DRLiPS: a novel method for prediction of druggable RNA-small molecule binding pockets using machine learning

Ribonucleic Acid (RNA) is the central conduit for information transfer in the cell. Identifying potential RNA targets in disease conditions is a challenging task, given the vast repertoire of functional non-coding RNAs in a human cell. A potential druggable target must satisfy several criteria, including disease association, cellular accessibility, binding pockets for drug-like molecules, and minimal cross-reactivity. While several methods exist for prediction of druggable proteins, they cannot be repurposed for RNAs due to fundamental differences in their binding modality. Taking all these constraints into account, a new structure-based model, Druggable RNA-Ligand binding Pocket Selector (DRLiPS), is developed here to predict binding site-level druggability of any given RNA target. A novel strategy for sampling negative binding sites in RNA structures using three parallel approaches is demonstrated here to improve model specificity: backbone motif search, exhaustive pocket prediction, and blind docking. An external blind test dataset has also been curated to showcase the model's generalizability to both experimental and modelled apo state RNA structures. DRLiPS has achieved an F1-score of 0.70, precision of 0.61, specificity of 0.89, and recall of 0.73 on this external test dataset, outperforming two existing methods, DrugPred_RNA and RNACavityMiner. Further analysis indicates that the features selected for model-building generalize well to both apo and holo states with a backbone RMSD tolerance of 3 Å. It can also predict the effect of binding site single point mutations on druggability, which can aid in optimizing synthetic RNA aptamers for small molecule recognition. The DRLiPS model is freely accessible at https://web.iitm.ac.in/bioinfo2/DRLiPS/.