Are vanadium complexes druggable against the main protease Mpro of SARS-CoV-2? - A computational approach.

In silico techniques helped explore the binding capacities of the SARS-CoV-2 main protease (Mpro) for a series of metalloorganic compounds. Along with small size vanadium complexes a vanadium-containing derivative of the peptide-like inhibitor N3 (N-[(5-methylisoxazol-3-yl)carbonyl]alanyl-l-valyl-N1-((1R,2Z)-4-(benzyloxy)-4-oxo-1-{[(3R)-2-oxopyrrolidin-3-yl] methyl }but-2-enyl)-l-leucinamide) was designed from the crystal structure with PDB entry code 6LU7. On theoretical grounds our consensus docking studies evaluated the binding affinities at the hitherto known binding site of Chymotrypsin-like protease (3CLpro) of SARS-CoV-2 for existing and designed vanadium complexes. This main virus protease (Mpro) has a Cys-His dyad at the catalytic site that is characteristic of metal-dependent or metal-inhibited hydrolases. Mpro was compared to the human protein-tyrosine phosphatase 1B (hPTP1B) with a comparable catalytic dyad. HPTP1B is a key regulator at an early stage in the signalling cascade of the insulin hormone for glucose uptake into cells. The vanadium-ligand binding site of hPTP1B is located in a larger groove on the surface of Mpro. Vanadium constitutes a well-known phosphate analogue. Hence, its study offers possibilities to design promising vanadium-containing binders to SARS-CoV-2. Given the favourable physicochemical properties of vanadium nuclei, such organic vanadium complexes could become drugs not only for pharmacotherapy but also diagnostic tools for early infection detection in patients. This work presents the in silico design of a potential lead vanadium compound. It was tested along with 20 other vanadium-containing complexes from the literature in a virtual screening test by docking to inhibit Mpro of SARS-CoV-2.

Direct detection and characterization of bioinorganic peroxo moieties in a vanadium complex by 17O solid-state NMR and density functional theory.

Electronic and structural properties of short-lived metal-peroxido complexes, which are key intermediates in many enzymatic reactions, are not fully understood. While detected in various enzymes, their catalytic properties remain elusive because of their transient nature, making them difficult to study spectroscopically. We integrated 17O solid-state NMR and density functional theory (DFT) to directly detect and characterize the peroxido ligand in a bioinorganic V(V) complex mimicking intermediates non-heme vanadium haloperoxidases. 17O chemical shift and quadrupolar tensors, measured by solid-state NMR spectroscopy, probe the electronic structure of the peroxido ligand and its interaction with the metal. DFT analysis reveals the unusually large chemical shift anisotropy arising from the metal orbitals contributing towards the magnetic shielding of the ligand. The results illustrate the power of an integrated approach for studies of oxygen centers in enzyme reaction intermediates.

Oxidovanadium(IV/V) complexes as new redox mediators in dye-sensitized solar cells: a combined experimental and theoretical study.

Corrosiveness is one of the main drawbacks of using the iodide/triiodide redox couple in dye-sensitized solar cells (DSSCs). Alternative redox couples including transition metal complexes have been investigated where surprisingly high efficiencies for the conversion of solar to electrical energy have been achieved. In this paper, we examined the development of a DSSC using an electrolyte based on square pyramidal oxidovanadium(IV/V) complexes. The oxidovanadium(IV) complex (Ph4P)2[V(IV)O(hybeb)] was combined with its oxidized analogue (Ph4P)[V(V)O(hybeb)] {where hybeb(4-) is the tetradentate diamidodiphenolate ligand [1-(2-hydroxybenzamido)-2-(2-pyridinecarboxamido)benzenato}and applied as a redox couple in the electrolyte of DSSCs. The complexes exhibit large electron exchange and transfer rates, which are evident from electron paramagnetic resonance spectroscopy and electrochemistry, rendering the oxidovanadium(IV/V) compounds suitable for redox mediators in DSSCs. The very large self-exchange rate constant offered an insight into the mechanism of the exchange reaction most likely mediated through an outer-sphere exchange mechanism. The [V(IV)O(hybeb)](2-)/[V(V)O(hybeb)](-) redox potential and the energy of highest occupied molecular orbital (HOMO) of the sensitizing dye N719 and the HOMO of [V(IV)O(hybeb)](2-) were calculated by means of density functional theory electronic structure calculation methods. The complexes were applied as a new redox mediator in DSSCs, while the cell performance was studied in terms of the concentration of the reduced and oxidized form of the complexes. These studies were performed with the commercial Ru-based sensitizer N719 absorbed on a TiO2 semiconducting film in the DSSC. Maximum energy conversion efficiencies of 2% at simulated solar light (AM 1.5; 1000 W m(-2)) with an open circuit voltage of 660 mV, a short-circuit current of 5.2 mA cm(-2), and a fill factor of 0.58 were recorded without the presence of any additives in the electrolyte.

