Fate-tox: fragment attention transformer for E(3)-equivariant multi-organ toxicity prediction

Toxicity is a critical hurdle in drug development, often causing the late-stage failure of promising compounds. Existing computational prediction models often focus on single-organ toxicity. However, avoiding toxicity of an organ, such as reducing gastrointestinal side effects, may inadvertently lead to toxicity in another organ, as seen in the real case of rofecoxib, which was withdrawn due to increased cardiovascular risks. Thus, simultaneous prediction of multi-organ toxicity is a desirable but challenging task. The main challenges are (1) the variability of substructures that contribute to toxicity of different organs, (2) insufficient power of molecular representations in diverse perspectives, and (3) explainability of prediction results especially in terms of substructures or potential toxicophores. To address these challenges with multiple strategies, we developed FATE-Tox, a novel multi-view deep learning framework for multi-organ toxicity prediction. For variability of substructures, we used three fragmentation methods such as BRICS, Bemis-Murcko scaffolds, and RDKit Functional Groups to formulate fragment-level graphs so that diverse substructures can be used to identify toxicity for different organs. For insufficient power of molecular representations, we used molecular representations in both 2D and 3D perspectives. For explainability, our fragment attention transformer identifies potential 3D toxicophores using attention coefficients.

Scientific contribution: Our framework achieved significant improvements in prediction performance, with up to 3.01% gains over prior baseline methods on toxicity benchmark datasets from MoleculeNet (BBBP, SIDER, ClinTox) and TDC (DILI, Skin Reaction, Carcinogens, and hERG), while the multi-task learning approach further enhanced performance by up to 1.44% compared to the single-task learning framework that had already surpassed these baselines. Additionally, attention visualization aligning with literature contributes to greater transparency in predictive modeling. Our approach has the potential to provide scientists and clinicians with a more interpretable and clinically meaningful tool to assess systemic toxicity, ultimately supporting safer and more informed drug development processes.