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Sample records for acyclic ditopic ligand

  1. Acyclic Tethers Mimicking Subunits of Polysaccharide Ligands: Selectin Antagonists

    PubMed Central

    2014-01-01

    We report on the design and synthesis of molecules having E- and P-selectins blocking activity both in vitro and in vivo. The GlcNAc component of the selectin ligand sialyl LewisX was replaced by an acyclic tether that links two saccharide units. The minimization of intramolecular dipole–dipole interactions and the gauche effect would be at the origin of the conformational bias imposed by this acyclic tether. The stereoselective synthesis of these molecules, their biochemical and biological evaluations using surface plasmon resonance spectroscopy (SPR), and in vivo assays are described. Because the structure of our analogues differs from the most potent E-selectin antagonists reported, our acyclic analogues offer new opportunities for chemical diversity. PMID:25221666

  2. Multiphase enantioselective Kharasch-Sosnovsky allylic oxidation based on neoteric solvents and copper complexes of ditopic ligands.

    PubMed

    Aldea, Luis; García, José I; Mayoral, José A

    2012-07-21

    Recoverable multiphase enantioselective catalytic systems for the Kharasch-Sosnovsky oxidation of cycloalkenes with tert-butyl peroxybenzoate are described, based on the use of [BMIM][PF(6)] and a new solvent derived from glycerol as the catalyst reservoir phases, and chiral copper complexes with different ligands from the bis(oxazoline) family. The best results are obtained with the glycerol-derived solvent and a recently described azabisoxazoline-based ditopic ligand, allowing up to four uses of the catalytic phase with good results.

  3. Uranyl complexes of alkyl-bridged ditopic diaminotetraphenol ligands and their use as uranyl ion extractors.

    PubMed

    Riisiö, Antti; Väisänen, Ari; Sillanpää, Reijo

    2013-08-05

    The coordination chemistry of uranyl ions was studied using long n-alkyl chain (n = 5-8) bridged by N,N,N',N'-tetrakis(2-hydroxy-3-methyl-5-tert-butylbenzyl)diaminoalkanes (H4L1-H4L4) as ligands. All ligands formed 2:1 (U-to-L ratio) complexes with uranyl ions, but in addition 1:1 complexes could be characterized using ligands H4L2 and H4L3. The complexes were characterized by elemental analysis, spectroscopy (IR and NMR), and X-ray diffraction. The 2:1 complexes are of two types: [(UO2)2(H2Lm)(NO3)2(solvent)2] (m = 1 and 2; solvent = ethanol or propanol) or (cation)2[(UO2)2(H2Lm)(NO3)2(anion)2]·xsolvent (m = 2 and 4; cation = triethylammonium, anion = nitrate or thiocyanate, and solvent = dichloromethane and acetonitrile; x = 1 or 2). The 1:1 complexes have the formula [(UO2)2(H2Lm)2] (m = 2 and 3). In the solid state, 2:1 complexes are almost in a linear conformation with the uranyl ion at both ends of the ligand. The 1:1 complexes are cyclic dinuclear molecules. Preliminary studies of the ligands as uranyl ion extractors from water to dichloromethane were also performed. A high extraction efficiency was observed with H4L3 for uranyl ions, and in the presence of Cu(II), Ni(II), Co(II), and Zn(II) ions, a good extraction selectivity for uranyl ions was found with H4L1.

  4. Synthesis, structure, magnetic properties and EPR spectroscopy of a copper(II) coordination polymer with a ditopic hydrazone ligand and acetate bridges.

    PubMed

    Bikas, Rahman; Aleshkevych, Pavlo; Hosseini-Monfared, Hassan; Sanchiz, Joaquín; Szymczak, Ritta; Lis, Tadeusz