Chemical adaptability: the integration of different kinds of matter into giant molecular metal oxides.

Unique properties of the two giant wheel-shaped molybdenum-oxides of the type {Mo(154)}≡[{Mo(2)}{Mo(8)}{Mo(1)}](14) (1) and {Mo(176)}≡[{Mo(2)}{Mo(8)}{Mo(1)}](16) (2) that have the same building blocks either 14 or 16 times, respectively, are considered and show a "chemical adaptability" as a new phenomenon regarding the integration of a large number of appropriate cations and anions, for example, in form of the large "salt-like" {M(SO(4))}(16) rings (M = K(+), NH(4)(+)), while the two resulting {Mo(146)(K(SO(4)))(16)} (3) and {Mo(146)(NH(4)(SO(4)))(16)} (4) type hybrid compounds have the same shape as the parent ring structures. The chemical adaptability, which also allows the integration of anions and cations even at the same positions in the {Mo(4)O(6)}-type units of 1 and 2, is caused by easy changes in constitution by reorganisation and simultaneous release of (some) building blocks (one example: two opposite orientations of the same functional groups, that is, of H(2)O{Mo=O} (I) and O={Mo(H(2)O)} (II) are possible). Whereas Cu(2+) in [(H(4)Cu(II)(5))Mo(V)(28)Mo(VI)(114)O(432)(H(2)O)(58)](26-) (5 a) is simply coordinated to two parent O(2-) ions of {Mo(4)O(6)} and to two fragments of type II, the SO(4)(2-) integration in 3 and 4 occurs through the substitution of two oxo ligands of {Mo(4)O(6)} as well as two H(2)O ligands of fragment I. Complexes 3 and now 4 were characterised by different physical methods, for example, solutions of 4 in DMSO with sophisticated NMR spectroscopy (EXSY, DOSY and HSQC). The NH(4)(+) ions integrated in the cluster anion of 4 "communicate" with those in solution in the sense that the related H(+) ion exchange is in equilibrium. The important message: the reported "chemical adaptability" has its formal counterpart in solutions of "molybdates", which can form unique dynamic libraries containing constituents/building blocks that may form and break reversibly and can lead to the isolation of a variety of giant clusters with unusual properties.

Hydrophobic interactions and clustering in a porous capsule: option to remove hydrophobic materials from water.

The investigation of hydrophobic interactions under confined conditions is of tremendous interdisciplinary interest. It is shown that based on porous capsules of the type {(pentagon)}(12){(linker)}(30) ≡ {(Mo)Mo(5)(12){Mo(2)(ligand)}(30), which exhibit different hydrophobic interiors-achieved by coordinating related ligands to the internal sites of the 30 {Mo(2)} type linkers-there is the option to study systematically interactions with different uptaken/encapsulated hydrophobic molecules like long-chain alcohols as well as to prove the important correlation between the sizes of the related hydrophobic cavities and the option of water encapsulations. The measurements of 1D- and 2D-NMR spectra (e.g. ROESY, NOESY and HSQC) allowed the study of the interactions especially between encapsulated n-hexanol molecules and the hydrophobic interior formed by propionate ligands present in a new synthesized capsule. Future detailed studies will focus on interactions of a variety of hydrophobic species with different deliberately constructed hydrophobic capsule interiors.

Hexakis(tetra-aqua-sodium) deca-vanadate(V) dihydrate.

