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Closed-Loop Bayesian Molecular Inverse Design with Semantic LLM Surrogates

Authors: Yaoyao Xu, Xinjian Zhao, Xiaozhuang Song, Lei Bai, Tianshu Yu

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Abstract

Practical molecular inverse design is rarely a one-shot generation problem; it often takes the form of closed-loop candidate-pool enrichment, where under a limited oracle budget the goal is to increase the fraction of generated molecules that match a desired property profile. Bayesian optimization (BO) offers a natural framework for this setting, yet standard Gaussian-process surrogates typically operate in compressed continuous embeddings, which discard the substructural and reference-similarity signals that chemists naturally use to decide where to look next. We propose BoMolLLM, a closed-loop framework in which the surrogate, rather than the generator, is treated as the locus of design choice, and instantiate it with a frozen large language model that reasons directly over the task instruction, SMILES-level optimization history, and oracle feedback in their native textual form. At each iteration, the surrogate returns a structured decision signal that selects informative reference molecules under an exploration and exploitation principle, optionally with a concise guidance sentence. This signal is converted into next-round conditioning text for a frozen molecular generator, yielding an inspectable optimization trace in natural language. Experiments on MolQA drug and material design tasks show that BoMolLLM improves over one-shot prompting, is competitive with or stronger than GP-based BO baselines, and reveals a domain-dependent interface: reference-only transfer works best for binary drug targets, while adding a concise surrogate summary is more beneficial for continuous material

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