Identification of an Aminoacridine Derivative That Binds to RNA Tetraloops
- 1 August 2007
- journal article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 50 (17), 4096-4104
- https://doi.org/10.1021/jm070305p
Abstract
RNA folds into diverse structures that form unique targets for small molecules and thus provide significant potential for controlling biological processes involving RNA with small-molecule ligands. We are investigating molecular recognition of tetraloop RNA by small molecules. RNA tetraloops are four-nucleotide stem loops with unusual stability that are involved in biological processes involving RNA by forming binding sites for proteins and other RNAs. We have sequentially used the docking programs DOCK and AutoDock to screen 1990 small molecules in the NCI diversity set to identify molecules selective for RNA tetraloops over double-stranded RNA. The compounds predicted to bind to tetraloop RNA were evaluated for binding RNA tetraloops using 1H NMR spectroscopy and fluorescence techniques. An aminoacridine derivative (AD2) was identified that binds to a GAAA tetraloop in a 2:1 ratio with dissociation constants of 1.0 and 4.0 μM. AD2 binds with approximately 20-fold and 9-fold higher affinity to tetraloop RNA than to double- and single-stranded RNAs, respectively.Keywords
This publication has 54 references indexed in Scilit:
- Towards the discovery of drug-like RNA ligands?Drug Discovery Today, 2006
- RNA Helical Packing in Solution: NMR Structure of a 30kDa GAAA Tetraloop–Receptor ComplexJournal of Molecular Biology, 2005
- Validation of Automated Docking Programs for Docking and Database Screening against RNA Drug TargetsJournal of Medicinal Chemistry, 2004
- Study of the Functional Interaction of the 900 Tetraloop of 16S Ribosomal RNA with Helix 24 within the Bacterial RibosomeJournal of Molecular Biology, 2004
- RNA simulations: probing hairpin unfolding and the dynamics of a GNRA tetraloopJournal of Molecular Biology, 2002
- The major HIV-1 packaging signal is an extended bulged stem loop whose structure is altered on interaction with the gag polyproteinJournal of Molecular Biology, 2000
- Solution structure of Cobalt(III)Hexammine complexed to the GAAA tetraloop, and metal-ion binding to G·A mismatchesJournal of Molecular Biology, 2000
- The two faces of the Escherichia coli 23 S rRNA sarcin/ricin domain: the structure at 1.11 Å resolutionJournal of Molecular Biology, 1999
- Multiple tertiary interactions involving domain II of group II self-splicing intronsJournal of Molecular Biology, 1997
- A geometric approach to macromolecule-ligand interactionsJournal of Molecular Biology, 1982