title: Prediction of Protein Kinase-Ligand Interactions through 2.5D Kinochemometrics.
abstract: So far, 518 protein kinases have been identified in the human genome. They share a common mechanism of protein phosphorylation and are involved in many critical biological processes of eukaryotic cells. Deregulation of the kinase phosphorylation function induces severe illnesses such as cancer, diabetes, or inflammatory diseases. Many actors in the pharmaceutical domain have made significant efforts to design potent and selective protein kinase inhibitors as new potential drugs. Because the ATP binding site is highly conserved in the protein kinase family, the design of selective inhibitors remains a challenge and has negatively impacted the progression of drug candidates to late-stage clinical development. The work presented here adopts a 2.5D kinochemometrics (KCM) approach, derived from proteochemometrics (PCM), in which protein kinases are depicted by a novel 3D descriptor and the ligands by 2D fingerprints. We demonstrate in two examples that the protein descriptor successfully classified protein kinases based on their group membership and their Asp-Phe-Gly (DFG) conformation. We also compared the performance of our models with those obtained from a full 2D KCM model and QSAR models. In both cases, the internal validation of the models demonstrated good capabilities to distinguish "active" from "inactive" protein kinase-ligand pairs. However, the external validation performed on two independent data sets showed that the two statistical models tended to overestimate the number of "inactive" pairs.
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, Janssen Pharmaceutica N.V. , Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Berthold
authors.initials: B
authors.lastname: Wroblowski
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.identifier: 0000-0001-6485-138X
authors.initials: P
authors.lastname: Bonnet
mesh_terms: D019295:Computational Biology / Q000379:methods*; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D008024:Ligands; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases