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Diruthenium(ii,iii) paddlewheel carboxylates combine the pharmacological properties of the dimetallic center with those ascribed to the μ-bridged carboxylates, thus leading to novel, dual-acting anticancer metallodrugs.

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 Bi

Inorganic drugs are capable of tight interactions with proteins through coordination towards aminoacidic residues, and this feature is recognized as a key aspect for their pharmacological action. However, the "protein metalation process" is exploitable for solving the phase problem and structural resolution. In fact, the use of inorganic drugs bearing specific metal centers and ligands capable to drive the binding towards the desired portions of the protein target could represent a very intriguing and fruitful strategy. In this context, a theoretical approach may further contribute to solve protein structures and their refinement. Here, we delineate the main features of a reliable experimental-theoretical integrated approach, based on the use of metallodrugs, for protein structures solving.

Recently, dirhodium and diruthenium paddlewheel complexes have drawn attention as perspective anticancer drugs. In this study, the kinetics of reaction of typical paddlewheel scaffolds Rh

Metal complexes can be considered a "paradigm of promiscuity" when it comes to their interactions with proteins. They often form adducts with a variety of donor atoms in an unselective manner. We have characterized the adducts formed between a series of isostructural N-heterocyclic carbene (NHC) complexes with Ru, Os, Rh, and Ir centers and the model protein hen egg white lysozyme by X-ray crystallography and mass spectrometry. Distinctive behavior for the metal compounds was observed with the more labile Ru and Rh complexes targeting mainly a surface l-histidine moiety through cleavage of p-cymene or NHC co-ligands, respectively. In contrast, the more inert Os and Ir derivatives were detected abundantly in an electronegative binding pocket after undergoing ligand exchange of a chlorido ligand for an amino acid side chain. Computational studies supported the binding profiles and hinted at the role of the protein microenvironment for metal complexes eliciting selectivity for specific binding sites on the protein.

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]

Ammonium trichloro (dioxoethylene-O,O′) tellurate (AS101) is a potent immunomodulator prodrug that, in recent years, entered various clinical trials and was tested for a variety of potential therapeutic applications. It has been demonstrated that AS101 quickly activates in aqueous milieu, producing TeOCl3−, which likely represents the pharmacologically active species. Here we report on the study of the activation process of AS101 and of two its analogues. After the synthesis and characterization of AS101 and its derivatives, we have carried out a comparative study through a combined experimental and computational analysis. Based on the obtained results, we describe here, for the first time, the detailed reaction that AS101 and its bromido- and iodido-replaced analogues undergo in presence of water, allowing the conversion of the original molecule to the likely true pharmacophore. Interestingly, moving down in the halogens’ group we observed a higher tendency to react, attributable to the ligands’ effect. The chemical and mechanistic implications of these meaningful differences are discussed.

The structure and the reactivity of four half-sandwich metal complexes of Ru

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.

We herein report the synthesis and multi-technique characterization of [Ru2Cl((2-phenylindol-3-yl)glyoxyl-l-leucine-l-phenylalanine)4], a novel diruthenium(ii,iii) complex obtained by reacting [Ru2(μ-O2CCH3)4Cl] with a dual indolylglyoxylyl dipeptide anticancer agent. We soon realised that the compound is very stable under several different conditions including aqueous buffers or organic solvents. It is also completely unreactive toward proteins. The high stability is also suggested by cellular experiments in a glioblastoma cell line. Indeed, while the parent ligand exerts high cytotoxic effects in the low μM range, the complex is completely non-cytotoxic against the same line, most probably because of the lack of ligand release. To investigate the reasons for such high stability, we carried out DFT calculations that are fully consistent with the experimental findings. The results highlight that the stability of [Ru2Cl((2-phenylindol-3-yl)glyoxyl-l-leucine-l-phenylalanine)4] relies on the nature of the ligand, including its steric hindrance that prevents the reaction of any nucleophilic group with the Ru2 core. Ligand displacement is the key step to allow reactivity with the biological targets of metal-based prodrugs. Accordingly, we discuss the implications of some important aspects that should be considered when active molecules are chosen as ligands for the synthesis of paddle-wheel-like complexes with medicinal applications.

