Kinome-wide interaction modelling using alignment-based and alignment-independent approaches for kinase description...

Protein kinases play crucial roles in cell growth, differentiation, and apoptosis. Abnormal function of protein kinases can lead to many serious diseases, such as cancer. Kinase inhibitors have potential for treatment of these diseases. However, current inhibitors interact with a broad variety of kinases and interfere with multiple vital cellular processes, which causes toxic effects. Bioinformatics approaches that can predict inhibitor-kinase interactions from the chemical properties of the inhibitors and the kinase macromolecules might aid in design of more selective therapeutic agents, that show better efficacy and lower toxicity.

We applied proteochemometric modelling to correlate the properties of 317 wild-type and mutated kinases and 38 inhibitors (12,046 inhibitor-kinase combinations) to the respective combination's interaction dissociation constant (Kd). We compared six approaches for description of protein kinases and several linear and non-linear correlation methods. The best performing models encoded kinase sequences with amino acid physico-chemical z-scale descriptors and used support vector machines or partial least- squares projections to latent structures for the correlations. Modelling performance was estimated by double cross-validation. The best models showed high predictive ability; the squared correlation coefficient for new kinase-inhibitor pairs ranging P2 = 0.67-0.73; for new kinases it ranged P2kin = 0.65-0.70. Models could also separate interacting from non-interacting inhibitor-kinase pairs with high sensitivity and specificity; the areas under the ROC curves ranging AUC = 0.92-0.93. We also investigated the relationship between the number of protein kinases in the dataset and the modelling results. Using only 10% of all data still a valid model was obtained with P2 = 0.47, P2kin = 0.42 and AUC = 0.83.

Our results strongly support the applicability of proteochemometrics for kinome-wide interaction modelling. Proteochemometrics might be used to speed-up identification and optimization of protein kinase targeted and multi-targeted inhibitors.