Alessandro Marrone

The targeting of human thioredoxin reductase is widely recognized to be crucially involved in the anticancer properties of several metallodrugs, including Au(I) complexes. In this study, the mechanism of reaction between a set of five N-heterocyclic carbene Au(I) complexes and models of the active Sec residue in human thioredoxin reductase was investigated by means of density functional theory approaches. The study was specifically addressed to the kinetics and thermodynamics of the tiled process by aiming at elucidating and explaining the differential inhibitory potency in this set of analogous Au(I) bis-carbene complexes. While the calculated free energy profile showed a substantially similar reactivity, we found that the binding of these Au(I) bis-carbene at the active CysSec dyad in the TrxR enzyme could be subjected to steric and orientational restraints, underlining both the approach of the bis-carbene scaffold and the attack of the selenol group at the metal center. A new and detailed mechanistic insight to the anticancer activity of these Au(I) organometallic complexes was thus provided by consolidating the TrxR targeting paradigm.

Inorganic drugs are capable of tight interactions with proteins through coordination towards aminoacidic residues, and this feature is recognized as a key aspect for their pharmacological action. However, the “protein metalation process” is exploitable for solving the phase problem and structural resolution. In fact, the use of inorganic drugs bearing specific metal centers and ligands capable to drive the binding towards the desired portions of the protein target could represent a very intriguing and fruitful strategy. In this context, a theoretical approach may further contribute to solve protein structures and their refinement. Here, we delineate the main features of a reliable experimental‐theoretical integrated approach, based on the use of metallodrugs, for protein structure solving.