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bioRxiv · 10.1101/151407

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

Ganser, L. R.·Lee, J.·Sathyamoorthy, B.·Kansal, A. D.·Merriman, D. K.·Al-Hashimi, H. M.
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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 ...

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Ganser, L. R., Lee, J., Sathyamoorthy, B., Kansal, A. D., Merriman, D. K., Al-Hashimi, H. M.. 2017-06-18. High Performance Virtual Screening by Targeting a High-resolution RNA Dynamic Ensemble. https://doi.org/10.1101/151407

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