DrugTrail: Explainable Drug Discovery via Structured Reasoning and Druggability‑Tailored Preference Optimization

Abstract

Machine learning promises to revolutionize drug discovery, but its "black-box" nature and narrow focus limit adoption by experts. While Large Language Models (LLMs) offer a path forward with their broad knowledge and interactivity, existing methods remain data-intensive and lack transparent reasoning. To address these issues, we present DrugTrail, an LLM-based framework for explainable drug discovery that integrates structured reasoning trajectories with a Druggability‑Tailored Preference Optimization (DTPO) strategy. It not only introduces structured reasoning traces to articulate the "how" and "why" behind its conclusions but also serve to guide task-specific reasoning pathways within the LLM's vast knowledge space, thereby enhancing its interpretability and reliability of its final outputs. Furthermore, based on the fact that optimizing for binding affinity alone does not equate to optimizing for druggability, DTPO explicitly moves beyond single-metric optimization and opens up a broader search space that balances affinity with other essential factors. Extensive experiments demonstrate the effectiveness of our approach and its generalizability to a wider range of biomolecular optimization domains, bridging the gap between LLM reasoning capabilities and trustworthy AI-assisted drug discovery.