Chuanliu Fan, Zicheng Ma, Huanran Meng, Aijia Zhang, Wenjie Du, Jun Zhang, Ziqiang Cao, Guohong Fu. Proceedings of the 64th Annual Meeting of the Association for Computational Linguistics (Volume 1: Long Papers). 2026.

Goal-oriented de novo molecule design, namely generating molecules with specific property or substructure constraints from scratch, is a crucial yet challenging task in drug discovery. Existing research often relies on separate predictors for distinct properties and struggles with integrating substructure constraints due to the complexities involved in modeling structural information via multitask learning. This separation necessitates a dedicated prediction model for each constraint, limiting the flexibility and posing challenges for realworld applications. To address these limitations, we propose a unified framework for molecular design that incorporates multiple property and substructure constraints, leveraging LLMs to handle diverse constraint settings within a single model. We first integrate feedback learning derived from preference ranking to eliminate the need for separate property predictors. Then, we enhance the model's ability to follow numerical instructions by introducing a unified numerical encoding into the prompt. We conduct extensive experiments across single-property, substructureproperty, and multi-property constrained tasks. Experimental results demonstrate that LlaMol consistently outperforms state-of-the-art baselines across various constraint settings. Notably, in the multi-objective binding affinity maximization task, LlaMol achieves a significantly lower$\mathrm{K}_{\mathrm{D}}$value of 0.25 for the protein target ESR1, while maintaining the highest overall performance, surpassing previous methods by 4.76 %. These results underscore the effectiveness and versatility of LLM-based frameworks for molecule generation under complex constraints.