Structure-Based Discovery of Small Molecules Binding to RNA

Abstract

Ribonucleic acids (RNAs) constitute attractive drug targets. The wealth of structural information about RNAs is steadily increasing making it possible to use this information for the design of new ligands. Two methods that make heavy use of structural knowledge for ligand discovery are molecular docking and fragment screening. In molecular docking the structure of the binding site is used as a template for the design of new ligands using computational methods whereas in fragment screening biophysical methods are used for the detection of weak binding ligands which are subsequently elaborated into tighter binding molecules. In this chapter, we give an overview of both methods in the context of ligand discovery for RNA targets and illustrate their applications for hit discovery.

Insights into the development of chemical probes for RNA

“…Additional high-throughput screens could likewise discover novel chemotypes, though the expense may exceed the resources available in academia, where focused approaches are more attainable. Continued progress in the development and refinement of computational tools will also aid in expanding the boundaries of focused screening and structure-based design;( 56 , 57 ) although the latter will also depend upon advancements for accurately determining atomic resolution structures ( 8 , 9 , 37 , 38 ). In addition, in vitro or cellular activity-based assays that probe well-studied RNA functions (e.g.…”

“…The screen resulted in a biologically active ligand with an IC 50 value of 0.45 μM in cell-based models. Additional advances in computational structural prediction and RNA:ligand docking will undoubtedly lead to improved computational primary screens and thus more efficient experimental screens ( 56 , 57 ).…”

Riboswitches as Drug Targets for Antibiotics

“…There are only limited examples of riboswitch-oriented fragment-based screening, probably because screening RNA targets is generally considered to be challenging [ 121 ] Cressina et al used a hierarchical approach to discover TPP riboswitch binding fragments. First, they employed equilibrium dialysis to screen a library of 1300 fragments against the TPP riboswitch resulting in 20 hits [ 55 ].…”

“…Towards this end, our group and others have made some advancements and discovered novel ligands against purine, SAM and lysine riboswitches [ 123 , 124 , 125 , 126 ]. The developments in RNA-targeted virtual screening are discussed in detail elsewhere [ 121 , 127 ].…”

Challenges and current status of computational methods for docking small molecules to nucleic acids

“…However, docking to nucleic acids is comparatively underdeveloped. Generally, protein-ligand docking programs could be adapted to RNA-ligand docking as RNA-ligand and protein-ligand macromolecular complexes follow similar physicochemical binding principles [32,33]. However, many proteins contain a well-defined, generally hydrophobic binding site.…”