Vibrational analysis of auranofin complexes with cysteine and selenocysteine unveils distinct binding motifs and specific unimolecular reactivity

Auranofin (AF) is the most used gold(I)-containing drugs, whose mechanism of action involves targeting sulfur and selenium-containing amino acids, including cysteine (Cys) and selenocysteine (Sec). These residues are present in the active sites of crucial proteins including thioredoxin reductase. Despite extensive exploration of AF-protein interactions over the years, experimental data at the molecular level are still limited. In this work, we studied the vibrational and structural features of solvent-free complexes obtained by the reaction of AF with Cys and Sec, [(Et3P)AuCys]+ and [(Et3P)AuSec]+ ions, respectively. Using tandem mass spectrometry and IR ion spectroscopy supported by density functional theory (DFT) calculations, we unveiled markedly different behaviors for the Cys and Sec bound complexes. In particular, our results indicate that, whereas the [(Et3P)AuSec]+ ions are mainly Se-bound, in agreement with the well-known affinity of Se for gold(I), the sampled [(Et3P)AuCys]+ ionic population is composed of both N- and S-bound isomers, with their ratio depending on the dielectric constant of the solvent used in the starting solution. Additionally, we found that the deamination process occurring in the gas-phase during collision-induced dissociation experiments significantly differ between the two complexes. This work findings contribute to a deeper understanding of AF’s reactivity with Cys and Sec-containing protein targets and highlight how the chemical environment may influence target selectivity of gold-containing drugs, which is crucial for their pharmacological activities.