The prediction of RNA-small-molecule ligand binding affinity based on geometric deep learning

Small molecule-targeted RNA is an emerging technology that plays a pivotal role in drug discovery and inhibitor design, with widespread applications in disease treatment. Consequently, predicting RNA-small-molecule ligand interactions is crucial. With advancements in computer science and the availability of extensive biological data, deep learning methods have shown great promise in this area, particularly in efficiently predicting RNA-small molecule binding sites. However, few computational methods have been developed to predict RNA-small molecule binding affinities. Meanwhile, most of these approaches rely primarily on sequence or structural representations. Molecular surface information, vital for RNA and small molecule interactions, has been largely overlooked. To address these gaps, we propose a geometric deep learning method for predicting RNA-small molecule binding affinity, named RNA-ligand Surface Interaction Fingerprinting (RLASIF). In this study, we create RNA-ligand interaction fingerprints from the geometrical and chemical features present on molecular surface to characterize binding affinity. RLASIF outperformed other computational methods across ten different test sets from PDBbind NL2020. Compared to the second-best method, our approach improves performance by 10.01 %, 6.67 %, 2.01 % and 1.70 % on four evaluation metrics, indicating its effectiveness in capturing key features influencing RNA-ligand binding strength. Additionally, RLASIF holds potential for virtual screening of potential ligands for RNA and predicting small molecule binding nucleotides within RNA structures.