Reevaluating Gold(I) Thiophilicity in Reduced Dielectric Environments: IRMPD Spectroscopy and Theoretical Investigation of Auranofin-Glutathione Complexes.
5 affiliations
- 1Dipartimento di Farmacia Università G. D'Annunzio Chieti-Pescara Via dei Vestini 31 Chieti I-66100 Italy.
- 2Dipartimento di Chimica e Tecnologie del Farmaco Sapienza Università di Roma, I-00185 Roma Italy.
- 3HFML-FELIX Toernooiveld 7 6525ED Nijmegen the Netherlands.
- 4Institute for Molecules and Materials Radboud University Heyendaalseweg 135 6525AJ Nijmegen the Netherlands ru.nl.
- 5Laboratoire de Physique des Lasers CNRS Université Sorbonne Paris Nord 93430 Villetaneuse France cnrs.fr.
Abstract
The coordination of gold(I) to glutathione (GSH) is a fundamental process in the medicinal chemistry of auranofin and related therapeutics. Utilizing infrared multiple-photon dissociation (IRMPD) spectroscopy, electron-activated dissociation (EAD), and quantum-chemical calculations, we characterize the gas-phase structure of the complex [(Et₃P)AuGSH]⁺. Our results reveal that in the gas phase, the NH₂ group of the N-terminal glutamate residue of GSH serves as a competitive coordination site, challenging coordination by the canonical cysteine thiol, with both isomers coexisting in comparable abundances. This finding suggests that in microenvironments characterized by a reduced dielectric constant, the GSH-Au(I) complex might also exist as an N-bound isomer with a free thiol, which may significantly affect its biological reactivity and functions. Moreover, considering that the dielectric constant within buried protein active sites is substantially lower than that of bulk water, this N-binding motif identifies the unprotonated N-terminus as a plausible target for metalation, even in the presence of free thiols. These insights offer a broader perspective on the competitive binding landscape of gold(I) drugs. As a future direction, we hypothesize potential implications for the inhibition of enzymes with N-terminal catalytic groups, which are crucial for tumor progression, such as nucleophile (Ntn) hydrolases.
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BibTeX
@article{paciotti2026reevaluating,
title = {{Reevaluating Gold(I) Thiophilicity in Reduced Dielectric Environments: IRMPD Spectroscopy and Theoretical Investigation of Auranofin-Glutathione Complexes.}},
author = {Roberto Paciotti and Susanna Grasso and Cecilia Coletti and Nazzareno Re and Giel Berden and Jos Oomens and Charles Desfrançois and Simonetta Fornarini and Davide Corinti and Maria Elisa Crestoni},
journal = {Bioinorganic chemistry and applications},
year = {2026},
month = oct,
doi = {10.1155/bca/5944632},
url = {https://europepmc.org/article/MED/42903266},
note = {CC BY},
}
RIS
TY - JOUR
TI - Reevaluating Gold(I) Thiophilicity in Reduced Dielectric Environments: IRMPD Spectroscopy and Theoretical Investigation of Auranofin-Glutathione Complexes.
AU - Roberto Paciotti
AU - Susanna Grasso
AU - Cecilia Coletti
AU - Nazzareno Re
AU - Giel Berden
AU - Jos Oomens
AU - Charles Desfrançois
AU - Simonetta Fornarini
AU - Davide Corinti
AU - Maria Elisa Crestoni
PY - 2026
DA - 2026/10/19
JO - Bioinorganic chemistry and applications
DO - 10.1155/bca/5944632
UR - https://europepmc.org/article/MED/42903266
AB - The coordination of gold(I) to glutathione (GSH) is a fundamental process in the medicinal chemistry of auranofin and related therapeutics. Utilizing infrared multiple-photon dissociation (IRMPD) spectroscopy, electron-activated dissociation (EAD), and quantum-chemical calculations, we characterize the gas-phase structure of the complex [(Et₃P)AuGSH]⁺. Our results reveal that in the gas phase, the NH₂ group of the N-terminal glutamate residue of GSH serves as a competitive coordination site, challenging coordination by the canonical cysteine thiol, with both isomers coexisting in comparable abundances. This finding suggests that in microenvironments characterized by a reduced dielectric constant, the GSH-Au(I) complex might also exist as an N-bound isomer with a free thiol, which may significantly affect its biological reactivity and functions. Moreover, considering that the dielectric constant within buried protein active sites is substantially lower than that of bulk water, this N-binding motif identifies the unprotonated N-terminus as a plausible target for metalation, even in the presence of free thiols. These insights offer a broader perspective on the competitive binding landscape of gold(I) drugs. As a future direction, we hypothesize potential implications for the inhibition of enzymes with N-terminal catalytic groups, which are crucial for tumor progression, such as nucleophile (Ntn) hydrolases.
SN - 1565-3633
SN - 1687-479X
ER -