Kinetics of Reactions of Dirhodium and Diruthenium Paddlewheel Tetraacetate Complexes with Nucleophilic Protein Sites: Computational Insights

Recently, dirhodium and diruthenium paddlewheel complexes have drawn attention as perspective anticancer drugs. In this study, the kinetics of reaction of typical paddlewheel scaffolds Rh2(μ-O2CCH3)4(H2O)2, Ru2(μ-O2CCH3)4(H2O)Cl, and [Ru2(μ-O2CCH3)4(HO)Cl]− with protein nucleophiles were investigated by means of the density functional theory. The substitution of axial ligandswater and chlorideby the models of protein residue side chains was analyzed, revealing the binding selectivity displayed by these paddlewheel metal scaffolds. The substitution of water is under a thermodynamic control, in which, although the Arg, Cys–, and Sec– residues are the most favorable, their binding is expected to be scarcely selective in a biological context. On the other hand, the replacement of the axial water with a more stable hydroxo ligand induces the chloride substitution in diRu complexes, which also targets Arg, Cys–, and Sec–, although with a moderately higher activation barrier for any examined protein residue. Additionally, the carried out characterization of the geometrical parameters of the transition states permitted determination of the impact of an increased steric hindrance of diRh and diRu complexes on their protein site selectivity. This study corroborates the idea of the substitution of the acetate ligands with biologically active, but more hindering, carboxylate ligands, in order to yield dual acting metallodrugs. This study allows us to assume that the delivery of diRu paddlewheel complexes in their monoanionic form [Ru2(μ-O2CR)4(OH)Cl]− decorated by the bulky substituents R may constitute an approach to augment the selectivity toward anticancer targets, such as TrxR in tumor cells, although under the condition that such a selectivity is operative only in high pH conditions

Reactivity of N‑Heterocyclic Carbene Half-Sandwich Ru‑, Os‑, Rh‑, and Ir-Based Complexes with Cysteine and Selenocysteine: A Computational Study

The structure and the reactivity of four half-sandwich metal complexes of RuII, OsII, RhIII, and IrIII were investigated by means of density functional theory approaches. These piano-stool complexes, grouped in cym-bound complexes, RuII(cym)­(dmb)­Cl2, 1, and OsII(cym)­(dmb)­Cl2, 2, and Cp*-bound complexes, RhIII(Cp*)­(dmb)­Cl2, 3, and IrIII(Cp*)­(dmb)­Cl2, 4, with cym = η6-p-cymene, Cp* = η5-pentamethylcyclopentadienyl, and dmb = 1,3-dimethylbenzimidazol-2-ylidene, were recently proposed as anticancer metallodrugs that preferably target Cys- or Sec-containing proteins. Thus, density functional theory calculations were performed here to characterize in detail the thermodynamics and the kinetics underlining the targeting of these metallodrugs at either neutral or anionic Cys and Sec side chains. Calculations evidenced that all these complexes preferably target at Cys or Sec via chloro exchange, although cym-bound and Cp*-bound complexes resulted to be more prone to bind at neutral or anionic forms, respectively, of these soft protein sites. Further decomposition analyses of the activation free energies for the reaction between 1–4 complexes and either Cys or Sec, paralleled with the comparison among the optimized transition-state structures, allowed us to spotlight the significant role played by solvation in determining the overall reactivity and selectivity expected for these prototypical metallodrugs

Structural Reshaping of the Zinc-Finger Domain of the SARS-CoV‑2 nsp13 Protein Using Bismuth(III) Ions: A Multilevel Computational Study

