Role of Aromatic Rings in the Molecular Recognition of Aminoglycoside Antibiotics: Implications for Drug Design

  1. Vacas, T. 1
  2. Corzana, F. 2
  3. Jiménez-Osés, G. 3
  4. González, C. 4
  5. Gómez, A.M. 1
  6. Bastida, A. 1
  7. Revuelta, J. 1
  8. Asensio, J.L. 1
  1. 1 Instituto de Química Orgánica General
    info

    Instituto de Química Orgánica General

    Madrid, España

    ROR https://ror.org/05e0q7s59

  2. 2 Universidad de La Rioja
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    Universidad de La Rioja

    Logroño, España

    ROR https://ror.org/0553yr311

  3. 3 Universidad de Zaragoza
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    Universidad de Zaragoza

    Zaragoza, España

    ROR https://ror.org/012a91z28

  4. 4 Instituto de Química Física Rocasolano
    info

    Instituto de Química Física Rocasolano

    Madrid, España

    ROR https://ror.org/03xk60j79

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Revista:
Journal of the American Chemical Society

ISSN: 0002-7863

Año de publicación: 2010

Volumen: 132

Número: 34

Páginas: 12074-12090

Tipo: Artículo

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DOI: 10.1021/JA1046439 PMID: 20698528 SCOPUS: 2-s2.0-77956071603 WoS: WOS:000281296700056 GOOGLE SCHOLAR

Otras publicaciones en: Journal of the American Chemical Society

Resumen

Aminoglycoside antibiotics participate in a large variety of binding processes involving both RNA and proteins. The description, in recent years, of several clinically relevant aminoglycoside/receptor complexes has greatly stimulated the structural-based design of new bioactive derivatives. Unfortunately, design efforts have frequently met with limited success, reflecting our incomplete understanding of the molecular determinants for the antibiotic recognition. Intriguingly, aromatic rings of the protein/RNA receptors seem to be key actors in this process. Indeed, close inspection of the structural information available reveals that they are frequently involved in CH/π stacking interactions with sugar/aminocyclitol rings of the antibiotic. While the interaction between neutral carbohydrates and aromatic rings has been studied in detail during past decade, little is known about these contacts when they involve densely charged glycosides. Herein we report a detailed experimental and theoretical analysis of the role played by CH/π stacking interactions in the molecular recognition of aminoglycosides. Our study aims to determine the influence that the antibiotic polycationic character has on the stability, preferred geometry, and dynamics of these particular contacts. With this purpose, different aminoglycoside/aromatic complexes have been selected as model systems. They varied from simple bimolecular interactions to the more stable intramolecular CH/π contacts present in designed derivatives. The obtained results highlight the key role played by electrostatic forces and the desolvation of charged groups in the molecular recognition of polycationic glycosides and have clear implications for the design of improved antibiotics. © 2010 American Chemical Society.