    2015-01-28

    A new one dimensional coordination polymer of copper(II), [Cu4(L)2(μ2-1,1-OAc)2(μ2-1,3-OAc)4]n (1), has been synthesized and characterized by spectroscopic methods and single crystal X-ray analysis [HL = (E)-N'-(phenyl(pyridin-2-yl)methylene)isonicotinhydrazide, OAc = acetate anion]. The coordination polymer contains two kinds of Cu(II) dimers which are connected by two types of acetate (μ2-1,1- and μ2-1,3-) bridging groups. The ditopic isonicotinhydrazone ligand coordinates to the Cu1 center through the N2O-donor set and connects to the Cu2 center by a pyridine group of the isonicotine part. The EPR and magnetic susceptibility measurements confirm the existence of two kinds of Cu(II) dimers. The intradimer isotropic exchange was estimated to be +0.80(1) cm(-1) for the ferromagnetic Cu1···Cu1 dimeric unit and -315 (1) cm(-1) for the antiferromagnetic Cu2···Cu2 dimeric unit.

  5. Synthesis and structural characterization of homochiral 2D coordination polymers of zinc and copper with conformationally flexible ditopic imidazolium-based dicarboxylate ligands.

    PubMed

    Nicasio, Antonio I; Montilla, Francisco; Álvarez, Eleuterio; Colodrero, Rosario P; Galindo, Agustín

    2017-01-03

    Different novel coordination polymers containing zinc, 1-4, and copper, 5-8, metals, connected via chiral imidazolium-based dicarboxylate ligands, [L(R)](-), were isolated by reaction between zinc acetate or copper acetate and enantiomerically pure HL(R) compounds. They were characterised and structurally identified by X-ray diffraction methods (single crystal and powder). These compounds are two-dimensional homochiral coordination polymers, [M(L(R))2]n, in which the metal ions are coordinated by the two carboxylate groups of [L(R)](-) anions in a general bridging monodentate μ(2)-κ(1)-O(1),κ(1)-O(3) fashion that afforded tetrahedral metal coordination environments for zinc, 1-4, and square planar for copper, 5-8, complexes. In all the compounds the 3D supramolecular architecture is constructed by non-covalent interactions between the hydrophobic parts (R groups) of the homochiral 2D coordination polymers and, in some cases, by weak C-HO non-classical hydrogen bonds that provided, in general, a dense crystal packing. DFT calculations on the [L(R)](-) anions confirmed their conformational flexibility as ditopic linkers and this fact makes possible the formation of different coordination polymers for four-coordinated metal centers. Preliminary studies on the Zn-catalyzed synthesis of chiral α-aminophosphonates were carried out and, unfortunately, no enantioselectivity was observed in these reactions.

  6. Octahedral rhodium(III) complexes as kinase inhibitors: Control of the relative stereochemistry with acyclic tridentate ligands.

    PubMed

    Mollin, Stefan; Riedel, Radostan; Harms, Klaus; Meggers, Eric

    2015-07-01

    Octahedral metal complexes are attractive structural templates for the design of enzyme inhibitors as has been demonstrated, for example, with the development of metallo-pyridocarbazoles as protein kinase inhibitors. The octahedral coordination sphere provides untapped structural opportunities but at the same time poses the drawback of dealing with a large number of stereoisomers. In order to address this challenge of controlling the relative metal-centered configuration, the synthesis of rhodium(III) pyridocarbazole complexes with facially coordinating acyclic tridentate ligands was investigated. A strategy for the rapid synthesis of such complexes is reported, the diastereoselectivities of these reactions were investigated, the structure of several complexes were determined by X-ray crystallography, the high kinetic stability of such complexes in thiol-containing solutions was demonstrated in (1)H-NMR experiments, and the protein kinase inhibition ability of this class of complexes was confirmed. It can be concluded that the use of multidentate ligands is currently maybe the most practical strategy to avoid a large number of possible stereoisomers in the course of exploiting octahedral coordination spheres as structural templates for the design of bioactive molecules.

  7. Versatile Coordination Mode of a New Pyridine-Based Ditopic Ligand with Transition Metals: From Regular Pyridine to Alkyne and Alkenyl Bindings and Indolizinium Formation.

