Discovery of ligands by a combination of computational and NMR-based screening: RNA as an example target.

Abstract

NMR for screening of knowledge-based focused libraries of compounds provides an efficient, cost-effective method to develop promising drug leads that target functionally important RNA structures. A knowledge-based focused library may be constructed from virtual (i.e., computational) screening of commercial or proprietary databases of available compounds for binding to the three-dimensional structure of a selected RNA target. Alternatively, the library may be constructed from compounds with properties deemed desirable, e.g., molecular moiety commonly found in drugs or known to bind RNA. The library ideally should be composed of small water-soluble, nonpeptide, nonnucleotide organic compounds. Various simple, robust NMR experiments are described that enable experimental screening of such a library for binding to a selected RNA structure. Some of the NMR experiments enable rapid mapping of the interaction site on the RNA to verify that the targeted structure is hit rather than the double helical region or a commonly occurring tetraloop. Other experiments enable elucidation of the ligand's binding moiety. Of course, any compounds thus identified should represent promising scaffolds suitable for easy chemical modification to enhance their pharmaceutical properties for subsequent drug development.