Nitric Oxide Synthase Inhibitors That Interact with Both Heme Propionate and Tetrahydrobiopterin Show High Isoform Selectivity
Identifikátory výsledku
Kód výsledku v IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11110%2F14%3A10284256" target="_blank" >RIV/00216208:11110/14:10284256 - isvavai.cz</a>
Výsledek na webu
<a href="http://dx.doi.org/10.1021/jm5004182" target="_blank" >http://dx.doi.org/10.1021/jm5004182</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1021/jm5004182" target="_blank" >10.1021/jm5004182</a>
Alternativní jazyky
Jazyk výsledku
angličtina
Název v původním jazyce
Nitric Oxide Synthase Inhibitors That Interact with Both Heme Propionate and Tetrahydrobiopterin Show High Isoform Selectivity
Popis výsledku v původním jazyce
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.
Název v anglickém jazyce
Nitric Oxide Synthase Inhibitors That Interact with Both Heme Propionate and Tetrahydrobiopterin Show High Isoform Selectivity
Popis výsledku anglicky
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.
Klasifikace
Druh
J<sub>x</sub> - Nezařazeno - Článek v odborném periodiku (Jimp, Jsc a Jost)
CEP obor
CE - Biochemie
OECD FORD obor
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Návaznosti výsledku
Projekt
<a href="/cs/project/1M0520" target="_blank" >1M0520: Centrum aplikované genomiky</a><br>
Návaznosti
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)<br>Z - Vyzkumny zamer (s odkazem do CEZ)
Ostatní
Rok uplatnění
2014
Kód důvěrnosti údajů
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Údaje specifické pro druh výsledku
Název periodika
Journal of Medicinal Chemistry
ISSN
0022-2623
e-ISSN
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Svazek periodika
57
Číslo periodika v rámci svazku
10
Stát vydavatele periodika
US - Spojené státy americké
Počet stran výsledku
15
Strana od-do
4382-4396
Kód UT WoS článku
000336510100034
EID výsledku v databázi Scopus
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