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Développement de nouvelles approches protéo-chimiométriques appliquées à l'étude des interactions et de la sélectivité des inhibiteurs de kinases

Abstract : The human kinome contains 518 proteins. They share a common mechanism of protein phosphorylation known to play an important role in cellular signaling pathways. Impaired kinase function is recognized to be involved in severe diseases like cancer. Due to high structural similarity between protein kinases, development of potent and selective kinase inhibitors is a challenging task. The selectivity of kinase inhibitors may lead to side effects potentially harmful. In this thesis, we first developed new selectivity metrics to determine inhibitor selectivity directly from biological inhibition data. Compared to existing metrics, the new selectivity scores can be applied on diverse inhibition data types. Second, we developed a proteometric approach in order to understand why some protein kinases are never inhibited by Type II inhibitors. The statistical model built for this purpose allowed us to identify several discriminant residues of which few of them correspond to experimentally described residues of interest. Third, using a new 3D protein kinase descriptor, we developed and validated novel proteo-chemometrics approaches to study and discover new kinase inhibitors.
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Nicolas Bosc. Développement de nouvelles approches protéo-chimiométriques appliquées à l'étude des interactions et de la sélectivité des inhibiteurs de kinases. Autre. Université d'Orléans, 2015. Français. ⟨NNT : 2015ORLE2051⟩. ⟨tel-01343428⟩

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