The title compound, {[Na(H(2)O)(4)](6)[V(10)O(28)]·2H(2)O}(n), crystallized from a H(2)O/THF/CH(3)CN solution (pH ca 6) containing equimolar amounts of NaVO(3) and N-(2-hydroxy-benz-yl)-N-(2-picol-yl)glycine. In the crystal structure, the deca-vanadate [V(10)O(28)](6-) anion ( symmetry) is coordinated, via four terminal oxide ligands of V centres, to two dinuclear [{Na(H(2)O)(3)}(2)(µ-H(2)O)(2)](2+) units. Inter-connection of these aquasodium-ion-sandwiched deca-vanadates to chains parallel to [001] is effected by µ-[{Na(H(2)O)(3)}(2)(µ-H(2)O)(2)](2+) units, bridging adjacent deca-vanadates via O=V. The structure is consolidated by an extensive network of O-H⋯O hydrogen bonds.

The trigonal-bipyramidal NO4 ligand set in biologically relevant vanadium compounds and their inorganic models.

In the present focused review, vanadate-dependent haloperoxidases and vanadate-inhibited enzymes which catalyze the hydrolysis of phosphoester bonds are addressed. In these systems, vanadate [HxVO4](3-x)(-) is covalently coordinated to the imidazolyl moiety of an active site histidine, with a geometrical arrangement close to a trigonal bipyramid. The resulting ligand set, NO4, and ligand arrangement provide peroxidase activity to the haloperoxidases and, to a certain extent, also to vanadate-inhibited phosphatases. The haloperoxidases are responsible for the oxidative halogenation of a variety of organic substrates. They are also active in other oxidation reactions relying on peroxide as the oxidant, such as the oxidative cyclizations of terpenes and, specifically, the oxygenation of (prochiral) sulfides to (chiral) sulfoxides. These functions can be modeled by vanadium complexes. Attracted interest is paid to {V(NO4)} complexes that are functional and structural models of the peroxidases. In the vanadate-inhibited phosphatases - structural analogs of the transition state in phosphoester hydrolysis by the native enzymes - the position of the axial histidine can also be taken by cysteinate or serinate, a fact which has implications for the insulin-mimetic potential of vanadate.

Cellular cation transport studied by 6/7Li and 23Na NMR in a porous Mo132 Keplerate type nano-capsule as model system.

Li+ ions can interplay with other cations intrinsically present in the intra- and extra-cellular space (i.e. Na+, K+, Mg2+ and Ca2+) have therapeutic effects (e.g. in the treatment of bipolar disorder) or toxic effects (at higher doses), likely because Li+ interferes with the intra-/extra-cellular concentration gradients of the mentioned physiologically relevant cations. The cellular transmembrane transport can be modelled by molybdenum-oxide-based Keplerates, i.e. nano-sized porous capsules containing 132 Mo centres, monitored through 6/7Li as well as 23Na NMR spectroscopy. The effects on the transport of Li+ cations through the 'ion channels' of these model cells, caused by variations in water amount, temperature, and by the addition of organic cationic 'plugs' and the shift reagent [Dy(PPP)2](7-) are reported. In the investigated solvent systems, water acts as a transport mediator for Li+. Likewise, the counter-transport (Li+/Na+, Li+/K+, Li+/Cs+ and Li+/Ca2+) has been investigated by 7Li NMR and, in the case of Li+/Na+ exchange, by 23Na NMR, and it has been shown that most (in the case of Na+ and K+, all (Ca2+) or almost none (Cs+) of the Li cations is extruded from the internal sites of the artificial cell to the extra-cellular medium, while Na+, K+ and Ca2+ are partially incorporated.

Modelling the sulfoxygenation activity of vanadate-dependent peroxidases.

Vanadate-dependent peroxidases contain, in their active center, vanadate covalently attached to histidine in an overall trigonal-bipyramidal array. We describe here the synthesis and characterization of optically active amino alcohols and their vanadium(V) complexes, and we show that the structural models of the active center thus obtained are also functional models for the sulfide-peroxidase activity of the enzyme in heterogeneous catalysis. The heterogeneous systems were obtained by immobilizing the complexes on silica gel and mesoporous silicas, and by aggregation. The following ligands, ligand precursors, and V compounds have been structurally characterized: (R)-(2-phenylethanol)-(R)-1-phenylethylamine (HL(A)), (R,R)-bis[2-phenyl(ethylmethylether)]ammonium chloride ([L(D)]+Cl(-)), the carbasilatranes (R,R)-methoxy{N,N',N''-2,2',3-[bis(1-phenylethanolato)propyl]amino}silane ((R,R)-Si(OMe)L(E)), (R,R)-methoxy-{N,N',N''-1,2',3-[(1-phenylethanolato)-(2-phenylethanolato)propyl]amino}silane ((R,R)-Si(OMe)L(E')), and [VO(L(F))(OSiMe2(t)Bu)], where H2L(F)=ethylbis(2-hydroxy-2-phenylethyl)amine.

