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@ARTICLE{Calandrini:280472,
      author       = {Calandrini, Vania and Rossetti, Giulia and Arnesano, Fabio
                      and Natile, Giovanni and Carloni, Paolo},
      title        = {{C}omputational metallomics of the anticancer drug
                      cisplatin},
      journal      = {Journal of inorganic biochemistry},
      volume       = {153},
      issn         = {0162-0134},
      address      = {New York, NY [u.a.]},
      publisher    = {Elsevier},
      reportid     = {FZJ-2016-00246},
      pages        = {231 - 238},
      year         = {2015},
      abstract     = {Cisplatin, cis-diamminedichlorido-platinum(II), is an
                      important therapeutic tool in the struggle against different
                      tumors, yet it is plagued with the emergence of resistance
                      mechanisms after repeated administrations. This hampers
                      greatly its efficacy. Overcoming resistance problems
                      requires first and foremost an integrated and systematic
                      understanding of the structural determinants and molecular
                      recognition processes involving the drug and its cellular
                      targets. Here we review a strategy that we have followed for
                      the last few years, based on the combination of modern tools
                      from computational chemistry with experimental biophysical
                      methods. Using hybrid Quantum Mechanics/Molecular Mechanics
                      (QM/MM) simulations, validated by spectroscopic experiments
                      (including NMR, and CD), we have worked out for the first
                      time at atomic level the structural determinants in solution
                      of platinated cellular substrates. These include the copper
                      homeostasis proteins Ctr1, Atox1, and ATP7A. All of these
                      proteins have been suggested to influence the pre-target
                      resistance mechanisms. Furthermore, coupling hybrid QM/MM
                      simulations with classical Molecular Dynamics (MD) and free
                      energy calculations, based on force field parameters refined
                      by the so-called “Force Matching” procedure, we have
                      characterized the structural modifications and the free
                      energy landscape associated with the recognition between
                      platinated DNA and the protein HMGB1, belonging to the
                      chromosomal high-mobility group proteins HMGB that inhibit
                      the repair of platinated DNA. This may alleviate issues
                      relative to on-target resistance process. The elucidation of
                      the mechanisms by which tumors are sensitive or refractory
                      to cisplatin may lead to the discovery of prognostic
                      biomarkers. The approach reviewed here could be
                      straightforwardly extended to other metal-based drugs.},
      cin          = {IAS-5 / INM-9 / JSC},
      ddc          = {540},
      cid          = {I:(DE-Juel1)IAS-5-20120330 / I:(DE-Juel1)INM-9-20140121 /
                      I:(DE-Juel1)JSC-20090406},
      pnm          = {511 - Computational Science and Mathematical Methods
                      (POF3-511) / 572 - (Dys-)function and Plasticity (POF3-572)
                      / 574 - Theory, modelling and simulation (POF3-574)},
      pid          = {G:(DE-HGF)POF3-511 / G:(DE-HGF)POF3-572 /
                      G:(DE-HGF)POF3-574},
      typ          = {PUB:(DE-HGF)16},
      UT           = {WOS:000367563200026},
      doi          = {10.1016/j.jinorgbio.2015.10.001},
      url          = {https://juser.fz-juelich.de/record/280472},
}