@article{TEXTUAL, recid = {13472}, author = {Liu, Changchang and Kutchukian, Peter and Nguyen, Nhan D. and AlQuraishi, Mohammed and Sorger, Peter K.}, title = {A Hybrid Structure-Based Machine Learning Approach for Predicting Kinase Inhibition by Small Molecules}, journal = {Journal of Chemical Information and Modeling}, address = {2023-08-18}, number = {TEXTUAL}, abstract = {Kinases have been the focus of drug discovery programs for three decades leading to over 70 therapeutic kinase inhibitors and biophysical affinity measurements for over 130,000 kinase-compound pairs. Nonetheless, the precise target spectrum for many kinases remains only partly understood. In this study, we describe a computational approach to unlocking qualitative and quantitative kinome-wide binding measurements for structure-based machine learning. Our study has three components: (i) a Kinase Inhibitor Complex (KinCo) data set comprising in silico predicted kinase structures paired with experimental binding constants, (ii) a machine learning loss function that integrates qualitative and quantitative data for model training, and (iii) a structure-based machine learning model trained on KinCo. We show that our approach outperforms methods trained on crystal structures alone in predicting binary and quantitative kinase-compound interaction affinities; relative to structure-free methods, our approach also captures known kinase biochemistry and more successfully generalizes to distant kinase sequences and compound scaffolds.}, url = {http://knowledge.uchicago.edu/record/13472}, }