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  • Determination of the binding mode of novel MurD inhibitors : NMR and MD study
    Simčič, Mihael ...
    Increasing occurrence of bacterial resistance against antimicrobial agents is a serious problem. Development of novel antibacterial agents is one of the most important measures. MurD ligase belongs ... to a family of Mur ligases, essential bacterial intracellular enzymes, involved in the biosynthesis of peptidoglycan precursors and therefore represents an attractive target for the development of new antibacterial agents. Our research was focused on the determination of the binding mode of novel MurD ligase inhibitors. The binding mode of novel naphthalene-N-sulfonyl-D-glutamic acid derivatives,1-3 naphthalene-N-sulfonyl derivatives with rigid analogues of D-glutamic acid,4 hydroxy-substituted 5-benzelidenethiazolidin-4-one,5 and 2-thioxothiazolidine-4-one6 inhibitors of MurD was determined by application of high resolution NMR methods and molecular dynamics (MD) simulations. Conformational properties of the bound ligands were investigated using transferred NOE experiments. The ligand-protein contacts were studied by application of saturation transfer difference (STD) NMR. By application of 1H/13C HSQC experiment on the 13C methyl (Ile (\sigma1), Val and Leu) selectively labeled MurD, the binding sites of novel MurD inhibitors were determined. Comparison of the chemical shift perturbation patterns induced by the binding of structurally different ligands was applied to assign crucial methyl signalsin the active site. The binding mode was also studied by unrestrained molecular dynamics (MD) simulations in CHARMM program. Different degrees of ligand flexibility were observed, which affect the ligand-protein interactions. Our research is an important step towards the design of novel MurD inhibitors, since we were able to determine the binding mode of novel inhibitors, for which the crystal structures in complex with MurD could not bedetermined. Even in the case of ligand-MurD inhibitors with known crystal structure, we have upgraded static view with dynamic properties, valuable for the design of more active inhibitors. Developed methodology can be also used for binding studies for other muramyl ligases or receptors with similar size.
    Vir: Advanced mass spectrometric and NMR methods : abstract book (Str. 11)
    Vrsta gradiva - prispevek na konferenci
    Leto - 2012
    Jezik - angleški
    COBISS.SI-ID - 5099802

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