title: Visually interpretable models of kinase selectivity related features derived from field-based proteochemometrics.
abstract: Achieving selectivity for small organic molecules toward biological targets is a main focus of drug discovery but has been proven difficult, for example, for kinases because of the high similarity of their ATP binding pockets. To support the design of more selective inhibitors with fewer side effects or with altered target profiles for improved efficacy, we developed a method combining ligand- and receptor-based information. Conventional QSAR models enable one to study the interactions of multiple ligands toward a single protein target, but in order to understand the interactions between multiple ligands and multiple proteins, we have used proteochemometrics, a multivariate statistics method that aims to combine and correlate both ligand and protein descriptions with affinity to receptors. The superimposed binding sites of 50 unique kinases were described by molecular interaction fields derived from knowledge-based potentials and Schrödinger's WaterMap software. Eighty ligands were described by Mold(2), Open Babel, and Volsurf descriptors. Partial least-squares regression including cross-terms, which describe the selectivity, was used for model building. This combination of methods allows interpretation and easy visualization of the models within the context of ligand binding pockets, which can be translated readily into the design of novel inhibitors.
authors.affiliation: Computer-Aided Drug Design, Orion Pharma , Orionintie 1, FIN-02101 Espoo, Finland.
authors.forename: Vigneshwari
authors.initials: V
authors.lastname: Subramanian
authors.forename: Peteris
authors.initials: P
authors.lastname: Prusis
authors.forename: Lars-Olof
authors.initials: LO
authors.lastname: Pietilä
authors.forename: Henri
authors.initials: H
authors.lastname: Xhaard
authors.forename: Gerd
authors.initials: G
authors.lastname: Wohlfahrt
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry*; D001665:Binding Sites; D055808:Drug Discovery; D006801:Humans; D016018:Least-Squares Analysis; D008024:Ligands; D062105:Molecular Docking Simulation; D015999:Multivariate Analysis; D011485:Protein Binding; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D011494:Protein Kinases / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D008024:Ligands; D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; D011494:Protein Kinases