Structure-based ligand design is an integral part of modern drug discovery. However, depending on how established a target is, different challenges arise. An example for targets with little present for drug discovery a riboswitches. Riboswitches are cis-acting gene regulatory elements which are part of the .5′ untranslated region of mRNAs. As they occur mainly in bacteria they are sought to be targets for new antibiotics. Here, the challenge is to transfer docking methods that were mainly developed for protein targets to RNA and to discover any ligands at all. In contrast, protein kinases are established drug targets and the general pharmacophore for kinase ligands is well known. In this field, the focus is more one designing ligands with new cores and to predict selectivity. In this webinar, I will present how we demonstrated that RNA-ligand docking is as a suitable tool for hit discovery for riboswitches and our progress on hit discovery for the FMN riboswitch. Further, I will report on our structure-based de novo design approach that generates novel and synthetically accessible hinge-binding fragments that can be elaborated to small molecule libraries.