MPO Inhibitors Selected by Virtual Screening

The hemeprotein myeloperoxidase (MPO) participates in innate immune defense through its ability to generate potent microbicidal oxidants. However, these oxidants are also key mediators of the tissue damage associated with many inflammatory diseases. Thus, there is considerable interest in developing therapeutically useful MPO inhibitors. Here, we used structure-based drug design (SBDD) and ligand-based drug design (LBDD) to select for potentially new and selective MPO inhibitors. A pharmacophore model was developed based on the crystal structure of human MPO in complex with salicylhydroxamic acid (SHA), a known inhibitor of the enzyme. The pharmacophore model was used to screen the ZINC database for potential ligands, which were further filtered on the basis of their physical-chemical properties and docking score. The filtered compounds were visually inspected, and nine were purchased for experimental studies. Surprisingly, almost all of the selected compounds belonged to the aromatic hydrazide class, which had been previously described as MPO inhibitors. The compounds selected by virtual screening were shown to inhibit the chlorinating activity of MPO; the top four compounds displayed IC(50) values ranging from 1.0 to 2.8 mM. MPO inactivation by the most effective compound was shown to be irreversible. Overall, our results show that SBDD and LBDD may be useful for the rational development of new MPO inhibitors.

Isomers on the [H, S(2), Cl] potential energy surface: A high level investigation

This study reports a systematic state-of-the-art characterization of new sulfur-chlorine species on the [H, S(2), Cl] potential energy surface. Coupled cluster theory singles and doubles with perturbative contributions of connected triples, using the series of correlation consistent basis sets with extrapolations to the complete basis set limit (CBS), were employed to quantify the energetic quantities involved in the isomerization processes on this surface. The structures and vibrational frequencies are unique for some species and represent the most accurate investigation to date. These molecules are potentially a new route of coupling the sulfur and chlorine chemistries in the atmosphere, and conditions of high concentration of H(2)S (HS) like in volcanic eruptions might contribute to their formation. Also an assessment of the MP2/CBS approach relative to CCSD(T)/CBS provides insights on the expected performance of MP2/CBS on the characterization of polysulfides, and also of more complex systems containing disulfide bridges. (C) 2009 Elsevier B.V. All rights reserved.

Solvatochromism in Binary Mixtures: First Report on a Solvation Free Energy Relationship between Solvent Exchange Equilibrium Constants and the Properties of the Medium

We have employed UV-vis spectroscopy in order to investigate details of the solvation of six solvatochromic indicators, hereafter designated as ""probes"", namely, 2,6-diphenyl-4-(2,4,6-triphenylpyridinium-1-yl) phenolate (RB); 4-[(E)-2-(1-methylpyridinium-4-yl)ethenyl] phenolate, MePM; 1-methylquinolinium-8-olate, QB; 2-bromo-4-[(E)-2-(1-methylpyridinium-4-yl)ethenyl] phenolate, MePMBr, 2,6-dichloro-4-(2,4,6-triphenylpyridinium-1-yl) phenolate (WB); and 2,6-dibromo-4-[(E)-2-(1-methylpyridinium-4-yl)ethenyl] phenolate, MePMBr,, respectively. These can be divided into three pairs, each includes two probes of similar pK(a) in water and different lipophilicity. Solvation has been studied in binary mixtures, BMs, of water, W, with 12 protic organic solvents, S, including mono- and bifunctional alcohols (2-alkoxyethanoles, unsaturated and chlorinated alcohols). Each medium was treated as a mixture of S, W, and a complex solvent, S-W, formed by hydrogen bonding. Values of lambda(max) (of the probe intramolecular charge transfer) were converted into empirical polarity scales, E(T)(probe) in kcal/mol, whose values were correlated with the effective mole fraction of water in the medium, chi w(effective). This correlation furnished three equilibrium constants for the exchange of solvents in the probe solvation shell; phi(W/S) (W substitutes S): phi(S-W/W) (S-W substitutes W), and phi(S-W/S) (S-W substitutes S), respectively. The values of these constants depend on the physicochemical properties of the probe and the medium. We tested, for the first time, the applicability of a new solvation free energy relationship: phi = constant + a alpha(BM) + b beta(BM) + s(pi*(BM) + d delta) + p log P(BM), where a, b, s, and p are regression coefficients alpha(BM), beta(BM), and pi*(BM) are solvatochromic parameters of the BM, delta is a correction term for pi*, and log P is an empirical scale of lipophilicity. Correlations were carried out with two-, three-, and four-medium descriptors. In all cases, three descriptors gave satisfactory correlations; use of four parameters gave only a marginal increase of the goodness of fit. For phi(W/S), the most important descriptor was found to be the lipophilicity of the medium; for phi(S-W/W) and phi(S-W/S), solvent basicity is either statistically relevant or is the most important descriptor. These responses are different from those of E(T)(probe) of many solvatochromic indicators in pure solvents, where the importance of solvent basicity is usually marginal, and can be neglected.

