title: Dissecting kinase profiling data to predict activity and understand cross-reactivity of kinase inhibitors.
abstract: The development of selective and multitargeted kinase inhibitors has received much attention, because cross-reactivity with unintended targets may cause toxic side effects, while it can also give rise to efficacious multitargeted drugs. Here we describe a deconvolution approach to dissecting kinase profiling data in order to gain knowledge about cross-reactivity of inhibitors from large-scale profiling data. This approach not only enables activity predictions of given compounds on a kinome-wide scale, but also allows to extract residue-fragment pairs that are associated with activity. We demonstrate its effectiveness using a large-scale public chemogenomics data set and also apply our proposed model to a recently published bioactivity data set. We further illustrate that the preference of given compounds for kinases of interest is better understood by residue-fragment pairs, which could provide both biological and chemical insights into cross-reactivity.
authors.affiliation: Department of Systems Biosciences for Drug Discovery, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan. niijima@pharm.kyoto-u.ac.jp
authors.forename: Satoshi
authors.initials: S
authors.lastname: Niijima
authors.forename: Akira
authors.initials: A
authors.lastname: Shiraishi
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Okuno
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D001185:Artificial Intelligence; D001665:Binding Sites; D016000:Cluster Analysis; D062126:Databases, Chemical; D006801:Humans; D008024:Ligands; D016013:Likelihood Functions; D008969:Molecular Sequence Data; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D011494:Protein Kinases / Q000737:chemistry*; D012680:Sensitivity and Specificity; D054852:Small Molecule Libraries / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; D011494:Protein Kinases