About: Structure-Guided Design of Selective Inhibitors of Neuronal Nitric Oxide Synthase

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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/jm4000984
Description	Nitric oxide synthases (NOSs) comprise three closely related isoforms that catalyze the oxidation of L-arginine to L-citrulline and the important second messenger nitric oxide (NO). Pharmacological selective inhibition of neuronal NOS (nNOS) has the potential to be therapeutically beneficial in various neurodegenerative diseases. Here, we present a structure-guided, selective nNOS inhibitor design based on the crystal structure of lead compound 1 in nNOS. The best inhibitor, 7, exhibited low nanomolar inhibitory potency and good isoform selectivities (nNOS over eNOS and iNOS are 472-fold and 239-fold, respectively). Consistent with the good selectivity, 7 binds to nNOS and eNOS with different binding modes. The distinctly different binding modes of 7, driven by the critical residue Asp597 in nNOS, offers compelling insight to explain its isozyme selectivity, which should guide future drug design programs. Nitric oxide synthases (NOSs) comprise three closely related isoforms that catalyze the oxidation of L-arginine to L-citrulline and the important second messenger nitric oxide (NO). Pharmacological selective inhibition of neuronal NOS (nNOS) has the potential to be therapeutically beneficial in various neurodegenerative diseases. Here, we present a structure-guided, selective nNOS inhibitor design based on the crystal structure of lead compound 1 in nNOS. The best inhibitor, 7, exhibited low nanomolar inhibitory potency and good isoform selectivities (nNOS over eNOS and iNOS are 472-fold and 239-fold, respectively). Consistent with the good selectivity, 7 binds to nNOS and eNOS with different binding modes. The distinctly different binding modes of 7, driven by the critical residue Asp597 in nNOS, offers compelling insight to explain its isozyme selectivity, which should guide future drug design programs. (en)
Title	Structure-Guided Design of Selective Inhibitors of Neuronal Nitric Oxide Synthase Structure-Guided Design of Selective Inhibitors of Neuronal Nitric Oxide Synthase (en)
skos:prefLabel	Structure-Guided Design of Selective Inhibitors of Neuronal Nitric Oxide Synthase Structure-Guided Design of Selective Inhibitors of Neuronal Nitric Oxide Synthase (en)
skos:notation	RIV/00216208:11110/13:10190165!RIV14-MSM-11110___
http://linked.open...avai/predkladatel	1. lékařská fakulta
http://linked.open...avai/riv/aktivita	P Z
http://linked.open...avai/riv/aktivity	P(1M0520), Z(MSM0021620806)
http://linked.open...iv/cisloPeriodika	7
http://linked.open...vai/riv/dodaniDat	2014
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	108431
http://linked.open...ai/riv/idVysledku	RIV/00216208:11110/13:10190165
http://linked.open...riv/jazykVysledku	eng - angličtina
http://linked.open.../riv/klicovaSlova	nnos; disease; insights; discovery; refinement; identification; binding mode; escherichia-coli (en)
http://linked.open.../riv/klicoveSlovo	refinement escherichia-coli binding mode nnos disease identification insights discovery
http://linked.open...odStatuVydavatele	US - Spojené státy americké
http://linked.open...ontrolniKodProRIV	[1F664582E0FC]
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	6 (xsd:int)
http://linked.open...vavai/riv/projekt	Center for Applied Genomics
http://linked.open...UplatneniVysledku	2013
http://linked.open...v/svazekPeriodika	56
http://linked.open...iv/tvurceVysledku	Martásek, Pavel Li, Huiying Poulos, Thomas L. Roman, Linda J. Silverman, Richard B. Huang, He
http://linked.open...ain/vavai/riv/wos	000317551700025
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	9 (xsd:int)
http://bibframe.org/vocab/doi	10.1021/jm4000984
http://localhost/t...ganizacniJednotka	11110

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