My Chemical Harness: Evolutionary Molecular Design over Synthetic Pathways with Large Language Model Agents

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.

Real-world molecular design remains challenging for large language model (LLM)-based agents. It requires them to interpret design contexts, satisfy multiple constraints, identify infeasible specifications, and reason over multi-step tool outputs. Existing benchmarks do not capture this complexity, focusing instead on explicit and narrow constraints, only feasible problems, and single-path solutions. To address this gap, we propose MolDesignBench, a scenario-grounded benchmark that more closely reflects real-world molecular design for evaluating tool-augmented LLM agents. MolDesignBench comprises 2K generation and optimization instances that combine implicit requirements embedded in design narratives with explicit property and functional-group constraints, including infeasible cases, and require the effective use of 17 specialized chemistry tools. Experiments across diverse frontier LLMs reveal low success rates--with the best achieving only $\sim43$%--and frequent failures in implicit-constraint reasoning, infeasibility detection, and tool reasoning. The corresponding fine-grained failure-mode analysis identifies implicit constraint interpretation and infeasibility detection as the primary bottlenecks, establishing MolDesignBench as a rigorous testbed to guide future research on chemical agents. The benchmark, tool interface, and evaluation code are publicly available.

We present MolLingo, a multi-agent system that emulates the reasoning process of a chemist to automate molecular design. Existing LLM-based approaches either operate as standalone generative models without access to external tools or lack the multi-agent coordination and shared memory needed for iterative, evidence-driven reasoning across the molecular design pipeline. MolLingo addresses this by coordinating a Literature Agent, a Chemist Agent, and an Orchestrator through a shared memory module, with each agent equipped with domain-specific tools. To enable effective molecular reasoning, we introduce BRICS-based Fragment Enumeration (BFE), a synthesis-aware molecular fragmentation method that decomposes molecules into chemically meaningful building blocks represented as block-based SMILES paired with common chemical names. This representation bridges molecular structure and LLM semantic space, enabling block-level reasoning and editing that is difficult with raw SMILES alone. As a case study in early-stage therapeutic design, MolLingo further grounds the Chemist Agent's reasoning in binding site geometry and residue-level protein context derived from molecular docking to optimize molecules for stronger target binding. Across four benchmarks, MolLingo consistently outperforms frontier LLMs and specialized baselines, including a fourfold docking score improvement over GPT-5.4 despite using the same underlying model, consistent drug property optimization gains across multiple LLM backbones, and state-of-the-art results on TOMG-Bench, surpassing both frontier LLMs and the RL-based optimization method RePO. Our results suggest that LLMs are already capable molecular design assistants when guided through chemically meaningful representations and biologically grounded structural context. Code is available at: https://anonymous.4open.science/status/MolLingo-7450.