3 years ago

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

Kansal, B., Lee, Al-Hashimi, Merriman, Ganser, L. R., H. M., D. K., Sathyamoorthy, J., A. D.
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 with decreasing accuracy of the target ensemble or when docking against a single RNA structure. These results demonstrate that experimentally determined ensembles can significantly enrich libraries with structure-specific RNA binders as well as motivate the continued development of methods for improving ensemble accuracy.

Publisher URL: http://biorxiv.org/cgi/content/short/151407v1

DOI: 10.1101/151407

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