First study on the thermo-solvatochromism in aqueous 1-(1-butyl)-3-methylimidazolium tetrafluoroborate: A comparison between the solvation by an ionic liquid and by aqueous alcohols

The thermo-solvatochrornic behaviors of 2,6-diphenyl-4-(2,4,6-triphenylpyridinium-1-yl) phenolate, RB; 2,6-dichloro-4-(2,4,6-triphenyloyridinium-1-yl) phenolate, WB; 2,6-dibromo-4-[(E)-2-(1-methylpyridinium-4-yl)ethenyl] phenolate, MePMBr(2); 2,6-dibromo-4-[(E)-2-(1-n-octylpyridinium-4-yl)ethenyl] phenolate, OcPMBr(2), have been investigated in binary mixtures of the ionic liquid, IL, 1-(1-butyl)-3-methylimidazolium tetrafluorborate, [BuMeIm][BF(4)], and water (W), in the temperature range from 10 to 60 degrees C. Plots of the empirical solvent polarities, ET (probe) in kcal mol(-1), versus the mole fraction of water in the binary mixture, chi(w) showed nonlinear, i.e., nonideal behavior. Solvation by these IL-W mixtures shows the following similarities to that by aqueous aliphatic alcohols: The same solvation model can be conveniently employed to treat the data obtained; it is based on the presence in the system-bulk medium and probe solvation shell of IL, W, and the ""complex"" solvent 1:1 IL-W. The origin of the nonideal solvation behavior appears to be the same, preferential solvation of the probe, in particular by the complex solvent. The strength of association of the IL-W complex, and the polarity of the IL are situated between the corresponding values of aqueous methanol and aqueous ethanol. Temperature increase causes a gradual desolvation of all probes employed. A difference between solvation by IL-W and aqueous alcohols is that probe-solvent hydrophobic interactions appear to play a minor role in case of the former mixture, probably because solvation is dominated by hydrogen-bonding and Coulombic interactions between the ions of the IL and the zwitterionic probes.

Probing the dependence of the properties of cellulose acetates and their films on the degree of biopolymer substitution: use of solvatochromic indicators and thermal analysis

Although cellulose acetates, CAs, are extensively employed there is scant information about the systematic dependence of their properties on their degree of substitution, DS; this is the subject of the present work. Nine CAs samples, DS from 0.83 to 3.0 were synthesized; their films were prepared. The following solvatochromic probes have been employed in order to determine the empirical polarity, E (T)(33); ""acidity, alpha""; ""basicity, beta"", and ""dipolarity/polarizability, pi*"" of the casted films: 2,6-dichloro-4-(2,4,6-triphenyl-pyridinium-1-yl) phenolate, WB; 4-nitroaniline; 4-nitroanisole; 4-nitro-N,N-dimethylaniline; 2,6-diphenyl-4-(2,4,6-triphenyl-pyridinium-1-yl)phenolate, RB. Additionally, two systems, ethanol plus ethyl acetate (EtOH-EtAc), and cellulose plus cellulose triacetate, CTA, were employed as models for CAs of different DS. Regarding the model systems, the following was observed: (i) For EtOH-EtAc, the dependence of all solvatochromic parameters on the ""equivalent-DS"" of the binary mixture was non-linear because of preferential solvation; (ii) The dependence of E (T)(33) on equivalent DS of the cellulose-CTA films is linear, but the slope is smaller than that of the corresponding plot for CAs. This is attributed to the more efficient hydrogen bonding in the model system, a conclusion corroborated by IR measurements. The dependence of solvatochromic parameters of CAs on their DS is described by the simple equations; a consequence of the substitution of the OH by the ester group. The thermal properties of bulk CAs samples were investigated by DSC and TGA; their dependence on DS is described by simple equations. The relevance of these data to the processing and applications of CAs is briefly discussed.

