Toward a Locally Deployable Agentic Co-Scientist: Small-Model Planning for Early-Stage Drug Discovery

Large language models are increasingly used as planning components in agentic systems, but current tool-use pipelines often require full tool schemas to be included in every prompt, creating substantial token overhead and limiting the practicality of smaller models. This paper investigates whether tool-use knowledge can be internalized into small language models through parameter-efficient fine-tuning, enabling structured planning without explicit tool descriptions at inference time. Using AssetOpsBench as the primary benchmark, we fine-tune Gemma 4 E4B and Qwen3-4B with 8-bit QLoRA on approximately 1,700 tool-use examples spanning tool knowledge, question-to-plan mappings, and execution-style traces. We evaluate the resulting models under description-free inference, where the prompt omits the tool catalog entirely. The fine-tuned models outperform an informed unfine-tuned baseline that receives full tool descriptions, reducing input length by 82.6% while improving structural and LLM-judge planning scores. In the best Gemma run, the model achieves an AT-F1 of 0.65 and an overall judge score of 3.88, compared with 0.47 and 2.88 for the informed baseline. Qwen3-4B achieves a strong overall judge score of 3.78 while using 62% less memory and running 2.5$\times$ faster than Gemma, though it also exhibits greater catastrophic forgetting on general multiple-choice benchmarks. Additional ablations show that LoRA rank controls a quality--retention trade-off, with $r=32$ maximizing planning quality and smaller ranks preserving more general knowledge. These results suggest that, for fixed tool catalogs, QLoRA fine-tuning can shift tool knowledge from prompt context into model weights, substantially reducing inference overhead while maintaining or improving tool-planning quality.

Drug discovery remains a resource-intensive and time-consuming process, involving billions of dollars and a decade of development to advance a drug to market. While many in silico tools have accelerated this process, operating them still demands substantial time, effort, and expertise from medicinal chemists. Autonomous systems built on Large Language Models (LLMs) have emerged as a promising solution, yet current designs limit their performance. Existing single-agent systems scale poorly to long-horizon, multi-step, and realistic tasks, whereas multi-agent systems typically execute predefined workflows that cannot capture the iterative, non-linear nature of a real drug discovery campaign. Here, we present MADDIE, a multi-agent drug discovery engine. It comprises a central agent, Orchestrator, and four specialized worker agents: HitIdentifier, LeadOptimizer, Synthesizer, and Evaluator, each representing a critical step in a drug discovery campaign. Under Orchestrator's orchestration and coordination, these worker agents are composed into flexible workflows, enabling MADDIE to adapt its strategy and navigate the drug discovery pipeline end-to-end. Across 50 protein targets, MADDIE produces molecules satisfying key property requirements and their synthesis routes, outperforming existing agentic systems, generative models, and general-purpose LLMs by a wide margin. Our analysis reveals how these agents collaborate and that MADDIE can employ different strategies across targets to achieve the campaign's goal, while still being efficient in time and tokens. Together, they demonstrate MADDIE as a low-cost, effective, and efficient autonomous engine for accelerating drug discovery. Code and dataset is available via https://github.com/ninglab/MADDIE.

Advances in large language models (LLMs) have recently opened new and promising avenues for small-molecule drug discovery. Yet existing LLM-based approaches for molecular generation often suffer from high rates of invalid and low-quality ligand candidates, a result of the syntactic limitations of current models with regard to molecular strings. In this paper, we introduce $\texttt{ToolMol}$, an evolutionary agentic framework for de novo drug design. $\texttt{ToolMol}$ combines a multi-objective genetic algorithm with an agentic LLM operator that iteratively updates the ligand population. We build a comprehensive toolbox of RDKit-backed functions that allows our agentic operator to consisently make precise ligand modifications. $\texttt{ToolMol}$ achieves state-of-the-art performance on multi-objective property optimization tasks, discovering drug-like and synthesizable ligands that have $>10\%$ stronger predicted binding affinity compared to existing methods, evaluated on three protein targets. $\texttt{ToolMol}$ ligands additionally achieve state-of-the-art results in gold-standard Absolute Binding Free Energy scores, gaining over existing methods by over $35\%$. By studying chain-of-thought reasoning traces, we observe that tool-calling enables the model to more faithfully execute its planned modifications, efficiently exploiting the strong chemical prior knowledge in LLMs.