Drug-dendrimer supramolecular complexation studied from molecular dynamics simulations and NMR spectroscopy

Pabla A. Barra, Luis F. Barraza, Verónica A. Jiménez, José A. Gavin, Joel B. Alderete

Resultado de la investigación: Article

11 Citas (Scopus)

Resumen

Fully atomistic molecular dynamics (MD) simulations and NMR spectroscopy were employed to get insights about the molecular details of drug-dendrimer supramolecular association phenomena, using piroxicam (PRX) and the third generation poly(amido amine) (PAMAM-G3) dendrimer as model systems. Theoretical results concerning the complex stoichiometry suggest that PRX forms drug-dendrimer complexes of the type 24:1 at pH 7.0. This result was validated with the experimental quantities obtained from aqueous solubility profiles, which led to an empiric stoichiometry of 23:1 for the PRX:PAMAM-G3 system. The predicted binding mode between PRX and PAMAM-G3 accounts for the preferred encapsulation of the drug inside dendrimer cavities, which is mainly driven by van der Waals and hydrogen bonding interactions, and to a lesser extent, for the external association of the guest through electrostatic contacts with the positively charged amino groups of PAMAM periphery. The binding mode obtained from MD simulations was confirmed with 2D-NOESY experiments, which evidence the preferred internal complexation of PRX with PAMAM-G3. The predominance of internal encapsulation over external contacts in the PRX:PAMAM-G3 system differs from the general behaviour expected for acidic anionic guests, for which external electrostatic interactions with the positively charged PAMAM surface have been postulated as the most relevant factor for drug association.

Idioma originalEnglish
Páginas (desde-hasta)1443-1455
Número de páginas13
PublicaciónStructural Chemistry
Volumen25
N.º5
DOI
EstadoPublished - 1 oct 2014

Huella dactilar

Piroxicam
Dendrimers
dendrimers
Complexation
Nuclear magnetic resonance spectroscopy
Molecular dynamics
drugs
molecular dynamics
nuclear magnetic resonance
Computer simulation
Pharmaceutical Preparations
spectroscopy
stoichiometry
simulation
Association reactions
electrostatics
Encapsulation
Stoichiometry
amines
solubility

ASJC Scopus subject areas

  • Condensed Matter Physics
  • Physical and Theoretical Chemistry

Citar esto

Barra, Pabla A. ; Barraza, Luis F. ; Jiménez, Verónica A. ; Gavin, José A. ; Alderete, Joel B. / Drug-dendrimer supramolecular complexation studied from molecular dynamics simulations and NMR spectroscopy. En: Structural Chemistry. 2014 ; Vol. 25, N.º 5. pp. 1443-1455.
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Drug-dendrimer supramolecular complexation studied from molecular dynamics simulations and NMR spectroscopy. / Barra, Pabla A.; Barraza, Luis F.; Jiménez, Verónica A.; Gavin, José A.; Alderete, Joel B.

En: Structural Chemistry, Vol. 25, N.º 5, 01.10.2014, p. 1443-1455.

Resultado de la investigación: Article

TY - JOUR

T1 - Drug-dendrimer supramolecular complexation studied from molecular dynamics simulations and NMR spectroscopy

AU - Barra, Pabla A.

AU - Barraza, Luis F.

AU - Jiménez, Verónica A.

AU - Gavin, José A.

AU - Alderete, Joel B.

PY - 2014/10/1

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AB - Fully atomistic molecular dynamics (MD) simulations and NMR spectroscopy were employed to get insights about the molecular details of drug-dendrimer supramolecular association phenomena, using piroxicam (PRX) and the third generation poly(amido amine) (PAMAM-G3) dendrimer as model systems. Theoretical results concerning the complex stoichiometry suggest that PRX forms drug-dendrimer complexes of the type 24:1 at pH 7.0. This result was validated with the experimental quantities obtained from aqueous solubility profiles, which led to an empiric stoichiometry of 23:1 for the PRX:PAMAM-G3 system. The predicted binding mode between PRX and PAMAM-G3 accounts for the preferred encapsulation of the drug inside dendrimer cavities, which is mainly driven by van der Waals and hydrogen bonding interactions, and to a lesser extent, for the external association of the guest through electrostatic contacts with the positively charged amino groups of PAMAM periphery. The binding mode obtained from MD simulations was confirmed with 2D-NOESY experiments, which evidence the preferred internal complexation of PRX with PAMAM-G3. The predominance of internal encapsulation over external contacts in the PRX:PAMAM-G3 system differs from the general behaviour expected for acidic anionic guests, for which external electrostatic interactions with the positively charged PAMAM surface have been postulated as the most relevant factor for drug association.

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KW - Molecular dynamics

KW - PAMAM

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