Interactions of gold(I) complexes with models of Thioredoxin reductase; DFT & QM/MM studies


                       Milan Říha^a*, Markéta Munzarová^a, Jaroslav Burda^b


  ^aDepartment of Chemistry, Faculty of Science, Masaryk University, Brno, 62500, Czech Republic

     ^bDepartment of Chemical Physics and Optics, Faculty of Mathematics and Physics, Charles
                             University, Prague, 12116, Czech Republic

*Correspondence: milan.riha.23@gmail.com


One of the treatment options for oncological diseases is programmed cell death (PCD) induced by
increased oxidative stress. One of the main PCD types is so-called apoptosis, which is regulated by
thioredoxin systems. [1] The thioredoxin reductase enzyme, one of the key thioredoxin system
components, can be blocked by gold(I) complexes and hence cause therapeutic oxidative stress. [2]

First, we investigated the interactions of a selected gold(I) complex with the active site of the
enzyme using the density functional method. For this purpose, structures of reactants, transition
states, and products for different redox states and (de)protonations of the active site were
explored. From these calculations, Gibbs activation energies and standard reaction energies of the
reaction profiles were determined.

Recently we performed QM/MM MD calculations with Umbrella sampling technique on the more extended
systems where the quantum core comprised tetrapeptide sequence on the C-end of the enzyme together
with the gold(I) complex. This active site was completed by the rest of the enzyme and explicit
solvent water treated by classical MD force field.

All the computational models predict spontaneous gold coordination to both S- and Se- sites
especially in neutral and basic environments.


Keywords: thioredoxin reductase, gold(I) complexes, DFT, QM/MM

References:

[1] Lu, J.; Holmgren, A. Thioredoxin System in Cell Death Progression. Antioxidants & Redox
Signaling 2012, 17 (12), 1738-1747.

[2] Rubbiani, R.; Kitanovic, I.; Alborzinia, H.; Can, S.; Kitanovic, A.; Onambele, L. A.;
Stefanopoulou, M.; Geldmacher, Y.; Sheldrick, W. S.; Wolber, G.; Prokop, A.; Woelfl, S.; Ott, I.,
Benzimidazol-2-ylidene Gold(I) Complexes Are Thioredoxin Reductase Inhibitors with Multiple
Antitumor Properties. J. Med. Chem. 2010, 53, 8608–8618.