# Efficient Evolutionary Search Over Chemical Space with Large Language Models

arXiv: https://arxiv.org/abs/2406.16976 · HTML: https://mlsanity.com/paper/2406.16976/

## Key facts

- Cited by 61 papers in the map (data through 14 Oct 2026).
- Builds on 48 of its 89 references that are in the map.
- First posted on arXiv 23 Jun 2024.

## Builds on (most cited first, 30 of 48)

- [GPT-4 Technical Report](https://mlsanity.com/paper/2303.08774/) (2023)
- [Exploring the Limits of Transfer Learning with a Unified Text-to-Text Transformer](https://mlsanity.com/paper/1910.10683/) (2019)
- [Large Language Models as Optimizers](https://mlsanity.com/paper/2309.03409/) (2023)
- [Large Language Models](https://mlsanity.com/paper/2307.05782/) (2023)
- [Automatic chemical design using a data-driven continuous representation of molecules](https://mlsanity.com/paper/1610.02415/) (2016)
- [Galactica: A Large Language Model for Science](https://mlsanity.com/paper/2211.09085/) (2022)
- [Equivariant Diffusion for Molecule Generation in 3D](https://mlsanity.com/paper/2203.17003/) (2022)
- [Junction Tree Variational Autoencoder for Molecular Graph Generation](https://mlsanity.com/paper/1802.04364/) (2018)
- [Eureka: Human-Level Reward Design via Coding Large Language Models](https://mlsanity.com/paper/2310.12931/) (2023)
- [Promptbreeder: Self-Referential Self-Improvement Via Prompt Evolution](https://mlsanity.com/paper/2309.16797/) (2023)
- [ChemBERTa: Large-Scale Self-Supervised Pretraining for Molecular Property Prediction](https://mlsanity.com/paper/2010.09885/) (2020)
- [GraphAF: a Flow-based Autoregressive Model for Molecular Graph Generation](https://mlsanity.com/paper/2001.09382/) (2020)
- [Molecular De Novo Design through Deep Reinforcement Learning](https://mlsanity.com/paper/1704.07555/) (2017)
- [Therapeutics Data Commons: Machine Learning Datasets and Tasks for Drug Discovery and Development](https://mlsanity.com/paper/2102.09548/) (2021)
- [SciBench: Evaluating College-Level Scientific Problem-Solving Abilities of Large Language Models](https://mlsanity.com/paper/2307.10635/) (2023)
- [Molecular Transformer - A Model for Uncertainty-Calibrated Chemical Reaction Prediction](https://mlsanity.com/paper/1811.02633/) (2018)
- [Structure-based Drug Design with Equivariant Diffusion Models](https://mlsanity.com/paper/2210.13695/) (2022)
- [MoFlow: An Invertible Flow Model for Generating Molecular Graphs](https://mlsanity.com/paper/2006.10137/) (2020)
- [What can Large Language Models do in chemistry? A comprehensive benchmark on eight tasks](https://mlsanity.com/paper/2305.18365/) (2023)
- [Translation between Molecules and Natural Language](https://mlsanity.com/paper/2204.11817/) (2022)
- [Multi-modal Molecule Structure-text Model for Text-based Retrieval and Editing](https://mlsanity.com/paper/2212.10789/) (2022)
- [Sample Efficiency Matters: A Benchmark for Practical Molecular Optimization](https://mlsanity.com/paper/2206.12411/) (2022)
- [Evolution through Large Models](https://mlsanity.com/paper/2206.08896/) (2022)
- [Large Language Models as Evolutionary Optimizers](https://mlsanity.com/paper/2310.19046/) (2023)
- [GraphNVP: An Invertible Flow Model for Generating Molecular Graphs](https://mlsanity.com/paper/1905.11600/) (2019)
- [Geometric Deep Learning on Molecular Representations](https://mlsanity.com/paper/2107.12375/) (2021)
- [The Impact of Large Language Models on Scientific Discovery: a Preliminary Study using GPT-4](https://mlsanity.com/paper/2311.07361/) (2023)
- [BioT5: Enriching Cross-modal Integration in Biology with Chemical Knowledge and Natural Language Associations](https://mlsanity.com/paper/2310.07276/) (2023)
- [Unifying Molecular and Textual Representations via Multi-task Language Modelling](https://mlsanity.com/paper/2301.12586/) (2023)
- [MolecularRNN: Generating realistic molecular graphs with optimized properties](https://mlsanity.com/paper/1905.13372/) (2019)

