# CoTox: Chain-of-Thought-Based Molecular Toxicity Reasoning and Prediction

arXiv: https://arxiv.org/abs/2508.03159 · HTML: https://mlsanity.com/paper/2508.03159/

## Key facts

- Cited by 5 papers in the map (data through 14 Oct 2026).
- Placed in Clinical and biomedical applications, one of 17 directions in LLM reasoning.
- Builds on 11 of its 38 references that are in the map.
- First posted on arXiv 5 Aug 2025.

## Placed in

- LLM reasoning / [Clinical and biomedical applications](https://mlsanity.com/lr/clinical-and-biomedical-applications/)

## Builds on (most cited first, 11 of 11)

- [Chain-of-Thought Prompting Elicits Reasoning in Large Language Models](https://mlsanity.com/paper/2201.11903/) (2022)
- [Qwen3 Technical Report](https://mlsanity.com/paper/2505.09388/) (2025)
- [XGBoost: A Scalable Tree Boosting System](https://mlsanity.com/paper/1603.02754/) (2016)
- [Gemini 2.5: Pushing the Frontier with Advanced Reasoning, Multimodality, Long Context, and Next Generation Agentic Capabilities](https://mlsanity.com/paper/2507.06261/) (2025)
- [A Review of Large Language Models and Autonomous Agents in Chemistry](https://mlsanity.com/paper/2407.01603/) (2024)
- [Advancing Reasoning in Large Language Models: Promising Methods and Approaches](https://mlsanity.com/paper/2502.03671/) (2025)
- [TxGemma: Efficient and Agentic LLMs for Therapeutics](https://mlsanity.com/paper/2504.06196/) (2025)
- [BioReason: Incentivizing Multimodal Biological Reasoning within a DNA-LLM Model](https://mlsanity.com/paper/2505.23579/) (2025)
- [Structured Chemistry Reasoning with Large Language Models](https://mlsanity.com/paper/2311.09656/) (2023)
- [Large Language Models in Drug Discovery and Development: From Disease Mechanisms to Clinical Trials](https://mlsanity.com/paper/2409.04481/) (2024)
- [Improving Chemical Understanding of LLMs via SMILES Parsing](https://mlsanity.com/paper/2505.16340/) (2025)

## Built on by (most cited first, 5 of 5)

- [VCWorld: A Biological World Model for Virtual Cell Simulation](https://mlsanity.com/paper/2512.00306/) (2025)
- [DrugReasoner: Interpretable Drug Approval Prediction with a Reasoning-augmented Language Model](https://mlsanity.com/paper/2508.18579/) (2025)
- [ToxReason: A Benchmark for Mechanistic Chemical Toxicity Reasoning via Adverse Outcome Pathway](https://mlsanity.com/paper/2604.06264/) (2026)
- [MolDeTox: Evaluating Language Model's Stepwise Fragment Editing for Molecular Detoxification](https://mlsanity.com/paper/2605.12181/) (2026)
- [Reasoning4Sciences: Bridging Reasoning Language Models to All Scientific Branches](https://mlsanity.com/paper/2606.01145/) (2026)

## Abstract (arXiv)

Drug toxicity remains a major challenge in pharmaceutical development. Recent machine learning models have improved in silico toxicity prediction, but their reliance on annotated data and lack of interpretability limit their applicability. This limits their ability to capture organ-specific toxicities driven by complex biological mechanisms. Large language models (LLMs) offer a promising alternative through step-by-step reasoning and integration of textual data, yet prior approaches lack biological context and transparent rationale. To address this issue, we propose CoTox, a novel framework that integrates LLM with chain-of-thought (CoT) reasoning for multi-toxicity prediction. CoTox combines chemical structure data, biological pathways, and gene ontology (GO) terms to generate interpretable toxicity predictions through step-by-step reasoning. Using GPT-4o, we show that CoTox outperforms both traditional machine learning and deep learning model. We further examine its performance across various LLMs to identify where CoTox is most effective. Additionally, we find that representing chemical structures with IUPAC names, which are easier for LLMs to understand than SMILES, enhances the model's reasoning ability and improves predictive performance. To demonstrate its practical utility in drug development, we simulate the treatment of relevant cell types with drug and incorporated the resulting biological context into the CoTox framework. This approach allow CoTox to generate toxicity predictions aligned with physiological responses, as shown in case study. This result highlights the potential of LLM-based frameworks to improve interpretability and support early-stage drug safety assessment. The code and prompt used in this work are available at https://github.com/dmis-lab/CoTox.