Investigation of the diverse evolutionary developed mechanisms enabling bacteria to maintain homeostasis and to be resistant to lead is crucial for the discovery of novel strategies for isolation of this highly toxic metal and its subsequent elimination from contaminated environments. The metalloregulatory protein pbrR and its homologues that were identified in the Cupriavidus metallidurans CH34 chromosome are the only characterized natural metalloproteins that have a special affinity toward Pb(II) and that bind it with at least a 1000-fold selectivity over other heavy metals. The X-ray structures of apo and Pb(II)-bound pbrR have been recently reported. In the present study, the binding of Pb(II) at pbrR was investigated by means of multiscale computational modeling. Molecular dynamics simulations substantiated how conformations amenable for the Pb(II) complexation through the tris-cysteine motif are formed from the antiparallel coiled-coil packing interaction of two dimerization helices of two pbrR monomers, and the phase space of apo-pbrR has been extensively sampled. Hybrid quantum mechanics/molecular mechanics (QM/MM) calculations on metal-bound structures of pbrR also allowed us to determine the most probable protonation state for the lead binding motif and evaluate the structural features mostly affecting the Pb(II) coordination in this protein. In agreement with available experimental data, we found that pbrR may control its Pb(II) affinity, probably, by conformational changes that affect the distance between Cys78' and Cys122 and their protonation states, thus being able to switch on the Pb(II) sequestration/release-prone states in response to external stimuli. The protein structure enveloping the metal binding motif favors the thiol-thiolate-thiolate protonation state of Pb(II)-pbrR, thus probably enhancing the binding selectivity for Pb(II), compared to other metal ions.

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 b...

The coordination of Pb(II) in aqueous solutions containing thiols is a pivotal topic to the understanding of the pollutant potential of this cation. Based on its hard/soft borderline nature, Pb(II) forms stable hydrated ions as well as stable complexes with the thiol groups of proteins. In this paper, the modeling of Pb(II) coordination via classical molecular dynamics simulations was investigated to assess the possible use of non-bonded potentials for the description of the metal–ligand interaction. In particular, this study aimed at testing the capability of cationic dummy atom schemes—in which part of the mass and charge of the Pb(II) is fractioned in three or four sites anchored to the metal center—in reproducing the correct coordination geometry and, also, in describing the hard/soft borderline character of this cation. Preliminary DFT calculations were used to design two topological schemes, PB3 and PB4, that were subsequently implemented in the Amber force field and employed in molecular dynamics simulation of either pure water or thiol/thiolate-containing aqueous solutions. The PB3 scheme was then tested to model the binding of Pb(II) to the lead-sensing protein pbrR. The potential use of CDA topological schemes in the modeling of Pb(II) coordination was here critically discussed.

In this paper it is demonstrated that the nature of the ligands of two Ru2(II,III) paddlewheel complexes dramatically affects the overall anticancer properties in cells. Herein, the complex [Ru2(EB776)4Cl] was found to be more active against a glioblastoma model with respect to its isomer [Ru2(EB106)4Cl]. These different effects depend on the steric hindrance, on the allowed conformations of the complexes and on the presence of hydrophilic regions in [Ru2(EB776)4Cl], which overall lead to a lower “steric protection”.

Seven different density functionals, including GGAs, meta-GGAs, hybrids and range-separated hybrids, and considering Grimme’s empirical dispersion correction (M06-L, M06-2X, PBE0, B3LYP, B3LYP-D3, CAM-B3LYP, ωB97X) have been tested for their performance in the prediction of molecular structures, energies and energy barriers for a class of newly developed antitumor platinum complexes involving main group heavy elements such as arsenic. The calculated structural parameters, energies and energy barriers have been compared to the available experimental data. The results show that range-separated hybrid functionals CAM-B3LYP and ωB97X give good results in predicting both geometrical parameters and isomerization energies and barrier heights and are promising new tools for the theoretical study of novel platinum(II) arsenic compounds.

The reaction of the dinuclear phosphinito bridged complex [(PHCy2)Pt(μ-PCy2){κ2P,O-μ-P(O)Cy2}Pt(PHCy2)](Pt-Pt) (1) with phenylacetylene affords the η1-alkenyl-μ,η1:η2-alkynyl complex [(η1-trans-(Ph)HC[double bond, length as m-dash]CH)(PHCy2)Pt(μ-PCy2)(μ,η1:η2-PhC[triple bond, length as m-dash]C)Pt{κP-P(O)Cy2}(PHCy2)] (4) displaying a σ-bonded 2-phenylethenyl ligand and an alkynyl (μ-κCα:η2) bridge between the platinum atoms. Complex 4 was shown to form in two steps: initially, the attack of the first molecule of phenylacetylene gives the σ-acetylide complex [(PHCy2)(η1-PhC[triple bond, length as m-dash]C)Pt1(μ-PCy2)Pt2(PHCy2){κP-P(OH)Cy2}](Pt-Pt) (5) featuring an intramolecular π-type hydrogen bond between the POH and the C[triple bond, length as m-dash]C triple bond; fast reaction of 5 with a second molecule of phenylacetylene results in the oxidative addition of the terminal C-H bond of the second alkyne to Pt1 that, after rearrangements, leads to 4. When left in solution for two weeks, complex 4 spontaneously isomerizes completely to [(PHCy2)(η1-trans-(Ph)HC[double bond, length as m-dash]CH)Pt(μ-PCy2){κ2P,O-μ-P(O)Cy2}Pt(η1-PhC[triple bond, length as m-dash]C)(PHCy2)] (7) displaying a 2-phenylethenyl ligand and a phenylethynyl group both σ-bonded to the metal. Density functional calculations at the B3LYP/LACV3P++**//DFT/LACVP* level were carried out to study the thermodynamics of the formation of all considered complexes and to trace the mechanism of formation of the observed products.