The identification of novel therapeutics against the pandemic SARS-CoV-2 infection is an indispensable new address of current scientific research. In the search for anti-SARS-CoV-2 agents as alternatives to the vaccine or immune therapeutics whose efficacy naturally degrades with the occurrence of new variants, the salts of Bi3+ have been found to decrease the activity of the Zn2+-dependent non-structural protein 13 (nsp13) helicase, a key component of the SARS-CoV-2 molecular tool kit. Here, we present a multilevel computational investigation based on the articulation of DFT calculations, classical MD simulations, and MIF analyses, focused on the examination of the effects of Bi3+/Zn2+ exchange on the structure and molecular interaction features of the nsp13 protein. Our calculations confirmed that Bi3+ ions can replace Zn2+ in the zinc-finger metal centers and cause slight but appreciable structural modifications in the zinc-binding domain of nsp13. Nevertheless, by employing an in-house-developed ATOMIF tool, we evidenced that such a Bi3+/Zn2+ exchange may decrease the extension of a specific hydrophobic portion of nsp13, responsible for the interaction with the nsp12 protein. The present study provides for a detailed, atomistic insight into the potential anti-SARS-CoV-2 activity of Bi3+ and, more generally, evidences the hampering of the nsp13–nsp12 interaction as a plausible therapeutic strategy

Insight into the Electrochemical Reduction Mechanism of Pt(IV) Anticancer Complexes

We carried out a theoretical study on the mechanism of electrochemical reduction of the prototypical platinum­(IV) anticancer complex [Pt­(NH₃)₂­(CH₃COO)₂­Cl₂] to the corresponding platinum­(II) [Pt­(NH₃)₂­Cl₂] derivative. Energies and geometric structures of the original Pt­(IV) complex and all possible Pt­(III) and Pt­(II) intermediates and transition states involved in the reduction process have been calculated using density functional theory and Møller–Plesset perturbation theory. This study allowed us to formulate a detailed mechanism for the two-electron reduction of the [Pt^IV­(NH₃)₂­(CH₃­COO)₂­Cl₂] complex. The results show that, in agreement with the experimental evidence from cyclic voltammetry, the initial one-electron reduction of the [Pt^IV­(NH₃)₂­(CH₃­COO)₂­Cl₂] complex occurs through a stepwise mechanism via a metastable hexacoordinated platinum­(III) [Pt^III­(NH₃)₂­(CH₃­COO)₂­Cl₂]⁻ intermediate and a subsequent acetate ligand detachment with an activation free energy of 5.1 kcal mol^–1. On the other hand, the second electron reduction of the resulting pentacoordinated [Pt^III­(NH₃)₂­(CH₃COO)­Cl₂] species occurs through a barrierless concerted process to the final [Pt^II­(NH₃)₂­Cl₂] derivative

An Insight on the Gold(I) Affinity of <i>golB</i> Protein via Multilevel Computational Approaches

Several bacterial species have evolutionary developed protein systems specialized in the control of intracellular gold ion concentration. In order to prevent the detrimental consequences that may be induced even at very low concentrations, bacteria such as Salmonella enterica and Cupriavidus metallidurans utilize Au-specific merR-type transcriptional regulators that detect these toxic ions and control the expression of specific resistance factors. Among these highly specialized proteins, golB has been investigated in depth, and X-ray structures of both apo and Au­(I)-bound golB have been recently reported. Here, the binding of Au­(I) at golB was investigated by means of multilevel computational approaches. Molecular dynamics simulations evidenced how conformations amenable for the Au­(I) chelation through the Cys-XX-Cys motif on helix 1 are extensively sampled in the phase space of apo-golB. Hybrid QM/MM calculations on metal-bound structures of golB also allowed to characterize the most probable protonation state for gold binding motif and to assess the structural features mostly influencing the Au­(I) coordination in this protein. Consistently with experimental evidence, we found that golB may control its Au­(I) affinity by conformational changes that affect the distance between Cys10 and Cys13, thus being able to switch between the Au­(I) sequestration/release-prone states in response to external stimuli. The protein structure enveloping the metal binding motif favors the thiol–thiolate protonation state of Au­(I)-golB, thus probably enhancing the binding selectivity for Au­(I) compared to other cations

Noble Metal Nanoparticles with Nanogel Coatings: Coinage Metal Thiolate-Stabilized Glutathione Hydrogel Shells

