title: 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.
abstract: Following our previous study (Piquemal et al., New J. Chem., 2003, 27, 909), 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 Cu(2)O(2) metallic core (Piquemal and Pilmé, J. Mol. Struct.: Theochem, 2006, 77, 764). 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.
authors.affiliation: UPMC Univ. Paris 06, UMR 7616, Laboratoire de Chimie Théorique, case courrier 137, 4 place Jussieu, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: de la Lande
authors.forename: J
authors.initials: J
authors.lastname: Maddaluno
authors.forename: O
authors.initials: O
authors.lastname: Parisel
authors.forename: T A
authors.initials: TA
authors.lastname: Darden
authors.forename: J-P
authors.initials: JP
authors.lastname: Piquemal
mesh_terms: D001667:Binding, Competitive; D020134:Catalytic Domain; D002626:Chemistry, Pharmaceutical / Q000379:methods; D019295:Computational Biology / Q000379:methods; D003198:Computer Simulation; D003300:Copper / Q000737:chemistry; D015195:Drug Design; D007093:Imidazoles / Q000737:chemistry; D008956:Models, Chemical; D008958:Models, Molecular; D008962:Models, Theoretical; D008968:Molecular Conformation; D014442:Monophenol Monooxygenase / Q000737:chemistry*; D011485:Protein Binding; D012984:Software
chemical_list: D007093:Imidazoles; D003300:Copper; C029899:imidazole; D014442:Monophenol Monooxygenase
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