    PubMed

    Kumar, Sushil; Mandon, Dominique

    2015-08-03

    The new BPMPB ligand, namely, bis[1-bis(2-pyridylmethyl),1 (pyridyl)]butyne, can be very easily obtained as a side product in the known reaction of picolyl chloride and sodium acetylide (which major product is the known terminal alkyne-substituted tripod). This symmetrical ligand contains two identical coordination sites with two methylenepyridines and one pyridyl group on each side, linked by an alkyne function providing a semirigid segment. Together with the molecular structure of the ligand which is reported, we describe the preparation of complexes with Fe(II)Cl2, Co(II)Cl2, Ni(II)Cl2, Cu(I)Cl, and Zn(II)Cl2 salts. All complexes have been characterized by X-ray diffraction studies as well as by standard spectroscopic techniques. The striking point in this work is the diversity of the structures that are obtained. Co(II) and Zn(II) provide isostructural dinuclear complexes in which both coordination sites are occupied within a tetrahedral symmetry. The Cu(I) complex is also a dinuclear compound, but in that case, the copper atom is coordinated to the alkyne moiety, two pyridines, and a bridging chloride. The (13)C NMR spectrum of the copper complex confirms that the metal center is coordinated to the alkyne in solution. The coordination of Ni(II) results in the formation of a mononuclear complex in which a pyridine has fused with the alkyne moiety to generate an indolizinium group; the structure of the corresponding alkenyl complex is reported. Finally, the addition of FeCl2 to the ligand results in the formation of a mononuclear complex with a free, noncoordinated indolizinium. The sequence developed in the present work illustrates the possibility for the metal centers to adopt various coordination modes which may be relevant to the conversion of an alkyne and a pyridyl unit into indolizinium.

  8. Synthesis, spectroscopic studies and inhibitory activity against bactria and fungi of acyclic and macrocyclic transition metal complexes containing a triamine coumarine Schiff base ligand

    NASA Astrophysics Data System (ADS)

    Abou-Hussein, A. A.; Linert, Wolfgang

    2015-04-01

    Two series of new mono and binuclear complexes with a Schiff base ligand derived from the condensation of 3-acetylcoumarine and diethylenetriamine, in the molar ratio 2:1 have been prepared. The ligand was characterized by elemental analysis, IR, UV-visible, 1H-NMR and mass spectra. The reaction of the Schiff base ligand with cobalt(II), nickel(II), copper(II), zinc(II) and oxovanadium(IV) lead to mono or binuclear species of cyclic or macrocyclic complexes, depending on the mole ratio of metal to ligand and as well as on the method of preparation. The Schiff base ligand behaves as a cyclic bidentate, tetradendate or pentaentadentae ligand. The formation of macrocyclic complexes depends significantly on the dimension of the internal cavity, the rigidity of the macrocycles, the nature of its donor atoms and on the complexing properties of the anion involved in the coordination. Electronic spectra and magnetic moments of the complexes indicate that the geometries of the metal centers are either square pyramidal or octahedral for acyclic or macro-cyclic complexes. The structures are consistent with the IR, UV-visible, ESR, 1H-NMR, mass spectra as well as conductivity and magnetic moment measurements. The Schiff base ligand and its metal complexes were tested against two pathogenic bacteria as Gram-positive and Gram-negative bacteria as well as one kind of fungi. Most of the complexes exhibit mild antibacterial and antifungal activities against these organisms.

  9. The Tolman electronic parameter (TEP) and the metal-metal electronic communication in ditopic NHC complexes.

    PubMed

    Gusev, Dmitry G; Peris, Eduardo

    2013-05-28

    Whereas the electronic communication between metals in dimetallic organometallic compounds is often assessed through cyclic voltammetric measurements, we have found that the variations in the Tolman electronic parameter (TEP) can also be an alternative and effective way of determining this type of interaction. The TEP values of several (CO)3Ni-NHC-X systems with five different ditopic NHC ligand systems [triazolyldiylidene (A), bis(imidazolylidene) (B), benzobis(imidazolylidene) (C), cyclopenta[f,g]acenaphthylenebis(imidazolylidene) (D) and bis(imidazolidinylidene) (F)] were determined by means of DFT calculations. Based on these values, the electron-withdrawing character of the X metal fragments employed in this study was found to increase in the order IrCp(CO) → RhCl(COD) → Ni(CO)3 → Cr(CO)5 → RhCl(CO)2. We found that the degree of electronic interaction through the ditopic NHC ligands is the strongest in A, followed by B and F, while being weak in B and C. The TEP values and the quantitative analysis of the upper molecular orbitals of A and F and their (CO)3Ni-NHC-Ni(CO)3 complexes strongly suggest that the principal electronic interaction between the metal centres of the M-NHC-M' complexes is of σ-type, via the delocalized HOMO and HOMO - 1 orbitals of the NHC ligands.

