ACES-GNN: can graph neural network learn to explain activity cliffs?

Abstract

Graph Neural Networks (GNNs) have revolutionized molecular property prediction by leveraging graph-based representations, yet their opaque decision-making processes hinder broader adoption in drug discovery. This study introduces the Activity-Cliff-Explanation-Supervised GNN (ACES-GNN) framework, designed to simultaneously improve predictive accuracy and interpretability by integrating explanation supervision for activity cliffs (ACs) into GNN training. ACs, defined by structurally similar molecules with significant potency differences, pose challenges for traditional models due to their reliance on shared structural features. By aligning model attributions with chemist-friendly interpretations, the ACES-GNN framework bridges the gap between prediction and explanation. Validated across 30 pharmacological targets, ACES-GNN consistently enhances both predictive accuracy and attribution quality for ACs compared to unsupervised GNNs. Our results demonstrate a positive correlation between improved predictions and accurate explanations, offering a robust and adaptable framework to better understand and interpret ACs. This work underscores the potential of explanation-guided learning to advance interpretable artificial intelligence in molecular modeling and drug discovery.

Graphical abstract: ACES-GNN: can graph neural network learn to explain activity cliffs?

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Article information

Article type
Paper
Submitted
11 Jan 2025
Accepted
25 Jun 2025
First published
30 Jun 2025
This article is Open Access
Creative Commons BY-NC license

Digital Discovery, 2025, Advance Article

ACES-GNN: can graph neural network learn to explain activity cliffs?

X. Chen, D. Yu, L. Zhao and F. Liu, Digital Discovery, 2025, Advance Article , DOI: 10.1039/D5DD00012B

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