engleski

Conformational Changes in Azithromycin in Different Media. Comparative Study Using NMR and Molecular Modelling

Azithromycin is an important macrolide antibiotic with a remarkable antibacterial effects. It exerts its activity by binding to the bacterial ribosome and thus inhibiting protein biosynthesis. However, resistance to antibiotic treatment enforces chemists and biologist to make efforts to discover molecules with improved biological profile. In that respect elucidation of the key structural elements responsible for biological activity is one of the main prerequisites for the rational design of a novel drug candidate. NMR spectroscopy combined with molecular modelling methods serves as an efficient tool for studing structural details and conformational properties. Vicinal homo- and hetero-nuclear scalar coupling constants interpreted by Karplus-type relationships together with NOEs or ROEs were used for the conformational space search of azithromycin in D2O buffered solutions and in organic solvents of different polarity. Proton-proton three-bond coupling constants were determined using 2D E. COSY sequence, whereas multi-site selective heteronuclear experiments were executed and Hadamard formalism employed to determine carbon-proton vicinal coupling constants. 2D NOESY, 2D ROESY and selective 1D ROESY with pulse field gradients sequences were performed to obtain information about spatial proximity between protons. These NMR derived constraints were used in molecular modelling which included different computational approaches like Monte Carlo simulations, molecular mechanics and dynamics with various force fields. Solvent effects were treated implicitly by using dielectric constants and explicit solvent molecules.

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