In the past year, two lines of research yielded publications. First, we continue to develop methodology for screening new agonists, antagonists and allosteric effectors of biologically important RNAs. The continued development of solution methodology that can readily detect the molecular response of RNAs to ligand binding, such as small-angle X-ray screening remains a priority. The TPP riboswitch is widely distributed phylogenetically. Previously, our collaborator Dr. Abell and coworkers have carried out a fragment-based screen against this riboswitch and found a number of small organic molecules that bind with high specificity, albeit low affinity, to the RNA. Fragment-based screening is predicated on being able to elucidate the binding location of the low affinity fragments so that they can be elaborated into high affinity binders. Crystallographic work in our laboratory has confirmed the specificity of binding of a number of fragments, and elaboration of these into more potent ligands for the TPP riboswitch is underway.
