HERGAI: an artificial intelligence tool for structure-based prediction of hERG inhibitors
Abstract The human Ether-à-go-go-Related Gene (hERG) potassium channel is crucial for repolarizing the cardiac action potential and regulating the heartbeat. Molecules that inhibit this protein can cause acquired long QT syndrome, increasing the risk of arrhythmias and sudden fatal cardiac arrests....
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| Format: | Article |
| Language: | English |
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BMC
2025-07-01
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| Series: | Journal of Cheminformatics |
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| Online Access: | https://doi.org/10.1186/s13321-025-01063-8 |
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| author | Viet-Khoa Tran-Nguyen Ulrick Fineddie Randriharimanamizara Olivier Taboureau |
| author_facet | Viet-Khoa Tran-Nguyen Ulrick Fineddie Randriharimanamizara Olivier Taboureau |
| author_sort | Viet-Khoa Tran-Nguyen |
| collection | DOAJ |
| description | Abstract The human Ether-à-go-go-Related Gene (hERG) potassium channel is crucial for repolarizing the cardiac action potential and regulating the heartbeat. Molecules that inhibit this protein can cause acquired long QT syndrome, increasing the risk of arrhythmias and sudden fatal cardiac arrests. Detecting compounds with potential hERG inhibitory activity is therefore essential to mitigate cardiotoxicity risks. In this article, we present a new hERG data set of unprecedented size, comprising nearly 300,000 molecules reported in PubChem and ChEMBL, approximately 2000 of which were confirmed hERG blockers identified through in vitro assays. Multiple structure-based artificial intelligence (AI) binary classifiers for predicting hERG inhibitors were developed, employing, as descriptors, protein–ligand extended connectivity (PLEC) fingerprints fed into random forest, extreme gradient boosting, and deep neural network (DNN) algorithms. Our best-performing model, a stacking ensemble classifier with a DNN meta-learner, achieved state-of-the-art classification performance, accurately identifying 86% of molecules having half-maximal inhibitory concentrations (IC50s) not exceeding 20 µM in our challenging test set, including 94% of hERG blockers whose IC50s were not greater than 1 µM. It also demonstrated superior screening power compared to virtual screening schemes that used existing scoring functions. This model, named “HERGAI,” along with relevant input/output data and user-friendly source code, is available in our GitHub repository ( https://github.com/vktrannguyen/HERGAI ) and can be used to predict drug-induced hERG blockade, even on large data sets. |
| format | Article |
| id | doaj-art-6893bb353528417c8d7373cf8902afb8 |
| institution | Kabale University |
| issn | 1758-2946 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Cheminformatics |
| spelling | doaj-art-6893bb353528417c8d7373cf8902afb82025-08-20T03:46:21ZengBMCJournal of Cheminformatics1758-29462025-07-0117111510.1186/s13321-025-01063-8HERGAI: an artificial intelligence tool for structure-based prediction of hERG inhibitorsViet-Khoa Tran-Nguyen0Ulrick Fineddie Randriharimanamizara1Olivier Taboureau2Université Paris Cité, CNRS UMR 8251Université Paris Cité, CNRS UMR 8251Université Paris Cité, CNRS UMR 8251Abstract The human Ether-à-go-go-Related Gene (hERG) potassium channel is crucial for repolarizing the cardiac action potential and regulating the heartbeat. Molecules that inhibit this protein can cause acquired long QT syndrome, increasing the risk of arrhythmias and sudden fatal cardiac arrests. Detecting compounds with potential hERG inhibitory activity is therefore essential to mitigate cardiotoxicity risks. In this article, we present a new hERG data set of unprecedented size, comprising nearly 300,000 molecules reported in PubChem and ChEMBL, approximately 2000 of which were confirmed hERG blockers identified through in vitro assays. Multiple structure-based artificial intelligence (AI) binary classifiers for predicting hERG inhibitors were developed, employing, as descriptors, protein–ligand extended connectivity (PLEC) fingerprints fed into random forest, extreme gradient boosting, and deep neural network (DNN) algorithms. Our best-performing model, a stacking ensemble classifier with a DNN meta-learner, achieved state-of-the-art classification performance, accurately identifying 86% of molecules having half-maximal inhibitory concentrations (IC50s) not exceeding 20 µM in our challenging test set, including 94% of hERG blockers whose IC50s were not greater than 1 µM. It also demonstrated superior screening power compared to virtual screening schemes that used existing scoring functions. This model, named “HERGAI,” along with relevant input/output data and user-friendly source code, is available in our GitHub repository ( https://github.com/vktrannguyen/HERGAI ) and can be used to predict drug-induced hERG blockade, even on large data sets.https://doi.org/10.1186/s13321-025-01063-8hERGInhibitorBinary classification modelMachine learningDeep learningDeep neural network |
| spellingShingle | Viet-Khoa Tran-Nguyen Ulrick Fineddie Randriharimanamizara Olivier Taboureau HERGAI: an artificial intelligence tool for structure-based prediction of hERG inhibitors Journal of Cheminformatics hERG Inhibitor Binary classification model Machine learning Deep learning Deep neural network |
| title | HERGAI: an artificial intelligence tool for structure-based prediction of hERG inhibitors |
| title_full | HERGAI: an artificial intelligence tool for structure-based prediction of hERG inhibitors |
| title_fullStr | HERGAI: an artificial intelligence tool for structure-based prediction of hERG inhibitors |
| title_full_unstemmed | HERGAI: an artificial intelligence tool for structure-based prediction of hERG inhibitors |
| title_short | HERGAI: an artificial intelligence tool for structure-based prediction of hERG inhibitors |
| title_sort | hergai an artificial intelligence tool for structure based prediction of herg inhibitors |
| topic | hERG Inhibitor Binary classification model Machine learning Deep learning Deep neural network |
| url | https://doi.org/10.1186/s13321-025-01063-8 |
| work_keys_str_mv | AT vietkhoatrannguyen hergaianartificialintelligencetoolforstructurebasedpredictionofherginhibitors AT ulrickfineddierandriharimanamizara hergaianartificialintelligencetoolforstructurebasedpredictionofherginhibitors AT oliviertaboureau hergaianartificialintelligencetoolforstructurebasedpredictionofherginhibitors |