Identifying RNA-small Molecule Binding Sites Using Geometric Deep Learning with Language Models

RNAs are emerging as promising therapeutic targets, yet identifying small molecules that bind to them remains a significant challenge in drug discovery. This underscores the crucial role of computational modeling in predicting RNA-small molecule binding sites. However, accurate and efficient computational methods for identifying these interactions are still lacking. Recently, advances in large language models (LLMs), previously successful in DNA and protein research, have spurred the development of RNA-specific LLMs. These models leverage vast unlabeled RNA sequences to autonomously learn semantic representations with the goal of enhancing downstream tasks, particularly those constrained by limited annotated data. Here, we develop RNABind, an embedding-informed geometric deep learning framework to detect RNA-small molecule binding sites from RNA structures. RNABind integrates RNA LLMs into advanced geometric deep learning networks, which encodes both RNA sequence and structure information. To evaluate RNABind, we first compile the largest RNA-small molecule interaction dataset from the entire multi-chain complex structure instead of single-chain RNAs. Extensive experiments demonstrate that RNABind outperforms existing state-of-the-art methods. Besides, we conduct an extensive experimental evaluation of eight pre-trained RNA LLMs, assessing their performance on the binding site prediction task within a unified experimental protocol. In summary, RNABind provides a powerful tool on exploring RNA-small molecule binding site prediction, which paves the way for future innovations in the RNA-targeted drug discovery.