Equivariant graph neural networks for toxicity prediction

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• dc.contributor.author Cremer, Julian
• dc.contributor.author Medrano Sandonas, Leonardo
• dc.contributor.author Tkatchenko, Alexandre
• dc.contributor.author Clevert, Djork-Arné
• dc.contributor.author De Fabritiis, Gianni
• dc.date.accessioned 2024-03-14T16:01:36Z
• dc.date.available 2024-03-14T16:01:36Z
• dc.date.issued 2023
• dc.description.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.
• dc.description.sponsorship This research used computational resources provided by the High-Performance Center (HPC) at the University of Luxembourg. J.C. received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie Actions grant agreement “Advanced machine learning for Innovative Drug Discovery (AIDD)” No. 956832. L.M.S. thanks S. Goger for fruitful discussions about the influence of functional groups in toxicity prediction. G.D.F. acknowledges funding from the European Union’s Horizon 2020 research and innovation program under Grant Agreement No. 823712; and the project PID2020-116564GB-I00 has been funded by MCIN/AEI/10.13039/501100011033.
• dc.format.mimetype application/pdf
• dc.identifier.citation Cremer J, Medrano Sandonas L, Tkatchenko A, Clevert DA, De Fabritiis G. Equivariant graph neural networks for toxicity prediction. Chem Res Toxicol. 2023 Sep 10;36(10):1561-73. DOI: 10.1021/acs.chemrestox.3c00032
• dc.identifier.doi http://dx.doi.org/10.1021/acs.chemrestox.3c00032
• dc.identifier.issn 0893-228X
• dc.identifier.uri http://hdl.handle.net/10230/59413
• dc.language.iso eng
• dc.publisher American Chemical Society (ACS)
• dc.relation.ispartof Chem Res Toxicol. 2023 Sep 10;36(10):1561-73
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/956832
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/823712
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2020-116564GB-I00
• dc.rights © 2023 The Authors. Published by American Chemical Society. This publication is licensed under CC-BY 4.0 (http://creativecommons.org/licenses/by/4.0/).
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.other Toxicologia
• dc.title Equivariant graph neural networks for toxicity prediction
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion