Unveiling Molecular Moieties through Hierarchical Grad-CAM Graph Explainability

• URL: http://arxiv.org/abs/2402.01744v4
• Date: Thu, 17 Apr 2025 12:16:35 GMT
• Title: Unveiling Molecular Moieties through Hierarchical Grad-CAM Graph Explainability
• Authors: Salvatore Contino, Paolo Sortino, Maria Rita Gulotta, Ugo Perricone, Roberto Pirrone,
• Abstract summary: The integration of explainable methods to elucidate the specific contributions of molecular substructures to biological activity remains a significant challenge.<n>We trained 20 GNN models on a dataset of small molecules with the goal of predicting their activity on 20 distinct protein targets from the Kinase family.<n>We implemented the Hierarchical Grad-CAM graph Explainer framework, enabling an in-depth analysis of the molecular moieties driving protein-ligand binding stabilization.
• Score: 0.0
• License: http://arxiv.org/licenses/nonexclusive-distrib/1.0/
• Abstract: Background: Virtual Screening (VS) has become an essential tool in drug discovery, enabling the rapid and cost-effective identification of potential bioactive molecules. Among recent advancements, Graph Neural Networks (GNNs) have gained prominence for their ability to model complex molecular structures using graph-based representations. However, the integration of explainable methods to elucidate the specific contributions of molecular substructures to biological activity remains a significant challenge. This limitation hampers both the interpretability of predictive models and the rational design of novel therapeutics.\\ Results: We trained 20 GNN models on a dataset of small molecules with the goal of predicting their activity on 20 distinct protein targets from the Kinase family. These classifiers achieved state-of-the-art performance in virtual screening tasks, demonstrating high accuracy and robustness on different targets. Building upon these models, we implemented the Hierarchical Grad-CAM graph Explainer (HGE) framework, enabling an in-depth analysis of the molecular moieties driving protein-ligand binding stabilization. HGE exploits Grad-CAM explanations at the atom, ring, and whole-molecule levels, leveraging the message-passing mechanism to highlight the most relevant chemical moieties. Validation against experimental data from the literature confirmed the ability of the explainer to recognize a molecular pattern of drugs and correctly annotate them to the known target. Conclusion: Our approach may represent a valid support to shorten both the screening and the hit discovery process. Detailed knowledge of the molecular substructures that play a role in the binding process can help the computational chemist to gain insights into the structure optimization, as well as in drug repurposing tasks.

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