1,721,003 research outputs found
Integrated experimental/computational approaches to characterize the systems formed by vanadium with proteins and enzymes
No full textDecoding the interactions of transition metal complexes with proteins is still an open challenge in many fields, like biology and medicinal chemistry, or in the design of de novo enzymes, including artificial metalloenzymes. Instrumental techniques like X-ray crystallography or nuclear magnetic resonance can provide an atomistic description of the systems, although their application is often not trivial. In this review, we illustrate how the integrated approach based on spectrometric and spectroscopic techniques with multilevel molecular modelling allows characterization of metallodrug-protein adducts at the molecular level. A series of applications are described, focusing on potential vanadium drugs, with a final generalization to other metals. The data provide a major proof-of-concept of the power of coupled experimental and theoretical methods for the rational design of new metallodrugs as well as for guiding a large number of fields of bioinorganic chemistry
Rationalizing the Decavanadate(V) and Oxidovanadium(IV) Binding to G-Actin and the Competition with Decaniobate(V) and ATP
Full text linkThe experimental data collected over the past 15 years on the interaction of decavanadate(V) (V10O286- V10), a polyoxometalate (POM) with promising anticancer and antibacterial action, with G-actin, were rationalized by using several computational approaches (docking, density functional theory (DFT), and molecular dynamics (MD)). Moreover, a comparison with the isostructural and more stable decaniobate(V) (Nb10O286- Nb10) was carried out. Four binding sites were identified, named α, β, γ, and δ, the site α being the catalytic nucleotide site located in the cleft of the enzyme at the interface of the subdomains II and IV. It was observed that the site α is preferred by V10, whereas Nb10 is more stable at the site β this indicates that, differently from other proteins, G-actin could contemporaneously bind the two POMs, whose action would be synergistic. Both decavanadate and decaniobate induce conformational rearrangements in G-actin, larger for V10 than Nb10. Moreover, the binding mode of oxidovanadium(IV) ion, VIVO2+, formed upon the reduction of decavanadate(V) by the -SH groups of accessible cysteine residues, is also found in the catalytic site α with (His161, Asp154) coordination; this adduct overlaps significantly with the region where ATP is bound, accounting for the competition between V10 and its reduction product VIVO2+ with ATP, as previously observed by EPR spectroscopy. Finally, the competition with ATP was rationalized: since decavanadate prefers the nucleotide site α, Ca2+-ATP displaces V10 from this site, while the competition is less important for Nb10 because thisPOM shows a higher affinity for β than for site α. Arelevant consequenceofthispaperisthatothermetallodrug-protein systems, intheabsenceorpresenceofeventualinhibitorsand/or competitionwithmoleculesoftheorganism, couldbestudiedwith thesameapproach, suggestingimportantelementsforanexplanation ofthebiologicaldataanda rationaldrugdesign
The binding modes of VIVO2+ions in blood proteins and enzymes
Full text linkThe binding modes of VIVO2+ ions to hemoglobin (Hb), human serum transferrin (hTf), immunoglobulin G (IgG), vanadium bromoperoxidase (VBrPO) and VIVO2+-substituted imidazoleglycerol-phosphatase dehydratase (IGPD) were determined by a combined approach of full DFT and MM techniques. These results reproduce and explain the experimental spectroscopic (EPR and ESEEM) data
Multiple and Variable Binding of Pharmacologically Active Bis(maltolato)oxidovanadium(IV) to Lysozyme
No full text: The interaction with proteins of metal-based drugs plays a crucial role in their transport, mechanism, and activity. For an active MLn complex, where L is the organic carrier, various binding modes (covalent and non-covalent, single or multiple) may occur and several metal moieties (M, ML, ML2, etc.) may interact with proteins. In this study, we have evaluated the interaction of [VIVO(malt)2] (bis(maltolato)oxidovanadium(IV) or BMOV, where malt = maltolato, i.e., the common name for 3-hydroxy-2-methyl-4H-pyran-4-onato) with the model protein hen egg white lysozyme (HEWL) by electrospray ionization mass spectrometry, electron paramagnetic resonance, and X-ray crystallography. The multiple binding of different V-containing isomers and enantiomers to different sites of HEWL is observed. The data indicate both non-covalent binding of cis-[VO(malt)2(H2O)] and [VO(malt)(H2O)3]+ and covalent binding of [VO(H2O)3-4]2+ and cis-[VO(malt)2] and other V-containing fragments to the side chains of Glu35, Asp48, Asn65, Asp87, and Asp119 and to the C-terminal carboxylate. Our results suggest that the multiple and variable interactions of potential VIVOL2 drugs with proteins can help to better understand their solution chemistry and contribute to define the molecular basis of the mechanism of action of these intriguing molecules
5,5′-Dibenzoimidazole as building block for a new 3D Co(II) coordination polymer: A combined EPR and DFT study using UB3LYP model
