NMR and Molecular Dynamics Study of the Binding Mode of Naphthalene-N-sulfonyl-d-glutamic Acid Derivatives: Novel MurD Ligase Inhibitors

The presented series of naphthalene-N-sulfonyl-d-glutamic acid derivatives are novel MurD ligase inhibitors with moderate affinity that occupy the d-Glu binding site. We performed an NMR study including transfer NOE to determine the ligand bound conformation, as well as saturation transfer difference experiments to obtain ligand epitope maps. The difference in overall appearance of the epitope maps highlights the importance of hydrophobic interactions and shows the segments of molecular structure that are responsible for them. Transfer NOE experiments indicate the conformational flexibility of bound ligands, which were then further examined by unrestrained molecular dynamics calculations. The results revealed the differing degrees of ligand flexibility and their effect on particular ligand−enzyme contacts. Conformational flexibility not evident in the crystal structures may have an effect on ligand-binding site adaptability, and this is probably one of the important reasons for the only moderate activity of novel derivatives.