About: Structure-guided discovery of cyclin-dependent kinase inhibitors

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rdf:type	skos:Concept http://linked.opendata.cz/ontology/domain/vavai/Vysledek
Description	CDK2 inhibitors containing the related bicyclic heterocycles pyrazolopyrimidines and imidazopyrazines were discovered through high-throughput screening. Crystal structures of inhibitors with these bicyclic cores and two more related ones show that all but one have a common binding mode featuring two hydrogen bonds (H-bonds) to the backbone of the kinase hinge region. Even though ab initio computations indicated that the imidazopyrazine core would bind more tightly to the hinge, pyrazolopyrimidines gain an advantage in potency through participation of N4 in an H-bond network involving two catalytic residues and bridging water molecules. Further insight into inhibitor/CDK2 interactions was gained from analysis of additional crystal structures. Significant gains in potency were obtained by optimizing the fit of hydrophobic substituents to the gatekeeper region of the ATP binding site. The most potent inhibitors have good selectivity. CDK2 inhibitors containing the related bicyclic heterocycles pyrazolopyrimidines and imidazopyrazines were discovered through high-throughput screening. Crystal structures of inhibitors with these bicyclic cores and two more related ones show that all but one have a common binding mode featuring two hydrogen bonds (H-bonds) to the backbone of the kinase hinge region. Even though ab initio computations indicated that the imidazopyrazine core would bind more tightly to the hinge, pyrazolopyrimidines gain an advantage in potency through participation of N4 in an H-bond network involving two catalytic residues and bridging water molecules. Further insight into inhibitor/CDK2 interactions was gained from analysis of additional crystal structures. Significant gains in potency were obtained by optimizing the fit of hydrophobic substituents to the gatekeeper region of the ATP binding site. The most potent inhibitors have good selectivity. (en)
Title	Structure-guided discovery of cyclin-dependent kinase inhibitors Structure-guided discovery of cyclin-dependent kinase inhibitors (en)
skos:prefLabel	Structure-guided discovery of cyclin-dependent kinase inhibitors Structure-guided discovery of cyclin-dependent kinase inhibitors (en)
skos:notation	RIV/00216224:14310/08:00035899!RIV10-MSM-14310___
http://linked.open...avai/riv/aktivita	N
http://linked.open...avai/riv/aktivity	N
http://linked.open...iv/cisloPeriodika	89
http://linked.open...vai/riv/dodaniDat	2010
http://linked.open...aciTvurceVysledku	Paruch, Kamil
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	Masarykova univerzita / Přírodovědecká fakulta
http://linked.open...dnocenehoVysledku	397862
http://linked.open...ai/riv/idVysledku	RIV/00216224:14310/08:00035899
http://linked.open...riv/jazykVysledku	eng - angličtina
http://linked.open.../riv/klicovaSlova	CDK2; kinase; inhibitor (en)
http://linked.open.../riv/klicoveSlovo	CDK2 inhibitor kinase
http://linked.open...odStatuVydavatele	US - Spojené státy americké
http://linked.open...ontrolniKodProRIV	[AA2C312E2DC6]
http://linked.open...i/riv/nazevZdroje	Biopolymers
http://linked.open...in/vavai/riv/obor	CC
http://linked.open...ichTvurcuVysledku	1 (xsd:int)
http://linked.open...cetTvurcuVysledku	15 (xsd:int)
http://linked.open...UplatneniVysledku	2008
http://linked.open...v/svazekPeriodika	2008
http://linked.open...iv/tvurceVysledku	Duca, Jose Dwyer, Michael Fischmann, Thierry Guzi, Timothy Madison, Vincent Parry, David Paruch, Kamil Seghezzi, Wolfgang Doll, Ronald Hruza, Alan Lees, Emma Windsor, William Le, Hung Mayhood, Todd Ramanathan, Lata
http://linked.open...ain/vavai/riv/wos	000254569700008
issn	0006-3525
number of pages	8 (xsd:int)
http://localhost/t...ganizacniJednotka	14310
is http://linked.open...avai/riv/vysledek of	Structure-guided discovery of cyclin-dependent kinase inhibitors Structure-guided discovery of cyclin-dependent kinase inhibitors Structure-guided discovery of cyclin-dependent kinase inhibitors Structure-guided discovery of cyclin-dependent kinase inhibitors

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