# SMDD-Bench: Can LLMs Solve Real-World Small Molecule Drug Design Tasks?

arXiv: https://arxiv.org/abs/2605.21740 · HTML: https://mlsanity.com/paper/2605.21740/

## Key facts

- Cited by 4 papers in the map (data through 14 Oct 2026).
- Placed in Medical and scientific domain agents, one of 16 directions in LLM agents and tool use.
- Builds on 13 of its 57 references that are in the map.
- First posted on arXiv 20 May 2026.

## Placed in

- LLM agents and tool use / [Medical and scientific domain agents](https://mlsanity.com/agents/medical-and-scientific-domain-agents/)

## Builds on (most cited first, 13 of 13)

- [Therapeutics Data Commons: Machine Learning Datasets and Tasks for Drug Discovery and Development](https://mlsanity.com/paper/2102.09548/) (2021)
- [DeepResearch Bench: A Comprehensive Benchmark for Deep Research Agents](https://mlsanity.com/paper/2506.11763/) (2025)
- [LAB-Bench: Measuring Capabilities of Language Models for Biology Research](https://mlsanity.com/paper/2407.10362/) (2024)
- [LlaSMol: Advancing Large Language Models for Chemistry with a Large-Scale, Comprehensive, High-Quality Instruction Tuning Dataset](https://mlsanity.com/paper/2402.09391/) (2024)
- [BixBench: a Comprehensive Benchmark for LLM-based Agents in Computational Biology](https://mlsanity.com/paper/2503.00096/) (2025)
- [Efficient Evolutionary Search Over Chemical Space with Large Language Models](https://mlsanity.com/paper/2406.16976/) (2024)
- [GeLLMO: Generalizing Large Language Models for Multi-property Molecule Optimization](https://mlsanity.com/paper/2502.13398/) (2025)
- [BioProBench: A Corpus and Benchmark for Biological Protocol Reasoning in Autonomous Science](https://mlsanity.com/paper/2505.07889/) (2025)
- [MolecularIQ: Characterizing Chemical Reasoning Capabilities Through Symbolic Verification on Molecular Graphs](https://mlsanity.com/paper/2601.15279/) (2026)
- [Agentic reinforcement learning empowers next-generation chemical language models for molecular design and synthesis](https://mlsanity.com/paper/2601.17687/) (2026)
- [Zatom-1: Towards a Multimodal Foundation Model for 3D Molecules and Materials](https://mlsanity.com/paper/2602.22251/) (2026)
- [Evaluating the Progression of Large Language Model Capabilities for Small-Molecule Drug Design](https://mlsanity.com/paper/2604.16279/) (2026)
- [LLM-Guided Dynamic Action Spaces for Synthesizable Molecular Optimization](https://mlsanity.com/paper/2604.07669/) (2026)

## Built on by (most cited first, 4 of 4)

- [CAi Copilot: Reducing Operational Workload in Molecular Design through Intent-Driven Agentic Workflows](https://mlsanity.com/paper/2608.06961/) (2026)
- [Training Large Language Models for Small-Molecule Design with Synthetic Task Scaling](https://mlsanity.com/paper/2609.04735/) (2026)
- [M3OS: A Monte Carlo Graph Search-Orchestrated Multi-Agent LLM System for Evidence-Traced Molecular Optimization](https://mlsanity.com/paper/2609.34491/) (2026)
- [Multi-LLM Collaborative Alignment via Stackelberg Games](https://mlsanity.com/paper/2609.39076/) (2026)

## Abstract (arXiv)

LLM agents have incredible potential for scientific discovery applications. However, the performance of LLM agents on real-world, small molecule drug design (SMDD) tasks across diverse chemistries and targets is unclear. Current evaluation methods are either ad hoc, too simple for real-world discovery, limited in scale, or restricted to single-turn question answering. In effort to standardize the evaluation of LLM agents on small molecule design, we introduce SMDD-Bench, a challenging, multi-turn, long-horizon agentic benchmark consisting of 502 guaranteed-solvable task instances spanning 5 task types: 2D Pharmacophore Identification, Interaction Point Discovery, Scaffold Hopping, Lead Optimization, and Fragment Assembly. SMDD-Bench tasks span a wide region of chemical space and involve 102 unique protein targets. Completely solving the benchmark would require having strong chemical and biological reasoning and 3D intuition, understanding specialized tool use, and displaying planning expertise over a limited number of oracle calls. We benchmark 7 frontier open and closed source LLMs and find even the most performant LLM, GPT5.4, solves only 40.2% of tasks. We hope SMDD-Bench provides a standardized testbed to invigorate the field towards training and evaluating LLM agents for fully autonomous computational drug design. We host a public leaderboard at smddbench.com .