Micellar properties of surface active ionic liquids: A comparison of 1-hexadecyl-3-methylimidazolium chloride with structurally related cationic surfactants

Ionic liquids, ILs, carrying long-chain alkyl groups are surface active, SAIIs. We investigated the micellar properties of the SAIL 1-hexadecyl-3-methylimidazolium chloride, C(16)MeImCl, and compared the data with 1-hexadecylpyridinium chloride, C(16)PYCl, and benzyl (3-hexadecanoylaminoethyl)dimethylammonium chloride, C(15)AEtBzMe(2)Cl. The properties compared include critical micelle concentration, cmc; thermodynamic parameters of micellization; empirical polarity and water concentrations in the interfacial regions. In the temperature range from 15 to 75 degrees C, the order of cmc in H(2)O and in D(2)O is C(16)PYCl > C(16)MeImCl > C(15)AEtBzMe(2)Cl. The enthalpies of micellization, Delta H(mic)(degrees), were calculated indirectly from by use of the van`t Hoff treatment; directly by isothermal titration calorimetry, ITC. Calculation of the degree of counter-ion dissociation, alpha(mic), from conductivity measurements, by use of Evans equation requires knowledge of the aggregation numbers, N(agg), at different temperatures. We have introduced a reliable method for carrying out this calculation, based on the volume and length of the monomer, and the dependence of N(agg) on temperature. The N(agg) calculated for C(16)PyCl and C(16)MeImCl were corroborated by light scattering measurements. Conductivity- and ITC-based Delta H(mic)(degrees) do not agree; reasons for this discrepancy are discussed. Micelle formation is entropy driven: at all studied temperatures for C(16)MeImCl; only up to 65 degrees C for C(16)PyCl; and up to 55 degrees C for C(15)AEtBzMe(2)Cl. All these data can be rationalized by considering hydrogen-bonding between the head-ions of the monomers in the micellar aggregate. The empirical polarities and concentrations of interfacial water were found to be independent of the nature of the head-group. (C) 2010 Elsevier Inc. All rights reserved.

Ion pair stabilization effects on a series of procaine structural analogs

In this work, a series of 10 structural procaine analogs have been synthesized in order to investigate the structural features affecting the stability of ion pair formation and its influence on the lipophilicity of ionizable compounds. The structural variation within this series was focused on the terminal nitrogen substituents and on the intermediate chain linkage nature. The hydrophobic parameters log P(n) and log P(i) (partition coefficient of the neutral and ionic species, respectively), as well as the ionization constants pK(a) and pK(a)(oct), were obtained from log D-pH profiles measured at pH values ranging from 2 to 12. The difference between log P(i) and log P(n) values (i.e. difflog P) of each prepared compound was considered a measure of the stability of ion pair formation. In this set, the difflog P values varied nearly over one log unit, ranging from -2.40 to -3.37. It has been observed that the presence of hydrogen bonding groups (especially donor) and low steric hindrance around the terminal amine ionizable group increases the relative lipophilicity of the ionic species as compared to the corresponding neutral species. These results were interpreted as due to the increased stability of ion pairs of the compounds bearing these structural features. (C) 2010 Elsevier B.V. All rights reserved.

Adsorption of 4-aminopyridine on Co and Ag electrodes probed by SERS

The adsorption of 4-aminopyridine (4-AP) on Co and Ag electrodes in acid or alkaline solutions of KCl and KI electrolyte salts were monitored by the Surface-enhanced Raman Spectroscopy (SERS) technique. The SERS intensity for the Ag electrode was in 2 orders of magnitude higher than for the Co electrode, due to the enhancement of the Raman cross-section on Ag by the surface-plasmon excitation. In acidic chloride medium (pH 4), the SERS results for Ag electrodes indicate that the protonated form of 4-AP (4-APH(+)) adsorbs in the potential range of -0.1 to -0.6 V (Ag broken vertical bar AgCl broken vertical bar KCl sat) through hydrogen-bonding between 4-APH(+) and Cl(-) adsorbed on the electrode surface: at more negative potentials the neutral form 4-AP is the predominant adsorbed species. For Co electrode in the same medium, only bands due to neutral 4-AP were observed in the spectra at -0.8 and -0.9 V. For more negative potentials bands assigned to both 4-AP and 4-AP surface complex are observed, with the lasts being enhanced, as the potentials are turned more negative. In alkaline chloride medium (pH 13), for less negative potentials the bands assigned to free 4-AP were observed in the spectra of both Ag and Co surfaces. For more negative potentials, only bands assigned to the 4-AP surface complex were observed. For 0.1 mol L(-1) KI acidic or alkaline solutions, bands assigned to 4-AP and 4-APH(+) were observed in a wider potential range than in chloride solutions. An adsorption scheme of 4-AP on Ag and Co is proposed for acidic and alkaline solutions. (C) 2010 Elsevier B.V. All rights reserved.