No full textA new Co(II) three-dimensional coordination polymer, [Co(L)(L')](n) (1) [where L = 5,5'-dibenzoimidazole, and L' = doubly deprotonated terephthalic acid] has been synthesized hydro(solvo)thermally and its molecular and crystal structure have been elucidated through single crystal X-ray diffraction analysis. Each Coal) ion displays a slightly distorted trigonal bipyramidal geometry, the apical positions being occupied by the nitrogen atoms of two symmetry-related dibenzoimidazole ligands, while the oxygen atoms from three distinct terephthalic acids are in the equatorial plane. Considering the Co2C2O6 dimeric moieties as nodes, and the ancillary ligands as connectors, the structure can be simplified as a 8-c uninodal net of the type bcu, body centered cubic, with point symbol 4(24).6(4) and vertex symbol [4.4.4.4.4.4.4.4.4.4.4.4.4(3).4(3).4(3).4(3).4(3).4(3).4(3).4(3).4(3).4(3).4(3).4(3).*.*.*.*]. The EPR spectra for 1 have been reported, showing g(parallel to) = 2.176 and g(perpendicular to) = 2.052 at RT (room temperature), and g(parallel to) = 2.172 and g(perpendicular to) = 2.060 at LNT (liquid nitrogen temperature). Finally, the electronic nature of the molecular geometry of 1 has been explored by DFT computation applying the UB3LYP/def2-TZVP level of theory, showing the energy difference between the high spin and low spin configurations. (C) 2019 Elsevier Ltd. All rights reserved
Synthesis, structural and DFT interpretation of a Schiff base assisted Mn(III) derivative
No full textA mononuclear MnIII derivative, [Mn(L)(SCN)(H2O)] (1) [where H2L = N,N′-bis(salicyaldehydene)-1,3-diaminopropan-2-ol] has been synthesized and systematically characterized. In 1, the central MnIII ion is linked to the NNOO donor atoms of the potentially binucleating precursor L2− and additionally coordinates one water molecule and the pseudohalide SCN−, thus yielding a distorted octahedral geometry. The UV–Vis spectra of 1 shows an intense band corresponding to a 5T2g − 5Eg transition at 545 nm; thus presuming the octahedral geometry around the Mn ion. The solid and solution EPR spectra of 1 have been simulated with an HP 53150A microwave frequency counter which has confirmed the +3 oxidation state of the metal ion. We have also conducted a DFT computational study which has confirmed that compound 1 self assembles into a two-dimensional network via O‒H⋯O, π–π, and unconventional C‒H ... π(SCN) interactions involving the π-system of the thiocyanate. The room temperature magnetic susceptibility of compound 1 has yielded an effective magnetic moment (μeff) value of 4.96 B.M
Interaction of the potent antitumoral compounds Casiopeinas® with blood serum and cellular bioligands
No full textCasiopeinas® are among the few CuII compounds patented for their antitumor activity, but their mode of action has not been fully elucidated yet. One of them, Cas II-gly, is formed by 4,7-dimethyl-1,10-phenanthroline (Me2phen) and glycinato (Gly). In blood and cells, Cas II-gly can keep its identity or form mixed species with serum or cytosol bioligands (bL or cL) with composition CuII–Me2phen–bL/cL, CuII–Gly–bL/cL, or CuII–bL/cL. In this study, the binding of Cas II-gly with low molecular mass bioligands of blood serum (citric, L-lactic acid, and L-histidine) and cytosol (reduced glutathione (GSH), reduced nicotinamide adenine dinucleotide (NADH), adenosine triphosphate (ATP), and L-ascorbic acid) was examined through the application of instrumental (ElectroSpray Ionization-Mass Spectrometry and Electron Paramagnetic Resonance) and computational (Density Functional Theory) methods. The results indicated that mixed species CuII–Me2phen–bL/cL are formed, with the bioligands replacing glycinato. The formation of these adducts may participate in the copper transport toward the target organs and facilitate the cellular uptake or, in constrast, preclude it. In the systems with GSH, NADH and L-ascorbate, a redox reaction occurs with the partial oxidation of cL to the corresponding oxidized form (GSSG, NAD+ and dehydroascorbate) which interact with CuII. Formed CuI ion does not give complexation reactions with reduced or oxidized form of bioligands for its ‘soft’ character and low affinity for oxygen and nitrogen donors compared to CuII. However, CuI could promote Fenton-like reactions with production of reactive oxygen species (ROS) related to the antitumor activity of Casiopeinas®
Temperature and solvent structure dependence of VO2+ complexes of pyridine-N-oxide derivatives and their interaction with human serum transferrin
No full textThe behaviour of the systems formed by VO2+, 2-hydroxypyridine-N-oxide (Hhpo) and 2-mercaptopyridine-N-oxide (Hmpo) was studied both in solution and in the solid state through the combined application of spectroscopic (EPR and UV-Vis spectroscopy) and DFT methods. The geometry of solid bis-chelated complexes [VOL2], with L = hpo and mpo, is square pyramidal, but it can change to cis-[VOL2S], where S is a solvent molecule, when these are dissolved in a coordinating solvent. The equilibrium between the square pyramidal and cis-octahedral forms is strongly affected by solvent and temperature. At room temperature, the predominant species is [VOL2], which gives a pink colour to the solutions; at lower temperatures, the equilibrium is shifted-partially or completely-toward the formation of cis-[VOL2S], which is green. In an acidic environment and in the presence of an excess of ligand, [VOL2] can transform into the tris-chelated complex [VL3](+), in which vanadium loses the oxido ligand and adopts a hexa-coordinated geometry intermediate between octahedral and trigonal prismatic. 1-Methylimidazole (1-MeIm), which represents a model for His-N coordination, forms mixed complexes with stoichiometry cis-[VOL2(1-MeIm)], occupying an equatorial position. In the ternary systems VO2+-Hhpo-hTf and VO2+-Hmpo-hTf at room temperature and pH 7.4, besides (VO)hTf and (VO)(2)hTf, the mixed species cis-VO(hpo)(2)(hTf) and VO(mpo)(hTf) are observed, with the equatorial binding of an accessible histidine residue. Finally, the contribution of the N-oxide group to (51)VA(z) and A(iso) hyperfine coupling constants, which can be important in the characterisation of similar species, is discussed
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