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.
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.
de la Lande
A
A
UPMC Univ. Paris 06, UMR 7616, Laboratoire de Chimie Théorique, case courrier 137, 4 place Jussieu, Paris, France.
Maddaluno
J
J
Parisel
O
O
Darden
T A
TA
Piquemal
J-P
JP
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
D007093:Imidazoles; D003300:Copper; C029899:imidazole; D014442:Monophenol Monooxygenase
J Mol Biol. 1989 Sep 20;209(2):249-79
2585484
J Biol Inorg Chem. 2006 Apr;11(3):261-71
16447049
J Phys Chem A. 2006 Feb 9;110(5):1991-2004
16451035
J Agric Food Chem. 2001 Aug;49(8):4060-3
11513710
J Chem Phys. 2004 Dec 22;121(24):12191-6
15606237
J Am Chem Soc. 2006 Mar 1;128(8):2654-65
16492052
Inorg Chem. 2008 Apr 7;47(7):2494-506
18293917
J Comput Chem. 2003 Dec;24(16):1963-70
14531050
Trends Biochem Sci. 2000 Aug;25(8):392-7
10916160
Cell Mol Life Sci. 2005 Aug;62(15):1707-23
15968468
Angew Chem Int Ed Engl. 2001 Dec 17;40(24):4570-4590
12404359
J Am Chem Soc. 2005 Dec 28;127(51):18031-6
16366554
Phys Rev B Condens Matter. 1988 Jan 15;37(2):785-789
9944570
Brain Res Mol Brain Res. 1997 Apr;45(1):159-62
9105685
Angew Chem Int Ed Engl. 2006 Jul 10;45(28):4546-50
16795103
Biochemistry. 1994 May 17;33(19):5739-44
8180200
J Comput Chem. 2008 Jul 15;29(9):1440-9
18293309
Inorg Chem. 2009 Aug 3;48(15):7003-5
19586039
Chemistry. 2008;14(21):6465-73
18512825
Inorg Chem. 2001 Feb 12;40(4):628-35
11225103
Cancer Lett. 1992 Mar 31;63(1):73-9
1555210
J Chem Phys. 2007 Jan 21;126(3):035102
17249901
Experientia. 1988 Oct 15;44(10):885-7
3141207
J Mol Struct. 2006 May 30;764(1-3):77-86
17893747
Phys Chem Chem Phys. 2006 Jul 21;8(27):3172-91
16902710
J Clin Invest. 1991 Mar;87(3):1119-22
1900309
J Chem Theory Comput. 2007 Nov;3(6):1960-1986
18978934
J Biol Chem. 2006 Mar 31;281(13):8981-90
16436386