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Flexible computational docking studies of new aminoglycosides targeting RNA 16S bacterial ribosome site.

Authors
  • Barbault, Florent
  • Ren, Bo
  • Rebehmed, Joseph
  • Teixeira, Catia
  • Luo, Yun
  • Smila-Castro, Ornella
  • François Maurel
  • Fan, BoTao
  • Zhang, Liangren
  • Zhang, Lihe
Type
Published Article
Journal
European Journal of Medicinal Chemistry
Publisher
Elsevier
Publication Date
Aug 26, 2008
Volume
43
Issue
8
Pages
1648–1656
Identifiers
DOI: 10.1016/j.ejmech.2007.10.022
PMID: 18096272
Source
USPC - SET - SVS
License
White

Abstract

Ribonucleic acids (RNAs) have only recently been viewed as a target for small-molecules drug discovery. Aminoglycoside compounds are antibiotics which bind the ribosomal A site (16S fragment) and cause misreading of the bacterial genetic code and inhibit translocation. In this work, a complete molecular modeling study is done for 16 newly derived aminoglycoside compounds where diverse nucleoside fragments are linked. Docking calculations are applied to 16S RNA target and a weak linear correlation, between experimental and calculated data, is obtained. However, one particularity of RNA is its high flexibility. To mimic this behavior, all docking calculations are followed by small molecular dynamic simulations. This last computational step improves significantly the correlation with experimental data and allowed us to establish structure-activity relationships. The overall results showed that the consideration of the RNA dynamic behavior is of great interest.

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