Validation and Applications of Protein-Ligand Docking Approaches Improved for Metalloligands with Multiple Vacant Sites

Altres ajuts: COST Action CM1306Decoding the interaction between coordination compounds and proteins is of fundamental importance in biology, pharmacy, and medicine. In this context, protein-ligand docking represents a particularly interesting asset to predict how small compounds could interact with biomolecules, but to date, very little information is available to adapt these methodologies to metal-containing ligands. Here, we assessed the predictive capability of a metal-compatible parameter set for the docking program GOLD for metalloligands with multiple vacant sites and different geometries. The study first presents a benchmark of 25 well-characterized X-ray metalloligand-protein adducts. In 100% of the cases, the docking solutions are superimposable to the X-ray determination, and in 92% the value of the root-mean-square deviation between the experimental and calculated structures is lower than 1.5 Å. After the validation step, we applied these methods to five case studies for the prediction of the binding of pharmacological active metal species to proteins: (i) the anticancer copper(II) complex [Cu II (Br)(2-hydroxy-1-naphthaldehyde benzoyl hydrazine)(indazole)] to human serum albumin (HSA); (ii) one of the active species of antidiabetic and antitumor vanadium compounds, V IV O 2+ ion, to carboxypeptidase; (iii) the antiarthritic species [Au I (PEt 3 )] + to HSA; (iv) the antitumor oxaliplatin to ubiquitin; (v) the antitumor ruthenium(II) compound RAPTA-PentaOH to cathepsin B. The calculations suggested that the binding modes are in good agreement with the partial information retrieved from spectroscopic and spectrometric analysis and allowed us, in certain cases, to propose additional hypotheses. This method is an important update in protein-metalloligand docking, which could have a wide field of application, from biology and inorganic biochemistry to medicinal chemistry and pharmacology

Influence of temperature on the equilibria of oxidovanadium(IV) complexes in solution.

The equilibria at different temperatures of VIVOL2complexes were investigated in order to elucidate their interaction with proteins

End-to-end thiocyanato-bridged helical chain polymer and dichlorido-bridged copper(II) complexes with a hydrazone ligand: synthesis, characterisation by electron paramagnetic resonance and variable- temperature magnetic studies, and inhibitory effects on human colorectal carcinoma cells

The reactions of the tridentate hydrazone ligand, N’-[1-(pyridin-2-yl)ethylidene]acetohydrazide (HL), obtained by condensation of 2-acetylpyridine with acetic hyadrazide, with copper nitrate trihydrate in the presence of thiocyanate, or with CuCl2 produce two distinct coordination compounds, namely a one-dimensional helical coordination chain of [CuL(NCS)]n (1) units, and a doubly chlorido-bridged dinuclear complex [Cu2L2Cl2] (2) (where L=CH3C(O)=N − N=CCH3C5H4N). Single-crystal X-ray structural determination studies reveal that in complex 1, a deprotonated hydrazone ligand L- coordinates a copper(II) ion that is bridged to two neighbouring metal centres by SCN- anions, generating a one-dimensional helical coordination chain. In complex 2, two symmetry-related, adjacent copper(II) coordination entities are doubly chlorido-bridged, producing a dicopper entity with a Cu···Cu distance of 3.402 (1). The two coordination compounds have been fully characterised by elemental analysis, spectroscopic techniques including IR, UV– vis and electron paramagnetic resonance, and variable-temperature magnetic studies. The biological effects of 1 and 2 on the viability of human colorectal carcinoma cells (COLO-205 and HT-29) were evaluated using an MTT assay, and the results indicate that these complexes induce a decrease in cell-population growth of human colorectal carcinoma cells with apoptosis

DFT Protocol for EPR prediction of paramagnetic Cu(II) complexes and application to protein binding sites

With the aim to provide a general protocol to interpret electron paramagnetic resonance (EPR) spectra of paramagnetic copper(II) coordination compounds, density functional theory (DFT) calculations of spin Hamiltonian parameters g and A for fourteen Cu(II) complexes with different charges, donor sets, and geometry were carried out using ORCA software. The performance of eleven functionals was tested, and on the basis of the mean absolute percent deviation (MAPD) and standard deviation (SD), the ranking of the functionals for Az is: B3LYP > B3PW91 ~ B3P86 > PBE0 > CAM-B3LYP > TPSSh > BH and HLYP > B2PLYP > MPW1PW91 > ω-B97x-D » M06; and for gz is: PBE0 > BH and HLYP > B2PLYP > ω-B97x-D > B3PW91~B3LYP~B3P86 > CAM-B3LYP > TPSSh~MPW1PW91 » M06. With B3LYP the MAPD with respect to A exp tl z is 8.6% with a SD of 4.2%, while with PBE0 the MAPD with respect to g exp tl z is 2.9% with a SD of 1.1%. The results of the validation confirm the fundamental role of the second order spin-orbit contribution to Az. The computational procedure was applied to predict the values of gz and Az of the adducts formed by Cu(II) with albumin and two fragments of prion protein, 106-126 and 180-193

