Deep Learning Enhancing Kinome-Wide Polypharmacology Profiling: Model Construction and Experiment Validation

The kinome-wide virtual profiling of small molecules with high-dimensional structure–activity data is a challenging task in drug discovery. Here, we present a virtual profiling model against a panel of 391 kinases based on large-scale bioactivity data and the multitask deep neural network algorithm. The obtained model yields excellent internal prediction capability with an auROC of 0.90 and consistently outperforms conventional single-task models on external tests, especially for kinases with insufficient activity data. Moreover, more rigorous experimental validations including 1410 kinase-compound pairs showed a high-quality average auROC of 0.75 and confirmed many novel predicted “off-target” activities. Given the verified generalizability, the model was further applied to various scenarios for depicting the kinome-wide selectivity and the association with certain diseases. Overall, the computational model enables us to create a comprehensive kinome interaction network for designing novel chemical modulators or drug repositioning and is of practical value for exploring previously less studied kinases.