N-H...S=C hydrogen bond in O-alkyl N-methoxycarbonyl thiocarbamates, ROC(S)N(H)C(O)O)CH(3) (R = CH(3)(-), CH(3)CH(2)-)

Pure O-methyl N-methoxycarbonyl thiocarbamate CH(3)OC(S)N(H)C(O)OCH(3) (I) and O-ethyl N-methoxycarbonyl thiocarbamate, CH(3)CH(2)OC(S)N(H)C(O)OCH(3) (II), are quantitatively prepared by the addition reaction between the CH(3)OC(O)NCS and the corresponding alcohols. The compounds are characterized by multinuclear ((1)H and (13)C) and bi-dimensional ((13)C HSQC) NMR, GC-MS and FTIR spectroscopy techniques. Structural and conformational properties are analyzed using a combined approach involving crystallographic data, vibration spectra and theoretical calculations. The low-temperature (150 K) crystal structure of II was determined by X-ray diffraction methods. The substance crystallizes in the monoclinic space group P2(1)/n with a = 4.088(1)angstrom. b = 22.346(1)angstrom, c = 8.284(1)angstrom, beta = 100.687(3)degrees and Z = 4 molecules per unit cell. The conformation adopted by the thiocarbamate group -OC(S)N(H)- is syn (C=S double bond in synperiplanar orientation with respect to the N-H single bond), while the methoxycarbonyl C=O double bond is in antiperiplanar orientation with respect to the N-H bond. The non-H atoms in II are essentially coplanar and the molecules are arranged in the crystal lattice as centro-symmetric dimeric units held by N-H center dot center dot center dot S=C hydrogen bonds Id(N center dot center dot center dot S) = 3.387(1)angstrom, <(N-H center dot center dot center dot S) = 166.4(2)degrees]. Furthermore, the effect of the it electronic resonance in the structural and vibrational properties is also discussed. (C) 2009 Elsevier Ltd. All rights reserved.

The three-dimensional structure of bothropasin, the main hemorrhagic factor from Bothrops jararaca venom: Insights for a new classification of snake venom metalloprotease subgroups

Bothropasin is a 48 kDa hemorrhagic PIII snake venom metalloprotease (SVMP) isolated from Bothrops jararaca, containing disintegrin/cysteine-rich adhesive domains. Here we present the crystal structure of bothropasin complexed with the inhibitor POL647. The catalytic domain consists of a scaffold of two subdomains organized similarly to those described for other SVMPs, including the zinc and calcium-binding sites. The free cysteine residue Cys(189) is located within a hydrophobic core and it is not available for disulfide bonding or other interactions. There is no identifiable secondary structure for the disintegrin domain, but instead it is composed mostly of loops stabilized by seven disulfide bonds and by two calcium ions. The ECD region is in a loop and is structurally related to the RGD region of RGD disintegrins, which are derived from I`ll SVMPs. The ECD motif is stabilized by the Cys(117)_Cys(310) disulfide bond (between the disintegrin and cysteine-rich domains) and by one calcium ion. The side chain of Glu(276) of the ECD motif is exposed to solvent and free to make interactions. In bothropasin, the HVR (hyper-variable region) described for other Pill SVMPs in the cysteine-rich domain, presents a well-conserved sequence with respect to several other Pill members from different species. We propose that this subset be referred to as PIII-HCR (highly conserved region) SVMPs. The differences in the disintegrin-like, cysteine-rich or disintegrin-like cysteine-rich domains may be involved in selecting target binding, which in turn could generate substrate diversity or specificity for the catalytic domain. (C) 2008 Elsevier Ltd. All rights reserved.

Crystal structure of the (Mg,Fe)[UO2(P,As)O-4](2) center dot 10H(2)O solid solution - A novel mineral variety of saleeite

The crystal structure of a novel variety {[(Mg0.81Fe0.19)(H2O)(6)](H2O)(4)}{(UO2)[(P0.67As0.33)O-4]}(2) of the mineral saleeite is determined using X-ray diffraction (Bruker Smart diffractometer, lambda MoK alpha, graphite monochromator, 2 theta(max) = 56.62 degrees, R = 0.0321 for 2317 reflections, T = 100 K). The main crystal data are as follows: a = 6.952(6) angstrom, b = 19.865(5) , angstrom, c = 6.969(2) angstrom, beta = 90.806(4)degrees, space group P12(l)/n1, Z = 2, and P-calcd = 3.34 g/cm(3). It is shown that the structure is formed by alternating (along the [010] direction) anionic layers, which are composed of uranium bipyramids and T(P,As) tetrahedra, and cation layers consisting of M(Mg, Fe) octahedra and water molecules, which are joined through a system of asymmetric hydrogen bonds. The hydrogen atoms are located, the scheme of hydrogen bonds is established, and their geometric characteristics are calculated.

