Calibrated geometric deep learning improves kinase–drug binding predictions

Protein kinases regulate various cellular functions and hold significant pharmacological promise in cancer and other diseases. Although kinase inhibitors are one of the largest groups of approved drugs, much of the human kinome remains unexplored but potentially druggable. Computational approaches, such as machine learning, offer efficient solutions for exploring kinase–compound interactions and uncovering novel binding activities. Despite the increasing availability of three-dimensional (3D) protein and compound structures, existing methods predominantly focus on exploiting local features from one-dimensional protein sequences and two-dimensional molecular graphs to predict binding affinities, overlooking the 3D nature of the binding process. Here we present KDBNet, a deep learning algorithm that incorporates 3D protein and molecule structure data to predict binding affinities. KDBNet uses graph neural networks to learn structure representations of protein binding pockets and drug molecules, capturing the geometric and spatial characteristics of binding activity. In addition, we introduce an algorithm to quantify and calibrate the uncertainties of KDBNet's predictions, enhancing its utility in model-guided discovery in chemical or protein space. Experiments demonstrated that KDBNet outperforms existing deep learning models in predicting kinase–drug binding affinities. The uncertainties estimated by KDBNet are informative and well-calibrated with respect to prediction errors. When integrated with a Bayesian optimization framework, KDBNet enables data-efficient active learning and accelerates the exploration and exploitation of diverse high-binding kinase–drug pairs. Geometric deep learning has become a powerful tool in virtual drug design, but it is not always obvious when a model makes incorrect predictions. Luo and colleagues improve the accuracy of their deep learning model using uncertainty calibration and Bayesian optimization in an active learning cycle.