🤖 AI Summary
This study investigates whether increasing model scale consistently enhances performance in predicting molecular properties and activities for drug discovery. The authors systematically evaluate classical machine learning methods (e.g., Random Forest, ExtraTrees), graph neural networks (GIN), and pretrained molecular sequence models (Ligandformer, MoLFormer, ChemBERTa2) across 22 benchmark tasks partitioned rigorously by structural similarity, introducing a baseline based on structure–activity relationship (SAR) rules. Results show that classical models outperform others in 10 tasks, GNNs in 9, and large-scale models in only 3, indicating that model scale is not the decisive factor—task-specific suitability matters more. This work is the first to reveal this pattern under a large-scale, multitask setting with strict data splits, while also suggesting that large models may hold promise in zero-shot reasoning and hypothesis generation.
📝 Abstract
The rapid growth of molecular foundation models and general-purpose large language models has encouraged a scale-centric view of artificial intelligence in drug discovery, in which larger pretrained models are expected to supersede compact cheminformatics models and task-specific graph neural networks (GNNs). We test this assumption on 22 molecular property and activity endpoints, including public ADMET and Tox21 benchmarks and two internal anti-infective activity datasets. Across 167,056 held-out task--molecule evaluations under structure-similarity-separated five-fold cross-validation (37,756 ADMET, 77,946 Tox21, 49,266 anti-TB and 2,088 antimalaria), classical machine-learning (ML) models such as RF(ECFP4) and ExtraTrees(RDKit descriptors) win ten primary-metric tasks, GNNs such as GIN and Ligandformer win nine, and pretrained molecular sequence models such as MoLFormer and ChemBERTa2 win three. Rule-based SAR reasoning baselines, represented by GPT5.5-SAR and Opus4.7-SAR, do not win under the prespecified primary metrics, although train-fold-derived SAR knowledge provides measurable but uneven gains for SAR reasoning and interpretation. These results indicate that compact, specialized models remain highly effective for molecular property and activity prediction. The performance differences among classical ML, GNN and pretrained sequence models are often modest and endpoint-dependent, whereas larger or more general models do not provide a universal predictive advantage. Large models may still add value for zero-shot reasoning, SAR interpretation and hypothesis generation, but the results suggest that predictive performance depends on the alignment among molecular representation, inductive bias, data regime, endpoint biology and validation protocol.