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.

Curly arrows meet electron density transfers in chemical reaction mechanisms: from electron localization function (ELF) analysis to valence-shell electron-pair repulsion (VSEPR) inspired interpretation

“…The name of quantum chemical topology 49,50 has been introduced to embrace all topological investigations of three-dimensional scalar fields [51][52][53][54][55][56][57][58] to rationalize the chemical bond and further understanding of the chemical reactivity. [59][60][61][62][63][64][65][66][67] A number of excellent works in the subject have been published to remark the importance of charge density analysis applied to chemical and biological systems and solids. 47,48,56,[68][69][70][71][72][73][74] Probing the electron density distribution during a chemical reaction can provide important insights, but this aim has required extension of the relationships between the traditional chemical concepts and the quantum mechanical ones.…”

Curly arrows, electron flow, and reaction mechanisms from the perspective of the bonding evolution theory

“…The name 'quantum chemical topology' 136,137 has been introduced to embrace all topological investigations of three-dimensional scalar fields 46,[138][139][140][141][142][143][144] in order to rationalize the chemical bond and gain further understanding of the chemical reactivity. [145][146][147][148][149][150][151][152][153] A number of excellent works on that subject have been published to highlight the importance of charge density analysis applied to chemical, biological systems, and solids. 46,[154][155][156][157][158][159][160][161][162] Very recently, Pendás and…”

Chemical structure and reactivity by means of quantum chemical topology analysis

“…QCT has been successfully employed for the analysis of chemical bond as well as to provide a further understanding of the chemical reactivity [131][132][133][134][135][136][137][138]. Likewise, Nasertayoob and Shahbazian [68] have presented an account on the mathematical foundations of the topological analysis of the electronic charge densities while Martín-Pendás et al have presented an outlook on the use of quantum chemical topology techniques in crystallography [63].…”