Naringenin Schiff base: antioxidant activity, acid–base profile, and interactions with DNA

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Interaction of Vanadium(IV) Species with Ubiquitin : A Combined Instrumental and Computational Approach

Altres ajuts: COST Action CM1306The interaction of VIVO2+ ion and five VIVOL2 compounds with potential pharmacological application, where L indicates maltolate (ma), kojate (koj), acetylacetonate (acac), 1,2-dimethyl-3-hydroxy-4(1H)-pyridinonate (dhp), and l-mimosinate (mim), with ubiquitin (Ub) was studied by EPR, ESI-MS, and computational (docking and DFT) methods. The free metal ion VIVO2+ interacts with Glu, Asp, His, Thr, and Leu residues, but the most stable sites (named 1 and 2) involve the coordination of (Glu16, Glu18) and (Glu24, Asp52). In the system with VIVOL2 compounds, the type of binding depends on the vanadium concentration. When the concentration is in the mM range, the binding occurs with cis-VOL2(H2O), L = ma, koj, dhp, and mim, or with VO(acac)2: in the first case, the equatorial coordination of His68, Glu16, Glu18, or Asp21 residues yields species with formula n[VOL2]-Ub where n = 2-3, while with VO(acac)2 only noncovalent surface interactions are revealed. When the concentration of V is on the order of micromolar, themono-chelated species VOL(H2O)2+ with L = ma, koj, acac, dhp, and mim, favored by the hydrolysis, interact with Ub, and adducts with composition n[VOL]-Ub (n = 1-2) are observed with the contemporaneous coordination of (Glu18, Asp21) or (Glu16, Glu18), and (Glu24, Asp52) or (Glu51, Asp52) donors. The results of this work suggest that the combined application of spectroscopic, spectrometric, and computational techniques allow the complete characterization of the ternary systems formed by a V compound and a model protein such as ubiquitin. The same approach can be applied, eventually changing the spectroscopic/spectrometric techniques, to study the interaction of other metal species with other proteins

quantitative prediction of electronic absorption spectra of copper ii bioligand systems validation and applications

Abstract The visible region of the electronic absorption spectra of Cu(II) complexes was studied by time-dependent density functional theory (TD-DFT). The performance of twelve functionals in the prediction of absorption maxima (λmax) was tested on eleven compounds with different geometry, donors and charge. The ranking of the functionals for λmax was determined in terms of mean absolute percent deviation (MAPD) and standard deviation (SD) and it is as follows: BHandHLYP > M06 ≫ CAM-B3LYP ≫ MPW1PW91 ~ B1LYP ~ BLYP > HSE06 ~ B3LYP > B3P86 ~ ω-B97x-D ≫ TPSSh ≫ M06-2X (MAPD) and BHandHLYP > M06 ~ HSE06 > ω-B97x-D ~ CAM-B3LYP ~ MPW1PW91 > B1LYP ~ B3LYP > B3P86 > BLYP ≫ TPSSh ≫ M06-2X (SD). With BHandHLYP functional the MAPD is 3.1% and SD is 2.3%, while with M06 the MAPD is 3.7% and SD is 3.7%. The protocol validated in the first step of the study was applied to: i) calculate the number of transitions in the spectra and relate them to the geometry of Cu(II) species; ii) determine the coordination of axial water(s); iii) predict the electronic spectra of the systems where Cu(II) is bound to human serum albumin (HSA) and to the regions 94–97 and 108–112 of prion protein (PrP). The results indicate that the proposed computational protocol allows a successful prediction of the electronic spectra of Cu(II) species and to relate an experimental spectrum to a specific structure

