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Labelling Herceptin with a novel oxaliplatin derivative: a computational approach towards the selective drug delivery

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Abstract

The clinical use of platinum(II)-based drugs has serious side effects due to the non-specific reactions with both malignant and normal cells. To circumvent such major drawback, novel metallodrugs might be combined with suitable carrier molecules, as antibodies, to ensure selective attacks on tumours while sparing healthy tissues. In this contribution, we investigate the stability of a novel oxaliplatin derivate drug embedded in Herceptin (trastuzumab), an antibody which is able to recognise breast cancer cells, by using a wide panel of theoretical tools: docking, molecular dynamics and quantum calculations. Our calculations reveal the binding mechanism: the drug initially interacts non-covalently with the Pro40A and Asp167A residues, and the nitrogen of His171B subsequently replaces one of the water molecules coordinated to the platinum center, where the latter step reversibly fixes the drug into the antibody. These data might be used to further rationalise the synthesis of improved drugs beyond classical platinum(II) derivatives by improving the ligand-protein coupling mode.

A wide panel of theoretical tools is used to determine the chemical interactions stablished between a novel platinum(II)-based drug when linked to the Herceptin antibody.

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Acknowledgments

J. P. C.-C. acknowledges the support from the FP7 EU Marie Curie Actions through the Campus Mare Nostrum 37/38 CMN UMU Incoming Mobility Programme ACTion (U-IMPACT). J.C. acknowledges a FPU fellowship provided by the Ministerio de Educación of Spain. This work was partially supported by the Spanish Ministerio de Ciencia e Innovación under Projects CTQ2011-25872 and CONSOLIDER CSD2009-00038, by the Fundación Séneca del Centro de Coordinación de la Investigación de la Región de Murcia under Projects 08735/PI/08 and 18946/JLI/13. This work has been funded by the Nils Coordinated Mobility under grant 012-ABEL-CM-2014A, in part financed by the European Regional Development Fund (ERDF). This work was partially supported by the computing facilities of Extremadura Research Centre for Advanced Technologies (CETA −CIEMAT), funded by the European Regional Development Fund (ERDF). CETA −CIEMAT belongs to CIEMAT and the Government of Spain. The authors also thankfully acknowledge the computer resources and the technical support provided by the Plataforma Andaluza de Bioinformática of the University of Málaga. The authors acknowledge that the results of this research have been also achieved through the PRACE-2IP project (FP7 RI-283493) using the resources provided by the IBM PLX-GPU and based in Italy at CINECA.

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Authors and Affiliations

  1. Departamento de Química Física, Facultad de Química, Universidad de Murcia, 30100 Campus de Espinardo, Murcia, Spain

    José P. Cerón-Carrasco, Javier Cerezo, Alberto Requena & José Zuñiga

  2. UPMC Université Paris 06, UMR 7616 CNRS, Laboratoire de Chimie Theorique, Case Courrier 137, 4 Place Jussieu, 75005, Paris, France

    Julia Contreras-García

  3. Bioinformatics Centre, University of Pune, Ganeshkhind Road, Pune, 411 007, Maharashtra State, India

    Sonali Chavan

  4. Bioinformatics and High Performance Computing Research Group (BIO-HPC), Computer Science Department, Universidad Católica San Antonio de Murcia (UCAM), Campus de los Jernimos, 30107, Murcia, Spain

    Miguel Manrubia-Cobo & Horacio Pérez-Sánchez

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  1. José P. Cerón-Carrasco
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  2. Javier Cerezo
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  7. Miguel Manrubia-Cobo
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  8. Horacio Pérez-Sánchez
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Corresponding authors

Correspondence to José P. Cerón-Carrasco or Horacio Pérez-Sánchez.

Additional information

This paper belongs to Topical Collection MIB 2013 (Modeling Interactions in Biomolecules VI)

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Cerón-Carrasco, J.P., Cerezo, J., Requena, A. et al. Labelling Herceptin with a novel oxaliplatin derivative: a computational approach towards the selective drug delivery. J Mol Model 20, 2401 (2014). https://doi.org/10.1007/s00894-014-2401-7

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  • DOI: https://doi.org/10.1007/s00894-014-2401-7

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