# Unveiling Molecular Moieties through Hierarchical Grad-CAM Graph Explainability

arXiv: https://arxiv.org/abs/2402.01744 · HTML: https://mlsanity.com/paper/2402.01744/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Builds on 12 of its 44 references that are in the map.
- First posted on arXiv 29 Jan 2024.

## Builds on (most cited first, 12 of 12)

- [U-Net: Convolutional Networks for Biomedical Image Segmentation](https://mlsanity.com/paper/1505.04597/) (2015)
- [Semi-Supervised Classification with Graph Convolutional Networks](https://mlsanity.com/paper/1609.02907/) (2016)
- [Grad-CAM: Visual Explanations from Deep Networks via Gradient-based Localization](https://mlsanity.com/paper/1610.02391/) (2016)
- [Neural Message Passing for Quantum Chemistry](https://mlsanity.com/paper/1704.01212/) (2017)
- [Graph Neural Networks: A Review of Methods and Applications](https://mlsanity.com/paper/1812.08434/) (2018)
- [Weisfeiler and Leman Go Neural: Higher-order Graph Neural Networks](https://mlsanity.com/paper/1810.02244/) (2018)
- [GNNExplainer: Generating Explanations for Graph Neural Networks](https://mlsanity.com/paper/1903.03894/) (2019)
- [Analyzing Learned Molecular Representations for Property Prediction](https://mlsanity.com/paper/1904.01561/) (2019)
- [Molecular Graph Convolutions: Moving Beyond Fingerprints](https://mlsanity.com/paper/1603.00856/) (2016)
- [Concept Whitening for Interpretable Image Recognition](https://mlsanity.com/paper/2002.01650/) (2020)
- [Imbalanced-learn: A Python Toolbox to Tackle the Curse of Imbalanced Datasets in Machine Learning](https://mlsanity.com/paper/1609.06570/) (2016)
- [Molecular graph generation with Graph Neural Networks](https://mlsanity.com/paper/2012.07397/) (2020)

## Abstract (arXiv)

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.