Synthesis, characterisation and insulin-mimetic activity of oxovanadium(IV) complexes with amidrazone derivatives.

The complexation of VO(2+) ion by ten acetamidrazone and 2-phenylacetamidrazone derivatives (L) was studied. Sixteen novel VO(2+) complexes were synthesised and characterised through the combined application of analytical and spectroscopic (EPR (electron paramagnetic resonance), FT-IR and diffuse reflectance electronic absorption) techniques. Eight are 1:2 species of composition [VOL(2)]SO(4) x xH(2)O and eight are 1:1 species with formula [VOL(SO(4))](n) x xH(2)O. The experimental data suggest a bidentate coordination mode for L with the donor set formed by the imine nitrogen and the carbonyl oxygen. EPR spectra indicate a square-pyramidal geometry for the 1:1 complexes and a penta-coordinated geometry intermediate between the square-pyramid and the trigonal-bipyramid for the 1:2 species. The hyperfine coupling constant along z axis, A(z), of the 1:2 complexes exhibits a marked reduction with respect to the predicted value (approximately 148x10(-4)cm(-1) vs. approximately 170x10(-4)cm(-1)). IR spectroscopic evidence supports the presence of sulphate as a counter-ion in the 1:2, and as a bridging bidentate ligand in the 1:1 complexes. Insulin-mimetic tests on modified fibroblasts, based on a modified MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazoliumbromide) assay, performed on three of the bis-chelated and eight of the mono-chelated derivatives, indicate that they are biologically active. The similar hydro/lipophilicity and the lack of ligand substituents recognizable by cell membrane receptors prevent substantial differentiation in the insulin-mimetic action.

Perspectives for vanadium in health issues.

Vanadium is omnipresent in trace amounts in the environment, in food and also in the human body, where it might serve as a regulator for phosphate-dependent proteins. Potential vanadium-based formulations--inorganic and coordination compounds with organic ligands--commonly underlie speciation in the body, that is, they are converted to vanadate(V), oxidovanadium(IV) and to complexes with the body's own ligand systems. Vanadium compounds have been shown to be potentially effective against diabetes Type 2, malign tumors including cancer, endemic tropical diseases (such as trypanosomiasis, leishmaniasis and amoebiasis), bacterial infections (tuberculosis and pneumonia) and HIV infections. Furthermore, vanadium drugs can be operative in cardio- and neuro-protection. So far, vanadium compounds have not yet been approved as pharmaceuticals for clinical use.

Porous inorganic capsules in action: modelling transmembrane cation-transport parameter-dependence based on water as vehicle.

Insight into basic principles of cation transport through "molecular channels", and especially details of the related fundamental H2O vehicle function, could be obtained via7Li NMR studies of the Li+ uptake/release processes by the unique porous nanocapsule [{(MoVI)MoVI5O21(H2O)6}12{MoV2O4(SO4)}30]72- which behaves as a semi-permeable inorganic membrane open for H2O and small cations; channel traffic as well as internal cavity distribution processes show a strong dependence on "environmental" effects such as exerted by solvent properties, the amount of water present, and competing complexing ligands, and end up in a complex equilibrium situation as in biological leak channels.

Synthesis and insulin-mimetic activities of metal complexes with 3-hydroxypyridine-2-carboxylic acid.