Decoding Surface Interaction of VIVO Metallodrug Candidates with Lysozyme

Altres ajuts: COST Action CM1306The interaction of metallodrugs with proteins influences their transport, uptake, and mechanism of action. In this study, we present an integrative approach based on spectroscopic (EPR) and computational (docking) tools to elucidate the noncovalent binding modes of various VIVO compounds with lysozyme, a prototypical model of protein receptor. Five VIVO-flavonoid drug candidates formed by quercetin (que), morin (mor), 7,8-dihydroxyflavone (7,8-dhf), chrysin (chr), and 5-hydroxyflavone (5-hf) - effective against several osteosarcoma cell lines - and two benchmark VIVO species of acetylacetone (acac) and catechol (cat) are evaluated. The results show a gradual variation of the EPR spectra at room temperature, which is associated with the strength of the interaction between the square pyramidal complexes [VOL2] and the surface residues of lysozyme. The qualitative strength of the interaction from EPR is [VO(que)2]2- ? [VO(mor)2] > [VO(7,8-dhf)2]2- > [VO(chr)2] ? [VO(5-hf)2] > [VO(acac)2] ? [VO(cat)2]2-. This observation is compared with protein-ligand docking calculations with GOLD software examining the GoldScore scoring function (F), for which hydrogen bond and van der Waals contact terms have been optimized to account for the surface interaction. The best predicted binding modes display an energy trend in good agreement with the EPR spectroscopy. Computation indicates that the strength of the interaction can be predicted by the Fmax value and depends on the number of OH or CO groups of the ligands that can interact with different sites on the protein surface and, more particularly, with those in the vicinity of the active site of the enzyme. The interaction strength determines the type of signal revealed (rigid limit, slow tumbling, or isotropic) in the EPR spectra. Spectroscopic and computational results also suggest that there are several sites with comparable binding energy, with the V complexes distributing among them in a bound state and in aqueous solution in an unbound state. This kind of study and analysis could be generalized to determine the noncovalent binding modes of a generic metal species with a generic protein

Prediction of the interaction of metallic moieties with proteins : An update for protein-ligand docking techniques

Altres ajuts: COST Action CM1306In this article, we present a new approach to expand the range of application of protein-ligand docking methods in the prediction of the interaction of coordination complexes (i.e., metallodrugs, natural and artificial cofactors, etc.) with proteins. To do so, we assume that, from a pure computational point of view, hydrogen bond functions could be an adequate model for the coordination bonds as both share directionality and polarity aspects. In this model, docking of metalloligands can be performed without using any geometrical constraints or energy restraints. The hard work consists in generating the convenient atom types and scoring functions. To test this approach, we applied our model to 39 high-quality X-ray structures with transition and main group metal complexes bound via a unique coordination bond to a protein. This concept was implemented in the protein-ligand docking program GOLD. The results are in very good agreement with the experimental structures: the percentage for which the RMSD of the simulated pose is smaller than the X-ray spectra resolution is 92.3% and the mean value of RMSD is < 1.0 Å. Such results also show the viability of the method to predict metal complexes-proteins interactions when the X-ray structure is not available. This work could be the first step for novel applicability of docking techniques in medicinal and bioinorganic chemistry and appears generalizable enough to be implemented in most protein-ligand docking programs nowadays available

Chelating properties of EDTA-type ligands containing six-membered backbone ring toward copper ion:Structure, EPR and TD-DFT evaluation

The P-APC ligands (EDTA-like aminopolycarboxylate ligands comprising 1,3-propanediamine backbone) H(4)pdta, H(4)pd(3)ap, H(4)pddadp and H(4)pdtp (H(4)pdta = 1,3-propanediamine-N,N,N',N'-tetraacetatic acid; H(4)pd(3)ap = 1,3-propanediamine-N,N,N'-triacetic-N'-3-propionic acid; H4pddadp = 1,3-propanediamine-N,N'-diacetatic-N,N'-di-3-propionic acid; H(4)pdtp = 1,3-propanediaminetetra-3-propionic acid) were investigated. The chelating ligands coordinate to copper(II) via five or six donor atoms affording distorted trigonal-bipyramid and octahedral structures that were verified by X-ray analysis for Ba[Cu(pd(3)ap)]center dot 6H(2)O (1) and trans(O-6)-Ba[Cu(pddadp)]center dot 8H(2)O (2) complexes respectively. The impact of counter-ions on the P-APC complexes is shown in detail together with the analysis of another strain parameters. EPR spectral results confirm the penta-coordination of 1 and hexa-coordination of 2 in aqueous solution, even if several Cu(II) species with different protonation degree exist as a function of pH, and indicate that a hexa-coordinated structure is favored when the two axial COO- donors close five-membered chelate rings. We also present here the results of molecular mechanics (LFMM) calculations based on our previously-developed force field along with results of DFT (Density Functional Theory). On the basis of extensive DFT and TD-DFT calculations the B1LYP/6-311++G(d,p) level has been seen as an accurate theory for calculating and predicting the UVVis spectra in case of copperP-APC compounds. (C) 2016 Elsevier Ltd. All rights reserved