Assessing the information content of structural and protein–ligand interaction representations for the classification of kinase inhibitor binding modes via machine learning and active learning

For kinase inhibitors, X-ray crystallography has revealed different types of binding modes. Currently, more than 2000 kinase inhibitors with known binding modes are available, which makes it possible to derive and test machine learning models for the prediction of inhibitors with different binding modes. We have addressed this prediction task to evaluate and compare the information content of distinct molecular representations including protein–ligand interaction fingerprints (IFPs) and compound structure-based structural fingerprints (i.e., atom environment/fragment fingerprints). IFPs were designed to capture binding mode-specific interaction patterns at different resolution levels. Accurate predictions of kinase inhibitor binding modes were achieved with random forests using both representations. The performance of IFPs was consistently superior to atom environment fingerprints, albeit only by less than 10%. An active learning strategy applying information entropy-based selection of training instances was applied as a diagnostic approach to assess the relative information content of distinct representations. IFPs were found to capture more binding mode-relevant information than atom environment fingerprints, leading to highly predictive models even when training instances were randomly selected. By contrast, for atom environment fingerprints, the derivation of accurate models via active learning depended on entropy-based selection of informative training compounds. Notably, higher information content of IFPs confirmed by active learning only resulted in small improvements in global prediction accuracy compared to models derived using atom environment fingerprints. For practical applications, prediction of binding modes of new kinase inhibitors on the basis of chemical structure is highly attractive. [Image: see text]