期刊
NATURE STRUCTURAL & MOLECULAR BIOLOGY
卷 25, 期 5, 页码 425-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41594-018-0062-4
关键词
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资金
- US National Institutes of Health [P50 GM103297, R01 AI066975, P01 GM0066275, T32 GM08487, F31 GM119306]
Dynamic ensembles hold great promise in advancing RNA-targeted drug discovery. Here we subjected the transactivation response element (TAR) RNA from human immunodeficiency virus type-1 to experimental high-throughput screening against similar to 100,000 drug-like small molecules. Results were augmented with 170 known TAR-binding molecules and used to generate sublibraries optimized for evaluating enrichment when virtually screening a dynamic ensemble of TAR determined by combining NMR spectroscopy data and molecular dynamics simulations. Ensemble-based virtual screening scores molecules with an area under the receiver operator characteristic curve of similar to 0.85-0.94 and with similar to 40-75% of all hits falling within the top 2% of scored molecules. The enrichment decreased significantly for ensembles generated from the same molecular dynamics simulations without input NMR data and for other control ensembles. The results demonstrate that experimentally determined RNA ensembles can significantly enrich libraries with true hits and that the degree of enrichment is dependent on the accuracy of the ensemble.
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