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

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Abstract

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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Acknowledgments

Authors thank FONDECYT Grant 1130531 and Programa de Intercambio Académico, Universidad de La Laguna. We also thank to the Servicio de Resonancia Magnética Nuclear, Universidad de La Laguna, for allocating instrument time to this project.

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Authors and Affiliations

  1. Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad de Concepción, Casilla 160-C, Concepción, Chile

    Pabla A. Barra, Luis F. Barraza & Joel B. Alderete

  2. Departamento de Ciencias Químicas, Facultad de Ciencias Exactas, Sede Concepción, Universidad Andrés Bello, Autopista Concepción-Talcahuano, 7100, Talcahuano, Chile

    Verónica A. Jiménez

  3. Instituto Universitario de Bioorgánica, “A. González,”, Universidad de la Laguna, Avda. Astrofísico F. Sánchez 2, La Laguna, Tenerife, Spain

    José A. Gavin

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  1. Pabla A. Barra
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Correspondence to Joel B. Alderete.

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Barra, P.A., Barraza, L.F., Jiménez, V.A. et al. Drug-dendrimer supramolecular complexation studied from molecular dynamics simulations and NMR spectroscopy. Struct Chem 25, 1443–1455 (2014). https://doi.org/10.1007/s11224-014-0424-4

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