Equivariant Graph Neural Networks for Toxicity Prediction

Julian Cremer; Leonardo Medrano Sandonas; Alexandre Tkatchenko; Djork-Arné Clevert; Gianni De Fabritiis

doi:10.1021/acs.chemrestox.3c00032

Equivariant Graph Neural Networks for Toxicity Prediction

Chem Res Toxicol. 2023 Sep 10;36(10):1561-1573. doi: 10.1021/acs.chemrestox.3c00032. Online ahead of print.

Authors

Julian Cremer^{1

2}, Leonardo Medrano Sandonas³, Alexandre Tkatchenko³, Djork-Arné Clevert², Gianni De Fabritiis^{1

4}

Affiliations

¹ Computational Science Laboratory, Universitat Pompeu Fabra, Barcelona Biomedical Research Park (PRBB), Carrer Dr. Aiguader 88, 08003 Barcelona, Spain.
² Machine Learning Research, Pfizer Worldwide Research Development and Medical, Linkstr. 10, 10785 Berlin, Germany.
³ Department of Physics and Materials Science, University of Luxembourg, L-1511 Luxembourg City, Luxembourg.
⁴ ICREA, Passeig Lluis Companys 23, 08010 Barcelona, Spain.

Abstract

Predictive modeling of toxicity is a crucial step in the drug discovery pipeline. It can help filter out molecules with a high probability of failing in the early stages of de novo drug design. Thus, several machine learning (ML) models have been developed to predict the toxicity of molecules by combining classical ML techniques or deep neural networks with well-known molecular representations such as fingerprints or 2D graphs. But the more natural, accurate representation of molecules is expected to be defined in physical 3D space like in ab initio methods. Recent studies successfully used equivariant graph neural networks (EGNNs) for representation learning based on 3D structures to predict quantum-mechanical properties of molecules. Inspired by this, we investigated the performance of EGNNs to construct reliable ML models for toxicity prediction. We used the equivariant transformer (ET) model in TorchMD-NET for this. Eleven toxicity data sets taken from MoleculeNet, TDCommons, and ToxBenchmark have been considered to evaluate the capability of ET for toxicity prediction. Our results show that ET adequately learns 3D representations of molecules that can successfully correlate with toxicity activity, achieving good accuracies on most data sets comparable to state-of-the-art models. We also test a physicochemical property, namely, the total energy of a molecule, to inform the toxicity prediction with a physical prior. However, our work suggests that these two properties can not be related. We also provide an attention weight analysis for helping to understand the toxicity prediction in 3D space and thus increase the explainability of the ML model. In summary, our findings offer promising insights considering 3D geometry information via EGNNs and provide a straightforward way to integrate molecular conformers into ML-based pipelines for predicting and investigating toxicity prediction in physical space. We expect that in the future, especially for larger, more diverse data sets, EGNNs will be an essential tool in this domain.