About: Nitric Oxide Synthase Inhibitors That Interact with Both Heme Propionate and Tetrahydrobiopterin Show High Isoform Selectivity

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An Entity of Type : http://linked.opendata.cz/ontology/domain/vavai/Vysledek, within Data Space : linked.opendata.cz associated with source document(s)

Attributes	Values
rdf:type	skos:Concept http://linked.opendata.cz/ontology/domain/vavai/Vysledek
rdfs:seeAlso	http://dx.doi.org/10.1021/jm5004182
Description	Overproduction of NO by nNOS is implicated in the pathogenesis of diverse neuronal disorders. Since NO signaling is involved in diverse physiological functions, selective inhibition of nNOS over other isoforms is essential to minimize side effects. A series of alpha-amino functionalized aminopyridine derivatives (3-8) were designed to probe the structure activity relationship between ligand, heme propionate, and H4B. Compound 8R was identified as the most potent and selective molecule of this study, exhibiting a K-i of 24 nM for nNOS, with 273-fold and 2822-fold selectivity against iNOS and eNOS, respectively. Although crystal structures of 8R complexed with nNOS and eNOS revealed a similar binding mode, the selectivity stems from the distinct electrostatic environments in two isoforms that result in much lower inhibitor binding free energy in nNOS than in eNOS. These findings provide a basis for further development of simple, but even more selective and potent, nNOS inhibitors. Overproduction of NO by nNOS is implicated in the pathogenesis of diverse neuronal disorders. Since NO signaling is involved in diverse physiological functions, selective inhibition of nNOS over other isoforms is essential to minimize side effects. A series of alpha-amino functionalized aminopyridine derivatives (3-8) were designed to probe the structure activity relationship between ligand, heme propionate, and H4B. Compound 8R was identified as the most potent and selective molecule of this study, exhibiting a K-i of 24 nM for nNOS, with 273-fold and 2822-fold selectivity against iNOS and eNOS, respectively. Although crystal structures of 8R complexed with nNOS and eNOS revealed a similar binding mode, the selectivity stems from the distinct electrostatic environments in two isoforms that result in much lower inhibitor binding free energy in nNOS than in eNOS. These findings provide a basis for further development of simple, but even more selective and potent, nNOS inhibitors. (en)
Title	Nitric Oxide Synthase Inhibitors That Interact with Both Heme Propionate and Tetrahydrobiopterin Show High Isoform Selectivity Nitric Oxide Synthase Inhibitors That Interact with Both Heme Propionate and Tetrahydrobiopterin Show High Isoform Selectivity (en)
skos:prefLabel	Nitric Oxide Synthase Inhibitors That Interact with Both Heme Propionate and Tetrahydrobiopterin Show High Isoform Selectivity Nitric Oxide Synthase Inhibitors That Interact with Both Heme Propionate and Tetrahydrobiopterin Show High Isoform Selectivity (en)
skos:notation	RIV/00216208:11110/14:10284256!RIV15-MSM-11110___
http://linked.open...avai/riv/aktivita	P Z
http://linked.open...avai/riv/aktivity	P(1M0520), Z(MSM0021620806)
http://linked.open...iv/cisloPeriodika	10
http://linked.open...vai/riv/dodaniDat	2015
http://linked.open...aciTvurceVysledku	Martásek, Pavel
http://linked.open.../riv/druhVysledku	J - Článek v odborném periodiku
http://linked.open...iv/duvernostUdaju	S - Úplné a pravdivé údaje nepodléhající ochraně podle zvláštních právních předpisů
http://linked.open...titaPredkladatele	Univerzita Karlova v Praze / 1. lékařská fakulta
http://linked.open...dnocenehoVysledku	32631
http://linked.open...ai/riv/idVysledku	RIV/00216208:11110/14:10284256
http://linked.open...riv/jazykVysledku	eng - angličtina
http://linked.open.../riv/klicovaSlova	nos; probe; strategy; prevention; disease; active-site; vascular system; escherichia-coli (en)
http://linked.open.../riv/klicoveSlovo	escherichia-coli active-site disease strategy nos prevention probe vascular system
http://linked.open...odStatuVydavatele	US - Spojené státy americké
http://linked.open...ontrolniKodProRIV	[91CE201FD3FF]
http://linked.open...i/riv/nazevZdroje	Journal of Medicinal Chemistry
http://linked.open...in/vavai/riv/obor	CE
http://linked.open...ichTvurcuVysledku	1 (xsd:int)
http://linked.open...cetTvurcuVysledku	8 (xsd:int)
http://linked.open...vavai/riv/projekt	Center for Applied Genomics
http://linked.open...UplatneniVysledku	2014
http://linked.open...v/svazekPeriodika	57
http://linked.open...iv/tvurceVysledku	Martásek, Pavel Chreifi, Georges Li, Huiying Poulos, Thomas L. Roman, Linda J. Silverman, Richard B. Kang, Soosung Tang, Wei
http://linked.open...ain/vavai/riv/wos	000336510100034
http://linked.open...n/vavai/riv/zamer	Molekulární biologie a patologie buňky za normy a u vybraných klinicky závažných patologických procesů
issn	0022-2623
number of pages	15 (xsd:int)
http://bibframe.org/vocab/doi	10.1021/jm5004182
http://localhost/t...ganizacniJednotka	11110

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