engleski

Free and ribosome-bound structures of macrolide antibiotics: the role of NMR and conformational analysis in ligand design

Macrolide antibiotics are therapeutically important molecules that are effective inhibitors of bacterial protein biosynthesis. They bind to the large 50S ribosomal subunit at or near the peptidyl transferase center and block the elongation of the peptide chain. Understanding the mechanism by which macrolides exert their activity is crucial for the design of novel molecules possessing bioactivity. Recently available crystal structures of some ribosome-macrolide complexes have thrown new light on the binding mechanisms and hence provide a good basis for the design of new ligands and inhibitors.1, 2 However, when analysing solid state structures of ribosome- macrolide complexes one should keep in mind the discrepancies between structures obtained for halophilic archeon H. marismortui2 and D. radiodurans.1 Therefore, important steps in the process of drug design should also include elucidation of the solution-state structures of free and bound ligand molecules since the structural features of the complex may not be exactly the same in solution and in the solid state. One and two-dimensional NMR techniques have proven usefull in conformational analysis and structure-based inhibitor design. Here, an approach which combine NMR parameters such as spin-spin coupling constants, nOe and relaxation times coupled with molecular modelling is employed to study free conformations of macrolide antibiotics such as azithromycin, telithromycin and oleandomycin.3 Furthermore, an application of transferred nOe and STD (saturation transfer difference) NMR experiments provides information on the bound state conformation and binding epitopes.4 The knowledge gained from these studies can serve as a platform for the design of novel compounds with an improved biological profile.

Macrolide antibiotics ; ribosome-macrolide interactions ; NMR

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