Can Current Molecular Docking Methods Accurately Predict RNA Inhibitors?

Ribonucleic acids (RNAs), particularly the noncoding RNAs, play key roles in cancer, making them attractive drug targets. While conventional methods such as high throughput screening are resource-intensive, computational methods such as RNA-ligand docking can be used as an alternative. However, currently available docking methods are fine-tuned to perform protein-ligand and protein-protein docking. In this work, we evaluated three commonly used docking methods─AutoDock Vina, HADDOCK, and HDOCK─alongside RLDOCK, which is specifically designed for RNA-ligand docking. Our evaluation was based on several criteria including cognate docking, blind docking, scoring potential, and ranking potential. In cognate docking, only RLDOCK showed a success rate of 70% for the top-scoring docked pose. Despite this, all four docking methods did not achieve an overall success rate exceeding 50% amidst our attempt to refine the top-scoring docked poses using molecular dynamics simulations. Meanwhile, all four docking methods showed poor performance in scoring potential evaluation. Although AutoDock Vina achieved an area under the receiver operating characteristic curve of 0.70, it showed poor performance in terms of Matthews' correlation coefficient, precision, enrichment factors, and normalized enrichment factors at 1, 2, and 5%. These results highlight the growing need for further optimization of docking methods to assess RNA-ligand interactions.