Integrating Prior Chemical Knowledge into the Graph Transformer Network to Predict the Stability Constants of Chelating Agents and Metal Ions

Abstract

The latest advancements in nuclear medicine indicate that radioactive isotopes and associated metal chelators play crucial roles in the diagnosis and treatment of diseases. The development of metal chelators mainly relies on traditional trialand-error methods, lacking rational guidance and design. In this study, we propose the structure-aware transformer (SAT) combined with molecular fingerprint (SATCMF), a novel graph transformer network framework that incorporates prior chemical knowledge to construct coordination edges and learns the interactions between chelating agents and metal ions. SATCMF is trained on stability data collected from metal ion−ligand complexes, leveraging the SAT network to extract structural features relevant to the binding of ligands with metal ions. It further integrates molecular fingerprint features to refine the prediction of the stability constants of the chelating agents and metal ions. The experimental results on benchmark data set demonstrate that SATCMF achieves state-of-the-art performance based on four different graph neural network architectures. Additionally, visualizing the learned molecular attention distribution provides interpretable insights from the prediction results, offering valuable guidance for the development of novel metal chelators.