Results of a Large-Scale Study of the Binding of 50 Type II Inhibitors to 348 Kinases: The Role of Protein Reorganization

Protein kinases constitute
the second largest class of
drug targets,
most prominently in cancer therapy. In this work, we focus on type
II kinase inhibitors that bind to the “classical” inactive
conformation. We analyze binding affinities of 50 type II inhibitors
across 348 kinases, combining earlier results for 16 inhibitors (the
“Davis data set”) with recently obtained measurements
for the remaining 34 (the “Schrödinger data set”).
Using a Potts statistical energy model, we investigate the role of
protein conformational reorganization in kinase selectivity and find
that protein reorganization makes a large contribution to the selectivity
(ROC AUC ∼0.8). We compare Potts threading predictions for
the binding of 50 type II inhibitors to 348 kinases with those of
DeepDTAGen, a sequence-based model trained on the Davis data set containing
both type I and type II kinase inhibitors. DeepDTAGen performs well
for the 16 inhibitors in the Davis data set but poorly for the remaining
34 in the Schrödinger data set, representing unseen data.