Domain-Adapted Molecular Language Models for Efficient Search of Make-on-Demand Libraries
Authors: Henrik Wille, Luis-Finley Schütz, Felix Strieth-Kalthoff
Organizations: University of Wuppertal, School of Mathematics and Natural Sciences, Gaußstr. 20, 42119 Wuppertal, Germany · University of Wuppertal, Interdisciplinary Center of Machine Learning and Data Analytics, Gaußstr. 20, 42119 Wuppertal, Germany
Pretrained molecular language models are increasingly used as molecular encoders for learning structure-property relationships. However, their practical suitability for molecular discovery within and beyond their pretraining domain remains unclear. Herein, we systematically benchmark four molecular language models across six virtual molecular libraries spanning drug discovery, organic materials, and catalysis. Native molecular language model embeddings show substantial variation in discovery performance across libraries, whereas molecular fingerprints provide a consistently strong and robust baseline. Consistent with a potential domain-representation mismatch, we show that explicit domain adaptation substantially improves representation performance. Fine-tuning molecular language model encoders on structures from the target virtual library consistently improves sample efficiency, with several adapted encoders emerging as the top-performing representations across the benchmark tasks. These results show that molecular representation quality depends strongly on the target domain and that explicit adaptation can improve the practical utility of molecular foundation models. More broadly, our findings establish domain-adapted molecular representations as a promising strategy for sample-efficient adaptive decision making in virtual screening and self-driving laboratories.
General-purpose large language models (LLMs) that rely on in-context learning do not reliably deliver the scientific understanding and performance required for drug discovery tasks. Simply increasing model size or introducing reasoning tokens does not yield significant performance gains. To address this gap, we introduce the MMAI Gym for Science, a one-stop shop molecular data formats and modalities as well as task-specific reasoning, training, and benchmarking recipes designed to teach foundation models the 'language of molecules' in order to solve practical drug discovery problems. We use MMAI Gym to train an efficient Liquid Foundation Model (LFM) for these applications, demonstrating that smaller, purpose-trained foundation models can outperform substantially larger general-purpose or specialist models on molecular benchmarks. Across essential drug discovery tasks - including molecular optimization, ADMET property prediction, retrosynthesis, drug-target activity prediction, and functional group reasoning - the resulting model achieves near specialist-level performance and, in the majority of settings, surpasses larger models, while remaining more efficient and broadly applicable in the domain.
Maksim Kuznetsov, Zulfat Miftahutdinov, Rim Shayakhmetov +17
Chemical language models (CLMs) are trained with linearized representations such as SMILES, yet it remains unclear which chemically meaningful substructures they encode. To foster a better understanding of CLMs, we conduct a systematic study and probe for 78 molecular substructures across eight pre-trained and six randomly initialized models. We furthermore study how fine-tuning on chemical downstream tasks affects the learned representations of molecular substructures. Our results show that pre-training generally improves molecular structure awareness of CLMs, particularly in the upper layers. Moreover, randomly initialized models already encode ring structures well in the first layer. Our analysis on two chemical downstream tasks further reveals that, interestingly, fine-tuning affects task-relevant molecular substructures more than others, indicating that the changes in the representations follow chemical theory.
Anna Karnysheva, Dietrich Klakow, Ji-Ung Lee
1RTG Neuroexplicit Models · 2Spoken Language Systems · Saarland University +1
Molecular optimization, the process of designing molecules with desirable properties, represents a critical challenge in drug discovery. The recent advancements in large language models (LLMs) have opened new opportunities for their integration with traditional molecular optimization algorithms to improve performance. In this work, we propose Molecular Language Model powered Evolutionary Algorithm (Mol-E), an evolutionary algorithm that relies on the generative capabilities of LLMs trained on molecules and molecular properties. Scientific Contribution. Mol-E obtains the highest aggregate Top-10 AUC among the comparable full-23-task results considered here, scoring 17.500 in the task-agnostic regime, in which the oracle is treated strictly as a black box, and 20.551 in the task-informed regime, in which the optimizer receives a fixed semantic description of the objective. Mol-E also improves over the evaluated baselines on multi-property optimization with docking against DRD2, MK2, and AChE.
Philipp Guevorguian, Menua Bedrosian, Tigran Fahradyan +3