Transition metal atoms possess the unique capacity to induce significant changes in the electronic structure of their ligands, often culminating in substantial modification of their chemical behavior, and this ability explains well their evolutionary incorporation into the living matter. Exactly this complexity of metal atom behaviours on the electronic level is the reason of various quantum chemistry strategies have been developed for their description. On the other hand, the application of quantum chemistry methodologies to gain a comprehensive understanding of the interaction between metal and biological matter, can only be approached through adequate modelling of the chemical phenomena in object, sometimes also requiring the support of classical or semiempirical computational methods. This minireview features the tactics developed in our group for analyzing the modus operandi of “transition metals in biology” of various settings: in the active sites of proteins, in the physiological solutions, and incorporated in metallodrug scaffolds.

The biomolecular affinity of three paddlewheel dinuclear complexes Rh2(µ-O2CCH3)4(H2O)2, Ru2(µ-O2CCH3)4(H2O)Cl, [Ru2(µ-O2CCH3)4(H2O)2]+ for the binding at cancer-specific protein targets was determined by means of DFT approaches. Thermodynamics of axial ligand substitution reaction by models of suitable protein sites was investigated in order to assess the binding selectivity displayed by the paddlewheel complexes. Both Rh2(µ-O2CCH3)4(H2O)2 and Ru2(µ-O2CCH3)4(H2O)Cl resulted to react favorably with most of the examined models of the protein side chains, with higher exergodicity demonstrated in the reaction of Arg, Cys, His, Lys, Sec, thus showing a limited selectivity. On the other hand, we identified Sec and His as the most suitable targets of the examined paddlewheel complexes, while Arg and Lys are expected to be also targetable at higher pH. Therefore, our calculations showed how both dirhodium and, majorly, diruthenium examined complexes undergo to a certain degree of destabilization upon the binding at nucleophilic protein sites. The presented computational results allowed us to shed light onto the protein sites’ affinity and on the therapeutic potential of both Rh2(µ-O2CCH3)4(H2O)2 and Ru2(µ-O2CCH3)4(H2O)Cl, and provided for a structural basis for the development of newly designed paddlewheel complexes.

The reaction of the antitumor M(I)-bis-N-heterocyclic carbene (M(I)-NHC) complexes, M = Cu, Ag, and Au, with their potential protein binding sites, i.e. cysteine and selenocysteine, was investigated by means of density functional theory approaches. Capped cysteine and selenocysteine were employed to better model the corresponding residues environment within peptide structures. By assuming the neutral or deprotonated form of the side chains of these amino acids and by considering the possible assistance of an external proton donor such as an adjacent acidic residue or the acidic component of the surrounding buffer environment, we devised five possible routes leading to the binding of the investigated M(I)-NHC scaffolds to these protein sites, reflecting their different location in the protein structure and exposure to the bulk. The targeting of either cysteine or selenocysteine in their neutral forms is a kinetically unfavored process, expected to be quite slow if observable at all at physiological temperature. On the other hand, the reaction with the deprotonated forms is much more favored, even though an external proton source is required to assist the protonation of the leaving carbene. Our calculations also show that all coinage metals are characterized by a similar reactivity toward the binding of cysteine and selenocysteine sites, although the Au(I) complex has significantly higher reaction and activation free energies compared to Cu(I) and Ag(I).

