title: Novel insights of structure-based modeling for RNA-targeted drug discovery.
abstract: 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 (R(2) < 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 R(2) = 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.
authors.affiliation: Integrated Molecular Discovery Laboratory, Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, 1901 East Road, Houston Texas 77054, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Chen
authors.forename: George A
authors.initials: GA
authors.lastname: Calin
authors.forename: Shuxing
authors.initials: S
authors.lastname: Zhang
mesh_terms: D000465:Algorithms; D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D055808:Drug Discovery; D057166:High-Throughput Screening Assays; D006801:Humans; D008024:Ligands; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D012313:RNA / Q000037:antagonists & inhibitors / Q000737:chemistry*; D012107:Research Design; D054852:Small Molecule Libraries / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014584:User-Computer Interface
chemical_list: D008024:Ligands; D054852:Small Molecule Libraries; D012313:RNA