Metal complexes of 3-hydroxypyridine-2-carboxylic acid (H(2)hpic), [Co(Hhpic)(2)(H(2)O)(2)] (1), [Fe(Hhpic)(2)(H(2)O)(2)] (2), [Zn(Hhpic)(2)(H(2)O)(2)] (3), [Mn(Hhpic)(2)(H(2)O)(2)] (4), and [Cu(Hhpic)(2)] (5) have been synthesized and characterized by mass spectrometry, elemental analysis, magnetic susceptibility, infrared, electronic absorption and electron paramagnetic resonance (EPR) spectroscopies. The solid-state structure of 1 has been established by X-ray crystallography. The EPR spectra of 4 and 5 displayed six and four-line hyperfine splitting patterns, respectively, due to coupling of the unpaired electron with the (55)Mn (I=5/2) nucleus and the (63)Cu (I=3/2) nucleus. In the EPR spectrum of 5, an additional five-line super-hyperfine splitting pattern was observed at 77 K, caused by additional interaction of the unpaired electron with ligand nitrogen atoms (I=1), indicating that the structure of 5 was retained in dimethyl sulfoxide solution. The insulin-mimetic activity of these complexes was evaluated by means of in vitro measurements of the inhibition of free fatty acid (FFA) release from epinephrine-treated, isolated rat adipocytes. Complex 5 was found to exhibit the most potent insulin-mimetic activity among the complexes examined in this study.

The (biological) speciation of vanadate(V) as revealed by (51)V NMR: A tribute on Lage Pettersson and his work.

Four decades of research carried out by Lage Pettersson, his group and his coworkers are reviewed, research that has been directed predominantly towards the speciation of vanadate and systems containing, along with vanadate and co-reactants such as phosphate and peroxide, biologically relevant organics. In particular, those organics have been addressed that either are (potential) ligands for vanadate-derived coordination compounds generated at physiological conditions and/or function as constituents in medicinally interesting oxidovanadium compounds. Examples for molecules introduced in the context of the physiological vanadate-ligand interaction include the dipeptides Pro-Ala, Ala-Gly, Ala-His and Ala-Ser, the serum constituents lactate and citrate, and the nucleobases adenosine and uridine. The speciation in the vanadate-picolinate and vanadate-maltol systems is geared towards insulin-enhancing vanadium drugs. The speciation as a function of pH, ionic strength and the concentration of vanadate and the ligand(s) is based on potentiometric and (51)V NMR investigations, a methodical combination that allows reliable access to composition, formation constants and, to some extent, also structural details for the manifold of species present in aqueous media at physiological pH and beyond. The time frame 1971 to 2014 is reviewed, emphasizing the interval 1985 to 2006, and thus focusing on biologically interesting vanadium systems. Figurative representations from the original literature have been included.

The role of vanadium in biology.

Vanadium is special in at least two respects: on the one hand, the tetrahedral anion vanadate(v) is similar to the phosphate anion; vanadate can thus interact with various physiological substrates that are otherwise functionalized by phosphate. On the other hand, the transition metal vanadium can easily expand its sphere beyond tetrahedral coordination, and switch between the oxidation states +v, +iv and +iii in a physiological environment. The similarity between vanadate and phosphate may account for the antidiabetic potential of vanadium compounds with carrier ligands such as maltolate and picolinate, and also for vanadium's mediation in cardiovascular and neuronal defects. Other potential medicinal applications of more complex vanadium coordination compounds, for example in the treatment of parasitic tropical diseases, may also be rooted in the specific properties of the ligand sphere. The ease of the change in the oxidation state of vanadium is employed by prokarya (bacteria and cyanobacteria) as well as by eukarya (algae and fungi) in respiratory and enzymatic functions. Macroalgae (seaweeds), fungi, lichens and Streptomyces bacteria have available haloperoxidases, and hence enzymes that enable the 2-electron oxidation of halide X(-) with peroxide, catalyzed by a Lewis-acidic V(V) center. The X(+) species thus formed can be employed to oxidatively halogenate organic substrates, a fact with implications also for the chemical processes in the atmosphere. Vanadium-dependent nitrogenases in bacteria (Azotobacter) and cyanobacteria (Anabaena) convert N2 + H(+) to NH4(+) + H2, but are also receptive for alternative substrates such as CO and C2H2. Among the enigmas to be solved with respect to the utilization of vanadium in nature is the accumulation of V(III) by some sea squirts and fan worms, as well as the purport of the nonoxido V(IV) compound amavadin in the fly agaric.

Structural models for the reduced form of vanadate-dependent peroxidases: vanadyl complexes with bidentate chiral Schiff base ligands.

