MolLedger: An Additive Graph Neural Network with Chemically Grounded ADME Attributions

Optimizing absorption, distribution, metabolism, and excretion (ADME) is an important part of small molecule drug discovery. Many machine learning models have been built to predict ADME properties to facilitate this optimization process, but explaining model predictions is challenging. We propose a new graph neural network architecture with built-in atom attributions. Our model MolLedger learns a global context vector for each molecule and a per-atom head to output atom scores that sum to the predicted property. The atom scores are regularized to align with relevant chemical properties. We prove that MolLedger is a universal approximator and demonstrate empirically that the new architecture obtains explainability with little effect on performance. We show that the interpretations from MolLedger are faithful, concordant with held-out physical properties, and align with the changes between matched molecular pairs. Our case studies comparing interpretations from multiple methods on molecular pairs reveal that MolLedger is much better at producing sensible explanations for predicted property changes.