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

TL;DR

SMDD-Bench is a new challenging benchmark for evaluating large language models on real-world small molecule drug design tasks, highlighting current limitations and encouraging progress in autonomous computational drug discovery.

Contribution

The paper introduces SMDD-Bench, a comprehensive, multi-turn benchmark with 502 tasks across diverse chemistries and targets for assessing LLMs in drug design.

Findings

Most LLMs solve less than 50% of tasks

Current models lack sufficient reasoning and planning skills

SMDD-Bench enables standardized evaluation of LLMs in drug discovery

Abstract

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 .