Computational toxicology in drug discovery: applications of artificial intelligence in ADMET and toxicity prediction

Abstract

Toxicity risk assessment plays a crucial role in determining the clinical success and market potential of drug candidates. Traditional animal-based testing is costly, time-consuming, and ethically controversial, which has led to the rapid development of computational toxicology. This review surveys over 20 ADMET prediction platforms, categorizing them into rule/statistical-based methods, machine learning (ML) methods, and graph-based methods. We also summarize major toxicological databases into four types: chemical toxicity, environmental toxicology, alternative toxicology, and biological toxin databases, highlighting their roles in model training and validation. Furthermore, we review recent advancements in ML and artificial intelligence (AI) applied to toxicity prediction, covering acute toxicity, organ-specific toxicities, and carcinogenicity. The field is transitioning from single-endpoint predictions to multi-endpoint joint modeling, incorporating multimodal features. We also explore the application of generative modeling techniques and interpretability frameworks to improve the accuracy and credibility of predictions. Additionally, we discuss the use of network toxicology in evaluating the safety of traditional Chinese medicines (TCMs) and the potential of large language models (LLMs) in literature mining, knowledge integration, and molecular toxicity prediction. Finally, we address current challenges, including data quality, model interpretability, and causal inference, and propose future directions such as multi-omics integration, interpretable AI models, and domain-specific LLMs, aiming to provide more efficient and precise technical support for preclinical toxicity assessments in drug development.