Study of the docking of competitive inhibitors at a model of tyrosinase active site: Insights from joint broken-symmetry/spin-flip DFT computations and ELF topological analysis

  • A. de la Lande
  • J. Maddaluno
  • O. Parisel
  • T. A. Darden
  • J. -P. Piquemal


Following our previous study (Piquemal et al., 2003), we present here a DFT study of the inhibition of the Tyrosinase enzyme. Broken-symmetry DFT computations are supplemented with Spin-Flip TD-DFT calculations, which, for the first time, are applied to such a dicopper enzyme. The chosen biomimetic model encompasses a dioxygen molecule, two Cu(II) cations, and six imidazole rings. The docking energy of a natural substrate, namely phenolate, together with those of several inhibitor and non-inhibitor compounds, are reported and show the ability of the model to rank the most potent inhibitors in agreement with experimental data. With respect to broken-symmetry calculations, the Spin-Flip TD-DFT approach reinforces the possibility for theory to point out potent inhibitors: the need for the deprotonation of the substrates, natural or inhibitors, is now clearly established. Moreover, Electron Localization Function (ELF) topological analysis computations are used to deeply track the particular electronic distribution of the Cu-O-Cu three-center bonds involved in the enzymatic Cu2O2 metallic core (Piquemal and Pilmé, 2006). It is shown that such bonds exhibit very resilient out-of-plane density expansions that play a key role in docking interactions: their 3D-orientation could be the topological electronic signature of oxygen activation within such systems.

Key words

Density Functional Theory Spin-Flip TD-DFT copper oxygenase tyrosinase competitive inhibition 


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Copyright information

© International Association of Scientists in the Interdisciplinary Areas and Springer Berlin Heidelberg 2010

Authors and Affiliations

  • A. de la Lande
    • 1
    • 2
    • 3
  • J. Maddaluno
    • 4
  • O. Parisel
    • 1
    • 2
  • T. A. Darden
    • 5
  • J. -P. Piquemal
    • 1
    • 2
  1. 1.Laboratoire de Chimie ThéoriqueUPMC Univ. Paris 06, UMR 7616ParisFrance
  2. 2.Laboratoire de Chimie ThéoriqueCNRS, UMR 7616ParisFrance
  3. 3.Institute for Biocomplexity and InformaticsUniversity of CalgaryCalgaryCanada
  4. 4.Institut de Recherche en Chimie Organique Fine, UMR 6014 CNRSUniversité de RouenMont St Aignan CedexFrance
  5. 5.Laboratory of Structural BiologyNational Institute of Environmental Health SciencesResearch Triangle ParkUSA

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