Computational Modeling of Kinase Inhibitor Selectivity

Abstract

An exhaustive computational exercise on a comprehensive set of 15 therapeutic kinase inhibitors was undertaken to identify as to which compounds hit which kinase off-targets in the human kinome. Although the kinase selectivity propensity of each inhibitor against ∼480 kinase targets is predicted, we compared our predictions to ∼280 kinase targets for which consistent experimental data are available and demonstrate an overall average prediction accuracy and specificity of ∼90%. A comparison of the predictions was extended to an additional ∼60 kinases for sorafenib and sunitinib as new experimental data were reported recently with similar prediction accuracy. The successful predictive capabilities allowed us to propose predictions on the remaining kinome targets in an effort to repurpose known kinase inhibitors to these new kinase targets that could hold therapeutic potential.

Keywords: Kinase selectivity; binding hot spots; binding site signature; computational prediction; kinase conformation; kinase inhibitors.

Figure 1

Number of kinase targets predicted to be active (yellow), classified as experimentally active (K_d ≤ 100 nM; green) and the true positives (blue) are shown for kinase inhibitors bound to the DFG-in (a) or DFG-out (b) kinase conformations.