We carried out a detailed theoretical study on the mechanism of the carbene ligand substitution by cysteine and selenocysteine residues in an Au(I) bis-N-heterocyclic carbene complex in order to model the initial stages of the mechanism of action of this promising class of antitumor metallodrug. Both neutral and deprotonated capped Cys and Sec species were considered as possible nucleophiles in the ligand exchange reaction on the metal center to model the corresponding protein side chains. Energies and geometric structures of the possible transition states and reactant- and product-adducts involved in the substitution process have been calculated using density functional theory and local MP2. Reaction and activation enthalpies and free energies have been evaluated and indicate a slightly exothermic and exergonic process with reasonably low barriers, 21.3 and 19.6 kcal mol

Quite surprisingly, cisplatin and cis-[PtI

Quite surprisingly, cisplatin and cis-[PtI2(NH3)2] were found to manifest significant differences in their reactions with the model protein lysozyme. We decided to explore whether these differences recur when reacting these two Pt compounds with other proteins. Notably, ESI-MS measurements carried out on cytochrome c nicely confirmed the reaction pattern observed for lysozyme. This prompted us to exploit a computational DFT approach to disclose the molecular basis of such behavior. We analyzed comparatively the reactions of cis-[PtCl2(NH3)2] and cis-[PtI2(NH3)2] with appropriate molecular models (Ls) of the sidechains of relevant aminoacids. We found that when Pt(II) complexes are reacted with sulfur ligands both quickly lose their halide ligands and then the resulting cis-[Pt(L)2(NH3)2] species loses ammonia upon reaction with a ligand excess. In the case of imidazole, again cis-[PtCl2(NH3)2] and cis-[PtI2(NH3)2] quickly lose their halide ligands but the resulting cis-[Pt(L)2(NH3)2] species does not lose ammonia by reaction with excess imidazole. These results imply that the two platinum complexes manifest a significantly different behavior in their reaction with representative small molecules in agreement with what observed in the case of model proteins. It follows that the protein itself must play a crucial role in triggering the peculiar reactivity of cis-[PtI2(NH3)2] and in governing the nature of the formed protein adducts. The probable reasons for the observed behavior are critically commented and discussed.

The reaction of the dinuclear phosphinito bridged complex [(PHCy2)Pt(μ-PCy2){κ2P,O-μ-P(O)Cy2}Pt(PHCy2)](Pt–Pt) (1) with phenylacetylene affords the η1-alkenyl-μ,η1:η2-alkynyl complex [(η1-trans-(Ph)HCCH)(PHCy2)Pt(μ-PCy2)(μ,η1:η2-PhCC)Pt{κP-P(O)Cy2}(PHCy2)] (4) displaying a σ-bonded 2-phenylethenyl ligand and an alkynyl (μ-κCα:η2) bridge between the platinum atoms. Complex 4 was shown to form in two steps: initially, the attack of the first molecule of phenylacetylene gives the σ-acetylide complex [(PHCy2)(η1-PhCC)Pt1(μ-PCy2)Pt2(PHCy2){κP-P(OH)Cy2}](Pt–Pt) (5) featuring an intramolecular π-type hydrogen bond between the POH and the CC triple bond; fast reaction of 5 with a second molecule of phenylacetylene results in the oxidative addition of the terminal C–H bond of the second alkyne to Pt1 that, after rearrangements, leads to 4. When left in solution for two weeks, complex 4 spontaneously isomerizes completely to [(PHCy2)(η1-trans-(Ph)HCCH)Pt(μ-PCy2){κ2P,O-μ-P(O)Cy2}Pt(η1-PhCC)(PHCy2)] (7) displaying a 2-phenylethenyl ligand and a phenylethynyl group both σ-bonded to the metal. Density functional calculations at the B3LYP/LACV3P++**//DFT/LACVP* level were carried out to study the thermodynamics of the formation of all considered complexes and to trace the mechanism of formation of the observed products.

Investigation of the diverse evolutionary developed mechanisms enabling bacteria to maintain homeostasis and to be resistant to lead is crucial for the discovery of novel strategies for isolation of this highly toxic metal and its subsequent elimination from contaminated environments. The metalloregulatory protein

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

Neutral N&ndash, heterocyclic carbene gold(I) compounds such as IMeAuCl are widely used both in homogeneous catalysis and, more recently, in medicinal chemistry as promising antitumor agents. In order to shed light on their reactivity with protein side chains, we have carried out density functional theory (DFT) calculations on the thermodynamics and kinetics of their reactions with water and various nucleophiles as a model of plausible protein binding sites such as arginine, aspartic acid, asparagine, cysteine, glutamic acid, glutamine, histidine, lysine, methionine, selenocysteine, and the N-terminal group. In agreement with recent experimental data, our results suggest that IMeAuCl easily interacts with all considered biological targets before being hydrated&mdash, unless sterically prevented&mdash, and allows the establishment of an order of thermodynamic stability and of kinetic reactivity for its binding to protein residues.

