title: A Proteometric Analysis of Human Kinome: Insight into Discriminant Conformation-dependent Residues.
abstract: Because of the success of imatinib, the first type-II kinase inhibitor approved by the FDA in 2001, sustained efforts have been made by the pharmaceutical industry to discover novel compounds stabilizing the inactive conformation of protein kinases. On the seven type-II inhibitors having reached the market, four were released in 2012, suggesting an acceleration of the research of such a class of compounds. Still, they represent less than a third of the protein kinase inhibitors available to patients today. The identification of key residues involved in the binding of this type of ligands in the kinase active site might ease the design of potent and selective type-II inhibitors. In order to identify those discriminant residues, we have developed a proteometric approach combining residue descriptors of protein kinase sequences and biological activities of various type-II kinase inhibitors. We applied Partial Least Squares (PLS) regression to identify 29 key residues that influence the binding of four type-II inhibitors to most proteins of the kinome. The gatekeeper residue was found to be the most relevant, confirming an essential role in ligand binding as well as in protein kinase conformational changes. Using the newly developed proteometric model, we predicted the propensity of each protein kinase to be inhibited by type-II ligands. The model was further validated using an external data set of protein/ligand activity pairs. Other residues present in the kinase domain, and more specifically in the binding site, have been highlighted by this approach, but their role in biological mechanisms is still unknown.
authors.affiliation: Institut de Chimie Organique et Analytique (ICOA), UMR CNRS-Université d'Orléans 7311 , Université d'Orléans BP 6759, 45067 Orléans Cedex 2, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Bosc
authors.affiliation: Janssen Research & Development, a division of Janssen Pharmaceutica N.V. , Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Berthold
authors.initials: B
authors.lastname: Wroblowski
authors.affiliation: Institut de Chimie Organique et Analytique (ICOA), UMR CNRS-Université d'Orléans 7311 , Université d'Orléans BP 6759, 45067 Orléans Cedex 2, France.
authors.forename: Samia
authors.initials: S
authors.lastname: Aci-Sèche
authors.affiliation: Centre de Recherche Janssen-Cilag , Campus de Maigremont - CS 10615, 27106 Val de Reuil Cedex, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Meyer
authors.affiliation: Institut de Chimie Organique et Analytique (ICOA), UMR CNRS-Université d'Orléans 7311 , Université d'Orléans BP 6759, 45067 Orléans Cedex 2, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Bonnet
mesh_terms: D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D000068877:Imatinib Mesylate / Q000737:chemistry / Q000494:pharmacology; D016018:Least-Squares Analysis; D008958:Models, Molecular; D009536:Niacinamide / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D011494:Protein Kinases / Q000737:chemistry* / Q000378:metabolism*; D040901:Proteomics / Q000379:methods*; D000077157:Sorafenib
chemical_list: D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D000068877:Imatinib Mesylate; D000077157:Sorafenib; D011494:Protein Kinases