## Built on by (most cited first, 30 of 61)

- [AlphaEvolve: A coding agent for scientific and algorithmic discovery](https://mlsanity.com/paper/2506.13131/) (2025)
- [Advances and Challenges in Foundation Agents: From Brain-Inspired Intelligence to Evolutionary, Collaborative, and Safe Systems](https://mlsanity.com/paper/2504.01990/) (2025)
- [Feynman-Kac Correctors in Diffusion: Annealing, Guidance, and Product of Experts](https://mlsanity.com/paper/2503.02819/) (2025)
- [Feedback Descent: Open-Ended Text Optimization via Pairwise Comparison](https://mlsanity.com/paper/2511.07919/) (2025)
- [The Superposition of Diffusion Models Using the Ito Density Estimator](https://mlsanity.com/paper/2412.17762/) (2024)
- [LICO: Large Language Models for In-Context Molecular Optimization](https://mlsanity.com/paper/2406.18851/) (2024)
- [A Survey on LLM Test-Time Compute via Search: Tasks, LLM Profiling, Search Algorithms, and Relevant Frameworks](https://mlsanity.com/paper/2501.10069/) (2025)
- [DrugPilot: LLM-based Parameterized Reasoning Agent for Drug Discovery](https://mlsanity.com/paper/2505.13940/) (2025)
- [SmileyLlama: Modifying Large Language Models for Directed Chemical Space Exploration](https://mlsanity.com/paper/2409.02231/) (2024)
- [LLM-Augmented Chemical Synthesis and Design Decision Programs](https://mlsanity.com/paper/2505.07027/) (2025)
- [LLEMA: Evolutionary Search with LLMs for Multi-Objective Materials Discovery](https://mlsanity.com/paper/2510.22503/) (2025)
- [AIRA_2: Overcoming Bottlenecks in AI Research Agents](https://mlsanity.com/paper/2603.26499/) (2026)
- [LLM-AutoSciLab: Closed-Loop Scientific Discovery via Active Experimentation with LLMs](https://mlsanity.com/paper/2605.24043/) (2026)
- [A Systematic Survey on Large Language Models for Evolutionary Optimization: From Modeling to Solving](https://mlsanity.com/paper/2509.08269/) (2025)
- [POLO: Preference-Guided Multi-Turn Reinforcement Learning for Lead Optimization](https://mlsanity.com/paper/2509.21737/) (2025)
- [Autonomous Agents for Scientific Discovery: Orchestrating Scientists, Language, Code, and Physics](https://mlsanity.com/paper/2510.09901/) (2025)
- [Towards Foundation-model-based Multiagent System to Accelerate AI for Social Impact](https://mlsanity.com/paper/2412.07880/) (2024)
- [ExLLM: Experience-Enhanced LLM Optimization for Molecular Design and Beyond](https://mlsanity.com/paper/2502.12845/) (2025)
- [AutoG: Towards automatic graph construction from tabular data](https://mlsanity.com/paper/2501.15282/) (2025)
- [MatLLMSearch: Crystal Structure Discovery with Evolution-Guided Large Language Models](https://mlsanity.com/paper/2502.20933/) (2025)
- [Learning Flexible Forward Trajectories for Masked Molecular Diffusion](https://mlsanity.com/paper/2505.16790/) (2025)
- [Towards autonomous quantum physics research using LLM agents with access to intelligent tools](https://mlsanity.com/paper/2511.11752/) (2025)
- [LLM-ACES: Closed-Loop Discovery of Dynamical Systems with LLM-Guided Adaptive Search](https://mlsanity.com/paper/2606.25039/) (2026)
- [AutoChemSchematic AI: Agentic Physics-Aware Automation for Chemical Manufacturing Scale-Up](https://mlsanity.com/paper/2505.24584/) (2025)
- [The Rise of Generative AI for Metal-Organic Framework Design and Synthesis](https://mlsanity.com/paper/2508.13197/) (2025)
- [Reference-guided Policy Optimization for Molecular Optimization via LLM Reasoning](https://mlsanity.com/paper/2603.05900/) (2026)
- [Neural Genetic Search in Discrete Spaces](https://mlsanity.com/paper/2502.10433/) (2025)
- [TritonDFT: Automating DFT with a Multi-Agent Framework](https://mlsanity.com/paper/2603.03372/) (2026)
- [Generative Design of Functional Metal Complexes Utilizing the Internal Knowledge of Large Language Models](https://mlsanity.com/paper/2410.18136/) (2024)
- [MolEvolve: LLM-Guided Evolutionary Search for Interpretable Molecular Optimization](https://mlsanity.com/paper/2603.24382/) (2026)

## Abstract (arXiv)

Molecular discovery, when formulated as an optimization problem, presents significant computational challenges because optimization objectives can be non-differentiable. Evolutionary Algorithms (EAs), often used to optimize black-box objectives in molecular discovery, traverse chemical space by performing random mutations and crossovers, leading to a large number of expensive objective evaluations. In this work, we ameliorate this shortcoming by incorporating chemistry-aware Large Language Models (LLMs) into EAs. Namely, we redesign crossover and mutation operations in EAs using LLMs trained on large corpora of chemical information. We perform extensive empirical studies on both commercial and open-source models on multiple tasks involving property optimization, molecular rediscovery, and structure-based drug design, demonstrating that the joint usage of LLMs with EAs yields superior performance over all baseline models across single- and multi-objective settings. We demonstrate that our algorithm improves both the quality of the final solution and convergence speed, thereby reducing the number of required objective evaluations. Our code is available at http://github.com/zoom-wang112358/MOLLEO