Benchmarking of Small Molecule Feature Representations for hERG, Nav1.5, and Cav1.2 Cardiotoxicity Prediction
Bibliographic record
Abstract
In the field of drug discovery, there is a substantial challenge in seeking out chemical structures that possess desirable pharmacological, toxicological, and pharmacokinetic properties. Complications arise when drugs interfere with the functioning of cardiac ion channels, leading to serious cardiovascular consequences. The discontinuation and removal of numerous approved drugs from the market or at late development stages in the pipeline due to such inhibitory effects further highlight the urgency of addressing this issue. Consequently, the early prediction of potential blockers targeting cardiac ion channels during the drug discovery process is of paramount importance. This study introduces a deep learning framework that computationally determines the cardiotoxicity associated with the voltage-gated potassium channel (hERG), the voltage-gated calcium channel (Cav1.2), and the voltage-gated sodium channel (Nav1.5) for drug candidates. The predictive capabilities of three feature representations─molecular fingerprints, descriptors, and graph-based numerical representations─are rigorously benchmarked. Additionally, a novel training and evaluation data set framework is presented, enabling predictive model training of drug off-target cardiotoxicity using a comprehensive and large curated data set covering these three cardiac ion channels. To facilitate these predictions, a robust and comprehensive small molecule cardiotoxicity prediction tool named CToxPred has been developed. It is made available as open source under the permissive MIT license at https://github.com/issararab/CToxPred.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".