Self-Supervised Learning for Molecular Property Prediction: Methods, Multimodal Insights, and Benchmark Comparisons

Abstract

Computer-aided drug discovery has substantially accelerated modern pharmaceutical research, where accurate molecular property prediction plays a central role in identifying promising therapeutic candidates. Self-supervised learning (SSL), which exploits large-scale unlabeled molecular data to learn transferable representations, has recently emerged as a powerful paradigm well-aligned with the data characteristics of cheminformatics. Integrating chemical domain knowledge further enhances the ability of SSL models to capture structural, physicochemical, and functional properties of molecules. In this review, we provide a systematic overview of recent advances in SSL-based molecular property prediction. We summarize representative methodological developments and analyze how multimodal molecular representation learning─by integrating sequence, graph, three-dimensional structure, and textual information─can improve the quality and expressiveness of molecular representations. We further examine the synergistic relationship between multimodal modeling and SSL, highlighting how complementary modalities can enhance representation learning in low-label settings. To demonstrate the practical benefits of multimodal molecular properties, we compare their performance with conventional SSL models on two downstream benchmark tasks with distinct prediction objectives. Finally, we discuss key open challenges, including the scarcity of high-quality 3D molecular data, modality imbalance across data sets, and the limited interpretability of learned representations. We conclude by outlining promising research directions toward more robust, generalizable, and biologically meaningful frameworks for molecular property prediction.