AustralieFrV1, Main, Exploration, bibRecord, 009D42

Novel structural features of CDK inhibition revealed by an ab initio computational method combined with dynamic simulations

Identifieur interne : 009D42 ( Main/Exploration ); précédent : 009D41; suivant : 009D43

Novel structural features of CDK inhibition revealed by an ab initio computational method combined with dynamic simulations

Auteurs : Lucy Heady [Royaume-Uni] ; Marivi Fernandez-Serra [France] ; Ricardo L. Mancera [Australie] ; Sian Joyce [Royaume-Uni, Irlande (pays)] ; Ashok R. Venkitaraman [Royaume-Uni] ; Emilio Artacho [Royaume-Uni] ; Chris-Kriton Skylaris [Royaume-Uni] ; Lucio Colombi Ciacchi [Royaume-Uni, Allemagne] ; Mike C. Payne [Royaume-Uni]

Source :

Journal of medicinal chemistry : (Print) [ 0022-2623 ] ; 2006.

RBID : Pascal:07-0022544

Descripteurs français

Pascal (Inist)
- Cyclin dependent kinase, Inhibiteur enzyme, Méthode ab initio, Méthode champ force, Energie libre, Modèle moléculaire, Mode liaison, Energie liaison, Interaction van der Waals, Méthode fonctionnelle densité, Liaison hydrogène, Purine dérivé, Pyrimidine dérivé, Indole dérivé, Protein kinase, Transduction signal, Modélisation, Propriété thermodynamique, Etude théorique, Alcaloïde, Staurosporine dérivé, Indolocarbazole, Indolo[2,3-a]pyrrolo[3,4-c]carbazol-5-one dérivé.

English descriptors

KwdEn :
- Ab initio method, Alkaloid, Binding energy, Binding mode, Cyclin dependent kinase, Density functional method, Enzyme inhibitor, Force field method, Free energy, Hydrogen bond, Indole derivatives, Modeling, Molecular model, Protein kinase, Purine derivatives, Pyrimidine derivatives, Signal transduction, Theoretical study, Thermodynamic properties, Van der Waals interaction.

Abstract

The rational development of specific inhibitors for the ∼500 protein kinases encoded in the human genome is impeded by a poor understanding of the structural basis for the activity and selectivity of small molecules that compete for ATP binding. Combining classical dynamic simulations with a novel ab initio computational approach linear-scalable to molecular interactions involving thousands of atoms, we have investigated the binding of five distinct inhibitors to the cyclin-dependent kinase CDK2. We report here that polarization and dynamic hydrogen bonding effects, so far undetected by crystallography, affect both their activity and selectivity. The effects arise from the specific solvation patterns of water molecules in the ATP binding pocket or the intermittent formation of hydrogen bonds during the dynamics of CDK/inhibitor interactions and explain the unexpectedly high potency of certain inhibitors such as 3-(3H-imidazol-4-ylmethylene)-5-methoxy-l,3-dihydro-indol-2-one (SU9516). The Lys89 residue in the ATP-binding pocket of CDK2 is observed to form temporary hydrogen bonds with the three most potent inhibitors. This residue is replaced in CDK4 by Thr89, whose shorter side-chain cannot form similar bonds, explaining the relative selectivity of the inhibitors for CDK2. Our results provide a generally applicable computational method for the analysis of biomolecular structures and reveal hitherto unrecognized features of the interaction between protein kinases and their inhibitors.

Affiliations:

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Le document en format XML

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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Ab initio method</term>
<term>Alkaloid</term>
<term>Binding energy</term>
<term>Binding mode</term>
<term>Cyclin dependent kinase</term>
<term>Density functional method</term>
<term>Enzyme inhibitor</term>
<term>Force field method</term>
<term>Free energy</term>
<term>Hydrogen bond</term>
<term>Indole derivatives</term>
<term>Modeling</term>
<term>Molecular model</term>
<term>Protein kinase</term>
<term>Purine derivatives</term>
<term>Pyrimidine derivatives</term>
<term>Signal transduction</term>
<term>Theoretical study</term>
<term>Thermodynamic properties</term>
<term>Van der Waals interaction</term>
</keywords>
<keywords scheme="Pascal" xml:lang="fr"><term>Cyclin dependent kinase</term>
<term>Inhibiteur enzyme</term>
<term>Méthode ab initio</term>
<term>Méthode champ force</term>
<term>Energie libre</term>
<term>Modèle moléculaire</term>
<term>Mode liaison</term>
<term>Energie liaison</term>
<term>Interaction van der Waals</term>
<term>Méthode fonctionnelle densité</term>
<term>Liaison hydrogène</term>
<term>Purine dérivé</term>
<term>Pyrimidine dérivé</term>
<term>Indole dérivé</term>
<term>Protein kinase</term>
<term>Transduction signal</term>
<term>Modélisation</term>
<term>Propriété thermodynamique</term>
<term>Etude théorique</term>
<term>Alcaloïde</term>
<term>Staurosporine dérivé</term>
<term>Indolocarbazole</term>
<term>Indolo[2,3-a]pyrrolo[3,4-c]carbazol-5-one dérivé</term>
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<front><div type="abstract" xml:lang="en">The rational development of specific inhibitors for the ∼500 protein kinases encoded in the human genome is impeded by a poor understanding of the structural basis for the activity and selectivity of small molecules that compete for ATP binding. Combining classical dynamic simulations with a novel ab initio computational approach linear-scalable to molecular interactions involving thousands of atoms, we have investigated the binding of five distinct inhibitors to the cyclin-dependent kinase CDK2. We report here that polarization and dynamic hydrogen bonding effects, so far undetected by crystallography, affect both their activity and selectivity. The effects arise from the specific solvation patterns of water molecules in the ATP binding pocket or the intermittent formation of hydrogen bonds during the dynamics of CDK/inhibitor interactions and explain the unexpectedly high potency of certain inhibitors such as 3-(3H-imidazol-4-ylmethylene)-5-methoxy-l,3-dihydro-indol-2-one (SU9516). The Lys89 residue in the ATP-binding pocket of CDK2 is observed to form temporary hydrogen bonds with the three most potent inhibitors. This residue is replaced in CDK4 by Thr89, whose shorter side-chain cannot form similar bonds, explaining the relative selectivity of the inhibitors for CDK2. Our results provide a generally applicable computational method for the analysis of biomolecular structures and reveal hitherto unrecognized features of the interaction between protein kinases and their inhibitors.</div>
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	Serveur d'exploration sur les relations entre la France et l'Australie
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Novel structural features of CDK inhibition revealed by an ab initio computational method combined with dynamic simulations

Novel structural features of CDK inhibition revealed by an ab initio computational method combined with dynamic simulations

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