Electronic structure and chemical bonding in W(2) molecule

The electronic structure of the lowest-lying electronic states of W(2) were investigated at the CASPT2 level. The ground state is a X(1)Sigma(+)(g) state, followed by the a(3)Delta(u), b(3)Sigma(+)(u) and A(1)Delta(u) electronic states. Seven low-lying Omega-states were computed: (1)0(g)(+), (2)3(u), (3)2(u), (4)1(u), (5)0(u)(-), (6)1(u), and (7)2(u), with the ground state corresponding to the (1)0(g)(+)(X(1)Sigma(+)(g)) state. Comparison with the other VIB transition metal group dimers indicates a common pattern of electronic structure and spectroscopic properties. (C) 2010 Elsevier B.V. All rights reserved.

Electronic Structure and Chemical Bonding in the Lowest Electronic States of TcN

Multiconfiguration second-order perturbation theory, with the inclusion of relativistic effects and spin-orbit Coupling, was employed to investigate the nature of the ground and low-lying Lambda-S and Omega states of the TcN molecule. Spectroscopic constants, effective bond order, and potential energy curves for 13 low-lying Lambda-S states and 5 Omega states are given, The computed ground state of TcN is of Omega = 3 symmetry (R(e) = 1.605 angstrom and omega(e) = 1085 cm(-1)), originating mainly from the (3)Delta Lambda-S ground state. This result is contrasted with the nature of the ground state for other VIIB transtion-metal mononitrides, including X(3)Sigma(-) symmetry for MnN and Omega = 0(+) symmetry for ReN, derived also from a X(3)Sigma(-) state.

Electronic structure and chemical bonding in the ground states of Tc(2) and Re(2)

Multiconfiguration second-order perturbation theory, including relativistic effects and spin-orbit coupling, has been employed to investigate the nature of the chemical bonding in the ground state of Tc(2) and Re(2). The Tc(2) ground state is found to be a 0(g)(+) state, with an effective bond order (EBO) of 4.4, and a dissociation energy of 3.25 eV. The Re(2) ground state is a 1(g) state, with EBO = 4.3. Almost degenerate to it, is a 0(g)(+) state (T(e) = 77 cm(-1)), with EBO = 4.1. Experimental evidence also indicates that the ground state is of 1(g) nature. The dissociation energy is computed to be 5.0 eV in agreement with an experimental estimate of 4 +/- 1 eV.

Electronic Structure and Chemical Bonding in the Ground and Low-Lying Electronic States of Ta(2)

The electronic structure and chemical bonding of the ground and low-lying Lambda - S and Omega states of Ta(2) were investigated at the multiconfiguration second-order perturbation theory (CASSCF//CASPT2) level. The ground state of Ta(2) is computed to be a X(3)Sigma(-)(g) state (R(e) = 2.120 angstrom, omega(e) = 323 cm(-1), and D(e) = 4.65 eV), with two low-lying singlet states close to it (a(1) Sigma(+)(g) : T(e) = 409 cm(-1), R(e) = 2.131 angstrom, and omega(e) = 313 cm(-1); b(1) Gamma(g): T(e) = 1, 038 cm(-1), R(e) = 2.127 angstrom, and omega(e) = 316 cm(-1)). These electronic states are derived from the same electronic configuration: vertical bar 13 sigma(2)(g)14 sigma(2)(g)7 delta(2)(g)13 pi(4)(u)>. The effective bond order of the X(3) Sigma(-)(g) state is 4.52, which indicates that the Ta atoms are bound by a quintuple chemical bond. The a(1) Sigma(+)(g) state interacts strongly with the X(3)Sigma(-)(g) g ground state by a second-order spin-orbit interaction, giving rise to the (1)0(g)(+) (ground state) (dominated by the X(3)Sigma(-)(g) Lambda - S ground state) and (9)0(g)(+) (dominated by the a(1) Sigma(+)(g) Lambda - S state) Omega states. These results are in line with those reported for the group 5B homonuclear transition metal diatomics. (C) 2010 Wiley Periodicals, Inc. Int J Quantum Chem 111: 1306-1315, 2011