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Biochemistry (Moscow)

, Volume 80, Issue 11, pp 1500–1507 | Cite as

Modeling interactions of erythromycin derivatives with ribosomes

  • A. V. Shishkina
  • T. M. Makarova
  • A. G. Tereshchenkov
  • G. I. Makarov
  • G. A. KorshunovaEmail author
  • A. A. Bogdanov
Article

Abstract

Using a method of static simulation, a series of erythromycin A analogs was designed with aldehyde functions introduced instead of one of the methyl substituents in the 3′-N-position of the antibiotic that was potentially capable of forming a covalent bond with an amino group of one of the nucleotide residues of the 23S rRNA in the ribosomal exit tunnel. Similar interaction is observed for antibiotics of the tylosin series, which bind tightly to the large ribosomal subunit and demonstrate high antibacterial activity. Binding of novel erythromycin derivatives with the bacterial ribosome was investigated with the method of fluorescence polarization. It was found that the erythromycin analog containing a 1-methyl-3oxopropyl group in the 3′-N-position demonstrates the best binding. Based on the ability to inhibit protein biosynthesis, it is on the same level as erythromycin, and it is significantly better than desmethyl-erythromycin. Molecular dynamic modeling of complexes of the derivatives with ribosomes was conducted to explain the observed effects.

Keywords

ribosomal tunnel macrolides erythromycin modeling 

Abbreviations

BODIPY

4,4-difluoro-4-bora-5,7-dimethyl3a,4a-diaza-s-indacene-3-pentanoic acid

DIPEA

diisopropylethylamine

Ery

erythromycin

LC-MS

liquid chromatography/mass-spectrometry

PTC

peptidyl transferase center

RT

ribosomal tunnel

XRD

X-ray diffraction analysis

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Copyright information

© Pleiades Publishing, Ltd. 2015

Authors and Affiliations

  • A. V. Shishkina
    • 1
  • T. M. Makarova
    • 2
  • A. G. Tereshchenkov
    • 2
  • G. I. Makarov
    • 2
  • G. A. Korshunova
    • 1
    Email author
  • A. A. Bogdanov
    • 1
  1. 1.Belozersky Institute of Physico-Chemical BiologyLomonosov Moscow State UniversityMoscowRussia
  2. 2.Faculty of ChemistryLomonosov Moscow State UniversityMoscowRussia

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