The penta-coordinated vanadyl complexes [VO(ON)(2)] have been obtained by reaction between [VOX(2)] (X = acetylacetonate or chloride) and the Schiff base ligands HON = (R)-sal-am, (R)-Clsal-am and (S)-naph-am, where sal and naph are the salicylidene and naphthalidene moieties, and am derives from phenylethylamine. The three complexes and the ligand (R)-Clsal-am have been structurally characterized. The geometry of the complexes is in-between trigonal-bipyramidal (with the two imine functions in the axis) and square-pyramidal; tau values range from 0.66 to 0.44. Structural and EPR (electron paramagnetic resonance) features are in accord with the coordination environment proposed for the inactive, reduced (V(IV)) form of the bromoperoxidase from the marine brown alga Ascophyllum nodosum.

Interactions of oxovanadium(IV) and the quinolone family member--ciprofloxacin.

The interactions of quinolone ciprofloxacin (cfH) and oxovanadium(IV) were studied by various methods. Green crystals of a complex [V(IV)O(cf)(2)(H(2)O)] were isolated and the molecular connectivities established, although the crystal structure was not perfectly refined due to the instability of the crystals. Based on a plausible interpretation of the data sets, two cf anions bidentately coordinate to a vanadyl cation through carboxylate and carbonyl oxygen atoms; in addition, there is a water molecule in the coordination sphere. Solution techniques (cyclic voltammetry, electronic and electron paramagnetic resonance spectroscopy, potentiometric measurements) confirmed the presence of various species in the solution, the composition of which strongly depends on the conditions in the system. The antibacterial activity of the complex against various microorganisms was tested and it was established that its activity is similar to that of free ciprofloxacin.

The future of/for vanadium.

Vanadium compounds are stored or employed by several groups of bacterial and eukaryotic organisms. Two types of vanadium-dependent enzymes have so far been characterised: vanadate-dependent haloperoxidases from fungi, lichens, marine macroalgae and Streptomyces bacteria, and vanadium nitrogenases in proteo- and cyanobacteria. Several bacterial strains can employ vanadate(V) as an external electron acceptor in respiration, reducing vanadate to VO(2+) and thus contributing to the mineralisation of vanadium and to the detoxification of vanadate-contaminated water. Amanita mushrooms and many sea squirts accumulate vanadium, without the importance of this practise being well understood. Further, the analogy between vanadate and phosphate implicates an interference of vanadate with metabolic processes involving phosphate, suggesting a regulatory role for vanadate in most if not all organisms, including humans, but also hinting at toxic effects at unphysiologically high vanadate concentrations. The antidiabetic effect of vanadium compounds is probably related to the phosphate-vanadate antagonism, as is the potentiality of vanadate in the amelioration of cardiovascular affliction. The anti-cancer action of vanadium compounds and their in vitro activity towards the protozoa causing amoebiasis, leishmaniasis and Chagas' disease again may be rooted in the intervention of vanadate with the activity of phosphatases and kinases. In addition, most likely the ability of vanadate(V) and oxidovanadium(IV) to regulate the cellular production of reactive oxygen species comes in, thus influencing cellular signalling. Future developments of vanadium chemistry are likely to emphasize topics related to biological, environmental and medicinal aspects. Condensation of monovanadate results in the formation of oligovanadates, polyvanadates and finally colloidal and solid vanadium oxides that, in part, convey bio-mimetic functions comparable to those of simple vanadate, including its catalytic potential as an active centre in haloperoxidases and the lethal action against viruses, bacteria and protozoan parasites. Decavanadate has been shown to be stabilised by docking to proteins, and by integration into nanoscopic water pools of intracellular compartments, modelled by reverse micelles. The well established and approved use of vanadium oxides in, amongst other applications, catalysis has been recently impacted by the elucidation of the active surface species--VO(x)--of catalysts based on mixed vanadium oxides, and vanadium oxides on supports. Finally, materials based on vanadium oxides and vanadates play an increasingly important role as cathode materials in high density lithium batteries. An example is Ag2VO2PO4, which, in the discharge process, is reduced to Li(3.2)VO2PO4 and Ag. Oncoming developments in vanadium chemistry thus include oxide-based materials.