Novel insights of structure-based modeling for RNA-targeted drug discovery

Substantial progress in RNA biology highlights the importance of RNAs (e.g., microRNAs) in diseases and the potential of targeting RNAs for drug discovery. However, the lack of RNA-specific modeling techniques demands the development of new tools for RNA-targeted rational drug design. Herein, we implemented integrated approaches of accurate RNA modeling and virtual screening for RNA inhibitor discovery with the most comprehensive evaluation to date of five docking and 11 scoring methods. For the first time, statistical analysis was heavily employed to assess the significance of our predictions. We found that GOLD:GOLD Fitness and rDock:rDock-solv could accurately predict the RNA ligand poses, and ASP rescoring further improved the ranking of ligand binding poses. Due to the weak correlations (R² < 0.3) of existing scoring with experimental binding affinities, we implemented two new RNA-specific scoring functions, iMDLScore1 and iMDLScore2, and obtained better correlations with R² = 0.70 and 0.79, respectively. We also proposed a multistep virtual screening approach and demonstrated that rDock:rDock-solv together with iMDLScore2 rescoring obtained the best enrichment on the flexible RNA targets, whereas GOLD:GOLD Fitness combined with rDock-solv rescoring outperformed other methods for rigid RNAs. This study provided practical strategies for RNA modeling and offered new insights into RNA-small molecule interactions for drug discovery.