High Performance Virtual Screening by Targeting a High-resolution RNA Dynamic Ensemble

Abstract

Dynamic ensembles that capture the flexibility of RNA three-dimensional (3D) structures hold great promise in advancing RNA-targeted drug discovery. Here, we experimentally screened the transactivation response element (TAR) RNA from human immunodeficiency virus type-1 (HIV-1) against ~100,000 small molecules. We used this dataset, along with 240 known hit molecules, to evaluate virtual screening (VS) against a high-resolution TAR ensemble determined by combining NMR spectroscopy and molecular dynamics (MD) simulations. Ensemble-based VS (EBVS) scores molecules with an area under the receiver operator characteristic curve (ROC AUC) of 0.87 with ~50% of all hits falling within the top 2% of scored molecules, and also correctly predicts the different TAR inter-helical structures when bound to six molecules. The prediction accuracy decreased significantly with decreasing accuracy of the target ensemble or when docking against a single RNA structure. These results demonstrate that experime ...