Structure-based virtual screening of unbiased and RNA-focused libraries to identify new ligands for the HCV IRES model system

Abstract

Targeting RNA including viral RNAs with small molecules is an emerging field. The hepatitis C virus internal ribosome entry site (HCV IRES) is a potential target for translation inhibitor development...

Assessment of Nucleobase Protomeric and Tautomeric States in Nucleic Acid Structures for Interaction Analysis and Structure-Based Ligand Design

“…RNA plays a fundamental role in many biological processes. Consequently, RNA has gained significant interest as a potential drug, such as with antisense oligonucleotide therapeutics, , but also as a target for small molecules. − To target RNA structures, multiple high-throughput screening (HTS) − assays or fragment screenings − have been developed, while structure-based approaches are still rare. − One frequently mentioned challenge or even limitation of RNA targeting approaches via small molecules is the low chemical diversity of RNA, which makes it difficult to find ligands with a high affinity and selectivity. Still, with only four nucleobases (Figure ) compared to 20 canonical amino acids in proteins, RNA is able to form complex folds, and its chemical diversity is not only enhanced by over 170 known RNA modifications, − but also by adapting to the local environment through different protomeric and tautomeric states of the nucleobases. − While X-ray structures do not include proton information, protonation states and tautomers can be deduced from only nucleobase geometries and atom distances.…”