Metals play an important role in many biological systems, not to mention that their use in the formulation of drugs with novel modes of action has boosted the investigations aimed at elucidating their reaction mechanisms. At variance with carbon-based (or purely organic) molecules which nowadays may be described rather satisfactorily with molecular mechanics, molecules involving metals cannot do without a proper quantum mechanical treatment of the metal atoms. For this reason, in the last years we have been investigating a wealth of methods ranging from pure quantum mechanical ones to multilayered approaches which allow the calculation of detailed information related to the structure, the dynamics and the reaction mechanisms of metal-based biomolecules or drugs.Metals play an important role in many biological systems, not to mention that their use in the formulation of drugs with novel modes of action has boosted the investigations aimed at elucidating their reaction mechanisms. At variance with carbon-based (or purely organic) molecules which nowadays may be described rather satisfactorily with molecular mechanics, molecules involving metals cannot do without a proper quantum mechanical treatment of the metal atoms. For this reason, in the last years we have been investigating a wealth of methods ranging from pure quantum mechanical ones to multilayered approaches which allow the calculation of detailed information related to the structure, the dynamics and the reaction mechanisms of metal-based biomolecules or drugs.

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...

Computational chemistry has proved to be extremely effective in the elucidation and clarification of structural and dynamical properties for metal-based complexes. The present reports gathers some recent activity related to the study of metal based compounds with anticancer properties, mainly, but not only, Pt(II) complexes, with the aim of showing how computational methods of different kinds and with different degrees of accuracy can shed light on their geometrical properties, on the thermodynamics, on reaction and activation mechanisms, and their interaction with proteins, so to better drive the search for more effective drugs and/or with less severe side effects.

Hydrogen economy has been suggested as a possible green alternative to produce energy, also in the framework of transport applications. According to the specific transport means, different kinds of materials can be adopted. The choice of the most suitable materials should then be addressed according to a systematic analysis of available data. In this paper, together with the major physical storage technologies typically used for aerospace applications, additional possible candidates are suggested, namely clathrates hydrates and metal-organic frameworks (MOFs). They are chosen according to the specific features that are asked in the aerospace industry, such as high storage capacities, low weight and materials cost, high cyclability and full reversibility. To this scope, a comprehensive database based on a large set of information from literature (containing, for example, details on the synthesis processes, the operating temperatures and pressures, volumetric and gravimetric capacities) has been created, and specific tools have been developed to query the database. Indeed, the selection of the materials has been performed via an alternative database approach where the queries can be managed using a user-friendly tool, and potential materials can be selected based on any pool of desirable properties in quantitative terms. Essential information and characterization on theoretical and experimental data about these performing materials are provided and commented. As an example, in this paper, the case of clathrates hydrates is shown, and their potential impact is explored and characterized in this context, suggesting the most suitable synthesis processes.

A number of Gaussian basis sets has been studied for performance in density functional calculations of core electron binding energies and chemical shifts of the carbon, nitrogen, and oxygen nuclei in the first-row hydrides methane, ammonia, and water, and in glycine. The ultimate goal is to identify methods sufficiently accurate and efficient to aid analysis of experimental X-ray photoelectron spectra for amino acids, large polypeptides, and DNA nucleosides in various environments. Several combinations of density functionals and basis sets have been identified as promising for such calculations with average accuracy of 0.20 eV or better.

A number of density functionals are benchmarked for calculation of 1s core electron binding energies for carbon, nitrogen, and oxygen nuclei in glycine, and for comparison in the first-row hydrides methane, ammonia, and water. The goal is to establish methods having potential to aid the analysis of experimental X-ray photoelectron spectra on compounds such as amino acids, DNA nucleosides, and large polypeptides in various environments. Several promising density functionals are identified that can reproduce experimental results within 0.2 eV on average for the absolute binding energies and also for the intramolecular and intermolecular shifts in the studied molecules.

The formation of monocarbon cluster ions has been investigated by electron ionization mass spectrometry of cold helium nanodroplets doped with nitrogen/methane mixtures. Ion yields for two groups of clusters, CHmN2(+) or CHmN4(+), were determined for mixtures with different molecular ratios of CH4. The possible geometrical structures of these clusters were analyzed using electronic structure computations. Little correlation between the ion yields and the associated binding energies has been observed indicating that in most cases kinetic control is more important than thermodynamic control for forming the clusters.