ArticleMolecular pharmaceutics2012
QSAR modeling and data mining link Torsades de Pointes risk to the interplay of extent of metabolism, active transport, and HERG liability.
Article in Molecular pharmaceutics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 39 citations in OpenAlex.
- 25 Years of Cardiac Ion Channel QSAR: From hERG Dominance to Multi-Channel Modeling.Journal of chemical information and modeling · 2026Review
- Unlocking the Potential of Clustering and Classification Approaches: Navigating Supervised and Unsupervised Chemical Similarity.Environmental health perspectives · 2024Article
- Deep Learning-Based Prediction of Drug-Induced Cardiotoxicity.Journal of chemical information and modeling · 2019Article
- Capsule Networks Showed Excellent Performance in the Classification of hERG Blockers/Nonblockers.Frontiers in pharmacology · 2019Article
- Compilation and physicochemical classification analysis of a diverse hERG inhibition database.Journal of computer-aided molecular design · 2016Article
- BDDCS, the Rule of 5 and drugability.Advanced drug delivery reviews · 2016Review
- Use of the Biopharmaceutics Drug Disposition Classification System (BDDCS) to Help Predict the Occurrence of Idiosyncratic Cutaneous Adverse Drug Reactions Associated with Antiepileptic Drug Usage.The AAPS journal · 2016Article
- BDDCS Predictions, Self-Correcting Aspects of BDDCS Assignments, BDDCS Assignment Corrections, and Classification for more than 175 Additional Drugs.The AAPS journal · 2016Review
- Tuning HERG out: antitarget QSAR models for drug development.Current topics in medicinal chemistry · 2014Article
- Fusing dual-event data sets for Mycobacterium tuberculosis machine learning models and their evaluation.Journal of chemical information and modeling · 2013Article
- Integrated analysis of drug-induced gene expression profiles predicts novel hERG inhibitors.PloS one · 2013Article
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
We collected 1173 hERG patch clamp (PC) data (IC50) from the literature to derive twelve classification models for hERG inhibition, covering a large variety of chemical descriptors and classification algorithms. Models were generated using 545 molecules and validated through 258 external molecules tested in PC experiments. We also evaluated the suitability of the best models to predict the activity of 26 proprietary compounds tested in radioligand binding displacement (RBD). Results proved the necessity to use multiple validation sets for a true estimation of model accuracy and demonstrated that using various descriptors and algorithms improves the performance of ligand-based models. Intriguingly, one of the most accurate models uncovered an unexpected link between extent of metabolism and hERG liability. This hypothesis was fairly reinforced by using the Biopharmaceutics Drug Disposition Classification System (BDDCS) that recognized 94% of the hERG inhibitors as extensively metabolized in vivo. Data mining suggested that high Torsades de Pointes (TdP) risk results from an interplay of hERG inhibition, extent of metabolism, active transport, and possibly solubility. Overall, these new findings might improve both the decision making skills of pharmaceutical scientists to mitigate hERG liability during the drug discovery process and the TdP risk assessment during drug development.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.