Combining experimental and computational tools to unravel copper-based metallodrug interactions with proteins
Peña, Quim (Universitat Autònoma de Barcelona. Departament de Química)
Zapirain Gysling, Iker (Universitat Autònoma de Barcelona. Departament de Química)
Simaan, A. Jalila (Aix-Marseille Université)
Capdevila Vidal, Mercè (Universitat Autònoma de Barcelona. Departament de Química)
Iranzo, Olga (Aix-Marseille Université)
Palacios Bonilla, Òscar (Universitat Autònoma de Barcelona. Departament de Química)
Maréchal, Jean-Didier (Universitat Autònoma de Barcelona. Departament de Química)
Bayón Rueda, Joan Pau (Universitat Autònoma de Barcelona. Departament de Química)
Rizzarelli, Enrico, ed.

Date:	2025
Description:	16 pàg.
Abstract:	Metallodrugs are widely used in the treatment of several diseases, including cancer. Many bloodstream proteins exhibit high affinities for metals and metal-based compounds, and these interactions have been shown to impact metallodrug pharmacokinetics and pharmacodynamics, ultimately influencing their therapeutic performance. Several spectroscopic, spectrometric, and computational techniques have been used to further understand drug-protein binding modes at the molecular level over the last few years. However, there is still plenty of room to ascertain the full potential of integrated experimental-computational methodologies in the field of metallodrugs. These studies have mostly been limited to a few metal-containing systems, such as platinates and vanadium drugs. In this work, we aim to expand and validate the use of combined experimental-theoretical approaches in studying copper (Cu)-based drug interactions with proteins. To do so, a tetracoordinated Cu(II) complex has been employed as a practical case study, and its interactions with several relevant proteins using different experimental and computational techniques have been evaluated, including electron paramagnetic resonance spectroscopy, mass spectrometry, density functional theory, and protein-ligand docking calculations. Experimental data highlight interactions of the Cu(II) complex with albumin, myoglobin, and cytochrome C. Further insights into the preferential modes of binding were evaluated by density functional theory and docking calculations, which revealed three main outer surface binding sites for both albumin and myoglobin, as well as three preferential inner pockets in the case of albumin. The most relevant binding modes found for both proteins include noncoordinative interactions with the Cu(II) dimeric structure intact upon binding, as well as metal-ligand exchange and direct metal-amino acid coordination, mainly to glutamate/aspartate residues after cleavage of the dimer. Altogether, an example of the applicability of a mixed experimental-theoretical framework in the study of Cu-based drug interactions with relevant proteins is shown.
Grants:	Agencia Estatal de Investigación PID2023-149492NB-I00 Agencia Estatal de Investigación PID2021-127983OB-C22 Agencia Estatal de Investigación PID2020-116861GB-I00 Agencia Estatal de Investigación RTI2018-098027-B-C22 Agencia Estatal de Investigación CTQ2017-87889-P Ministerio de Economía y Competitividad BIO2015-67358-C2-2-P Ministerio de Economía y Competitividad CTQ2015-70371-REDT Agència de Gestió d'Ajuts Universitaris i de Recerca 2021/SGR-00019 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/SGR-1584 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/SGR-864
Note:	Altres ajuts: acords transformatius de la UAB
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Albumin ; Cancer ; Copper ; Docking ; Metallodrug ; Protein binding
Published in:	Bioinorganic Chemistry and Applications, Vol. 2025 (2025) , art. 551967, ISSN 1687-479X

DOI: 10.1155/bca/5551967

16 p, 3.7 MB

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