Bringing Structure to Drug Discovery

Sammanfattning: Drug discovery is aided by structural information. The type of structural information needed depends on the question at hand. The methods that can be used to determine the absolute configuration of a newly synthesised compound are different from those needed to study ligand binding. This thesis employs a set of structural techniques to study a variety of research questions.NMR methods were used to understand the binding of an inhibitor to an enzyme responsible for antibiotic resistance. This thesis describes the backbone resonance assignment of the enzyme and the investigation of the protein-ligand interaction. The binding-site as well as the binding-affinity were investigated.Obtaining insights into the passive membrane permeability of unconventionally large drugs was achieved by looking at their solution ensembles in polar and apolar environments. NMR experiments were used to obtain the solution ensembles of eight antimicrobial and antiviral drugs.One of the antiviral drugs was studied by MicroED, a new methodology capable of obtaining crystal structures. MicroED requires less material, smaller crystals and the crystals can be of lower quality as compared to conventional X-ray diffraction. This thesis shows that MicroED can be used to obtain the crystal structure of a flexible small molecule that is challenging to elucidate by X-ray crystallography.The final study of this thesis investigated the applicability of time-saving sampling schemes for the acquisition of quantitative NOESY data. It explores different variables, but none of the investigated conditions lead to the level of accuracy needed for NOE-based distance determination.