Developing biocompatible nanocoatings is crucial for biomedical applications. Noble metal colloidal nanoparticles with biomolecular shells are thought to combine diverse chemical and optothermal functionalities with biocompatibility. Herein, we present nanoparticles with peptide hydrogel shells that feature an unusual combination of properties: the metal core possesses localized plasmon resonance, whereas a few-nanometer-thick shells open opportunities to employ their soft framework for loading and scaffolding. We demonstrate this concept with gold and silver nanoparticles capped by glutathione peptides stacked into parallel β-sheets as they aggregate on the surface. A key role in the formation of the ordered structure is played by coinage metal­(I) thiolates, i.e., Ag­(I), Cu­(I), and Au­(I). The shell thickness can be controlled via the concentration of either metal ions or peptides. Theoretical modeling of the shell’s molecular structure suggests that the thiolates have a similar conformation for all the metals and that the parallel β-sheet-like structure is a kinetic product of the peptide aggregation. Using third-order nonlinear two-dimensional infrared spectroscopy, we revealed that the ordered secondary structure is similar to the bulk hydrogels of the coinage metal thiolates of glutathione, which also consist of aggregated stacked parallel β-sheets. We expect that nanoparticles with hydrogel shells will be useful additions to the nanomaterial toolbox. The present method of nanogel coating can be applied to arbitrary surfaces where the initial deposition of the seed glutathione monolayer is possible

Reactions of Arsenoplatin‑1 with Protein Targets: A Combined Experimental and Theoretical Study

Arsenoplatin-1 (AP-1) is a dual-action anticancer metallodrug with a promising pharmacological profile that features the simultaneous presence of a cisplatin-like center and an arsenite center. We investigated its interactions with proteins through a joint experimental and theoretical approach. The reactivity of AP-1 with a variety of proteins, including carbonic anhydrase (CA), superoxide dismutase (SOD), myoglobin (Mb), glyceraldehyde 3-phosphate dehydrogenase (GAPDH), and human serum albumin (HSA), was analyzed by means of electrospray ionization mass spectrometry (ESI MS) measurements. In accordance with previous observations, ESI MS experiments revealed that the obtained metallodrug–protein adducts originated from the binding of the [(AP-1)-Cl]+ fragment to accessible protein residues. Remarkably, in two cases, i.e., Mb and GAPDH, the formation of a bound metallic fragment that lacked the arsenic center was highlighted. The reactions of AP-1 with various nucleophiles side chains of neutral histidine, methionine, cysteine, and selenocysteine, in neutral form as well as cysteine and selenocysteine in anionic form, were subsequently analyzed through a computational approach. We found that the aquation of AP-1 is energetically disfavored, with a reaction free energy of +19.2 kcal/mol demonstrating that AP-1 presumably attacks its biological targets through the exchange of the chloride ligand. The theoretical analysis of thermodynamics and kinetics for the ligand-exchange processes of AP-1 with His, Met, Cys, Sec, Cys–, and Sec– side chain models unveils that only neutral histidine and deprotonated cysteine and selenocysteine are able to effectively replace the chloride ligand in AP-1

Mechanistic Evaluations of the Effects of Auranofin Triethylphosphine Replacement with a Trimethylphosphite Moiety

Auranofin, a gold(I)-based complex, is under clinical trials for application as an anticancer agent for the treatment of nonsmall-cell lung cancer and ovarian cancer. In the past years, different derivatives have been developed, modifying gold linear ligands in the search for new gold complexes endowed with a better pharmacological profile. Recently, a panel of four gold(I) complexes, inspired by the clinically established compound auranofin, was reported by our research group. As described, all compounds possess an [Au{P(OMe)3}]+ cationic moiety, in which the triethylphosphine of the parent compound auranofin was replaced with an oxygen-rich trimethylphosphite ligand. The gold(I) linear coordination geometry was complemented by Cl–, Br–, I–, and the auranofin-like thioglucose tetraacetate ligand. As previously reported, despite their close similarity to auranofin, the panel compounds exhibited some peculiar and distinctive features, such as lower log P values which can induce relevant differences in the overall pharmacokinetic profiles. To get better insight into the P–Au strength and stability, an extensive study was carried out for relevant biological models, including three different vasopressin peptide analogues and cysteine, using 31P NMR and LC-ESI-MS. A DFT computational study was also carried out for a better understanding of the theoretical fundamentals of the disclosed differences with regard to triethylphosphine parent compounds