: Li, H., Poulos, T.L.

	Description: Structure of neuronal nitric oxide synthase heme domain in complex with 6-(5-(((3R,4R)-4-((6-amino-4-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)oxy)pentyl)-4-methylpyridin-2-amine		Description: Structure of neuronal nitric oxide synthase heme domain in complex with 6-(5-(((3R,4R)-4-((6-amino-4-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)oxy)pentyl)-4-methylpyridin-2-amine