Advanced NMR techniques for structural elucidation in medicinal chemistry

Sammanfattning: The nuclear Overhauser effect (NOE) is an NMR phenomenon that can reveal spatial proximity between two atoms. It has found applications in organic chemistry and structural biology including natural product chemistry, organic synthesis, medicinal chemistry, macromolecular structure elucidation and protein-ligand interactions.This work discusses the reliability of quantitative NOE measurements, with focus on the effect that non-uniform sampling (NUS) schemes have on the quantitativity. A variety of parameters have been explored to test the effect of NUS on quantitative NOE experiments including the variation of the sampling scheme, reconstruction algorithm, relaxation delay and number of sampled points. None of the investigated conditions matched the accuracy of uniformly sampled data for the studied system.Highly accurate interproton distances, derived from uniformly sampled NOE build-up rates, have been used to explain the cell permeability of macrocyclic drugs. The by NMR obtained solution ensembles improved prediction models and confirmed the standing hypothesis of chameleonic behaviour of macrocyclic drugs.The last study described in the thesis aims to elucidate the binding mode of a metallo-β-lactamase (MBL) inhibitor with the ultimate goal to improve the properties of the studied inhibitors and to create a broad-spectrum MBL inhibitor. This project includes the NMR backbone assignment of a MBL that has not been studied by NMR before. Initial titration experiments show clear binding of the studied inhibitor.