Computational Studies of Au(I) and Au(III) Anticancer MetalLodrugs: A Survey

Abstract

Owing to the growing hardware capabilities and the enhancing efficacy of computational methodologies, computational chemistry approaches have constantly become more important in the development of novel anticancer metallodrugs. Besides traditional Pt-based drugs, inorganic and organometallic complexes of other transition metals are showing increasing potential in the treatment of cancer. Among them, Au(I)- and Au(III)-based compounds are promising candidates due to the strong affinity of Au(I) cations to cysteine and selenocysteine side chains of the protein residues and to Au(III) complexes being more labile and prone to the reduction to either Au(I) or Au(0) in the physiological milieu. A correct prediction of metal complexes’ properties and of their bonding interactions with potential ligands requires QM computations, usually at the ab initio or DFT level. However, MM, MD, and docking approaches can also give useful information on their binding site on large biomolecular targets, such as proteins or DNA, provided a careful parametrization of the metal force field is employed. In this review, we provide an overview of the recent computational studies of Au(I) and Au(III) antitumor compounds and of their interactions with biomolecular targets, such as sulfur- and selenium-containing enzymes, like glutathione reductases, glutathione peroxidase, glutathione-S-transferase, cysteine protease, thioredoxin reductase and poly (ADP-ribose) polymerase 1.

Diruthenium(ii,iii) paddlewheel complexes: effects of bridging and axial ligands on anticancer properties

“…Such an approach is often applied to induce a multifaceted optimization of the drug delivery by effectively stabilizing nonconventional geometries of the compound, which can serve various purposes, such as peculiar ways of action, improved permeation of cell membranes, augmented solubility, or modified redox behaviour. 6,7 On the other hand, the disassembling of the dual drug structure is also exploited to trigger two active mechanisms in the target tissue to achieve a potentiated pharmacological response.…”

Inorganic Drugs as a Tool for Protein Structure Solving and Studies on Conformational Changes

“…For example, cisplatin may be present in either dichloro, i. e. non-activated, or monohydrated, i.e. active, forms [103] while auranofin (1-thio-β-D-glucopyranosatotriethylphosphine gold-2,3,4,6-tetraacetate, marketed under the brand name Ridaura®) almost invariably releases the thiosugar ligand, [104] and the prevalence of certain activated forms of N-heterocyclic carbene half-sandwich transition-metal based complexes ([Ru II /Os II (cym)(dmb)Cl 2 ] and [Rh III / Ir III (Cp*)(dmb)Cl 2 ], with cym = η 6 -p-cymene, Cp* = η 5 -pentamethylcyclopentadienyl, and dmb = 1,3-dimethylbenzimidazol-2ylidene) is favored only at the acidic pH. [105] The different hydrolysis products may disclose a different degree of capability and selectivity in the reaction with protein residues, which may depend on both thermodynamic and kinetic factors.…”

Auranofin Targeting the NDM-1 Beta-Lactamase: Computational Insights into the Electronic Configuration and Quasi-Tetrahedral Coordination of Gold Ions

“…Auranofin (AF, 1-thio-β-D-glucopyranosatotriethylphosphine gold-2,3,4,6-tetraacetate) was the first orally administered gold-based metallodrug developed specifically to remedy rheumatoid arthritis, certified by the US Food and Drug Administration (FDA) in 1985 ( Figure 2 ) [ 16 ]. Its therapeutic effect is ascribed to the [AuPEt 3 ] + cation yielded after the detachment of the thiosugar in the biological milieu [ 17 ]. This cation has an augmented preference to thiol- and selenol-based proteins [ 18 ], thus causing the disruption of cellular metabolism pathways and leading to the intended medicinal impacts.…”

“…Therefore, the experimental investigation of the chemical processes occurring after the administration of auranofin is very challenging due to the high chemical complexity impacted by this metallodrug either before or after its entry in the targeted cell. Nevertheless, the theoretical chemists have not yet succeeded in responding to this question either, despite numerous computational articles focused on the disentanglement of the mechanistic process of auranofin’s ligand exchange reactions [ 17 , 26 , 27 , 28 ]. Moreover, to the best of our knowledge, all the available computational studies of auranofin have addressed the behavior of one auranofin complex with its intended targets, for the sake of simplicity.…”