High-performance virtual screening by targeting a high-resolution RNA dynamic ensemble.

ABSTRACT: 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 ~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 ~0.85-0.94 and with ~40-75% of all hits falling within the top 2% of scored molecules. The enrichment decreased significantly for ensembles generated f

SUBMITTER: Ganser LR 

PROVIDER: S-EPMC5942591 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature