Docking-Informed Machine Learning for Kinome-wide Affinity Prediction

Kinase inhibitors are an important class of anticancer drugs, with 80 inhibitors clinically approved and >100 in active clinical testing. Most bind competitively in the ATP-binding site, leading to challenges with selectivity for a specific kinase, resulting in risks for toxicity and general off-target effects. Assessing the binding of an inhibitor for the entire kinome is experimentally possible but expensive. A reliable and interpretable computational prediction of kinase selectivity would greatly benefit the inhibitor discovery and optimization process. Here, we use machine learning on docked poses to address this need. To this end, we aggregated all known inhibitor-kinase affinities and generated the complete accompanying 3D interactome by docking all inhibitors to the respective high-quality X-ray structures. We then used this resource to train a neural network as a kinase-specific scoring function, which achieved an overall performance (R²) of 0.63-0.74 on unseen inhibitors across the kinome. The entire pipeline from molecule to 3D-based affinity prediction has been fully automated and wrapped in a freely available package. This has a graphical user interface that is tightly integrated with PyMOL to allow immediate adoption in the medicinal chemistry practice.