title: Labelling Herceptin with a novel oxaliplatin derivative: a computational approach towards the selective drug delivery.
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.
authors.affiliation: Departamento de Química Física, Facultad de Química, Universidad de Murcia, 30100 Campus de Espinardo, Murcia, Spain, jpceron@um.es.
authors.forename: José P
authors.initials: JP
authors.lastname: Cerón-Carrasco
authors.forename: Javier
authors.initials: J
authors.lastname: Cerezo
authors.forename: Alberto
authors.initials: A
authors.lastname: Requena
authors.forename: José
authors.initials: J
authors.lastname: Zuñiga
authors.forename: Julia
authors.initials: J
authors.lastname: Contreras-García
authors.forename: Sonali
authors.initials: S
authors.lastname: Chavan
authors.forename: Miguel
authors.initials: M
authors.lastname: Manrubia-Cobo
authors.forename: Horacio
authors.initials: H
authors.lastname: Pérez-Sánchez
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D017076:Computer-Aided Design; D015195:Drug Design; D004355:Drug Stability; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D000077150:Oxaliplatin; D011485:Protein Binding; D011487:Protein Conformation; D011789:Quantum Theory; D013329:Structure-Activity Relationship; D000068878:Trastuzumab / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000068878:Trastuzumab