  10. Variation of the Molecular Conformation, Shape, and Cavity Size in Dinuclear Metalla-Macrocycles Containing Hetero-Ditopic Dithiocarbamate-Carboxylate Ligands from a Homologous Series of N-Substituted Amino Acids.

    PubMed

    Torres-Huerta, Aaron; Cruz-Huerta, Jorge; Höpfl, Herbert; Hernández-Vázquez, Luis G; Escalante-García, Jaime; Jiménez-Sánchez, Arturo; Santillan, Rosa; Hernández-Ahuactzi, Irán F; Sánchez, Mario

    2016-12-05

    A homologous series of dithiocarbamate ligands derived from N-substituted amino acids was reacted with different diorganotin dichlorides to give 18 diorganotin complexes. Spectroscopic and mass spectrometric analysis evidenced the formation of assemblies with six-coordinate tin atoms embedded in skewed-trapezoidal bipyramidal coordination environments of composition C2SnS2O2. Single-crystal X-ray diffraction analysis for three of the compounds revealed a one-dimensional polymeric structure for the complex with the ligand derived from 5-aminopentanoic acid, which through further intermolecular Sn···O interactions generated an overall two-dimensional coordination polymer containing 40-membered hexanuclear tin macrocycles. On the contrary, the ligands derived from 6-aminohexanoic and 8-aminooctanoic acid provided the expected 22- and 26-membered dinuclear macrocyclic structures. Density functional theory calculations for a representative series of macrocyclic complexes of composition [Me2SnLx]2 with Lx = ¯S2CN(Me)-(CH2)x-COO¯ (x = 3-12) enabled a detailed analysis of the variations in the molecular conformation, shape, and cavity size of the macrocycles in dependence of the aliphatic spacer. Because of odd-even effects, the difunctional ligands can adopt either a curved or a twisted-pincer shape, while the SnSxO4-x (x = 0-4) moieties can act either as linear or angular tectons with varying connectivity angles.

  11. Dinuclear cadmium(II), zinc(II), and manganese(II), trinuclear nickel(II), and pentanuclear copper(II) complexes with novel macrocyclic and acyclic Schiff-base ligands having enantiopure or racemic camphoric diamine components.

    PubMed

    Jiang, Jue-Chao; Chu, Zhao-Lian; Huang, Wei; Wang, Gang; You, Xiao-Zeng

    2010-07-05

    Four novel [3 + 3] Schiff-base macrocyclic ligands I-IV condensed from 2,6-diformyl-4-substituted phenols (R = CH(3) or Cl) and enantiopure or racemic camphoric diamines have been synthesized and characterized. Metal-ion complexations of these enantiopure and racemic [3 + 3] macrocyclic ligands with different cadmium(II), zinc(II), manganese(II), nickel(II), and copper(II) salts lead to the cleavage of Schiff-base C horizontal lineN double bonds and subsequent ring contraction of the macrocyclic ligands due to the size effects and the spatial restrictions of the coordination geometry of the central metals, the steric hindrance of ligands, and the counterions used. As a result, five [2 + 2] and one [1 + 2] dinuclear cadmium(II) complexes (1-6), two [2 + 2] dinuclear zinc(II) (7 and 8), and two [2 + 2] dinuclear manganese(II) (9 and 10) complexes together with one [1 + 1] trinuclear nickel(II) complex (11) and one [1 + 2] pentanuclear copper(II) complex (12), bearing enantiopure or racemic ligands, different substituent groups in the phenyl rings, and different anionic ligands (Cl(-), Br(-), OAc(-), and SCN(-)), have been obtained in which the chiral carbon atoms in the camphoric backbones are arranged in different ways (RRSS for the enantiopure ligands in 1, 2, 4, 5, and 7-10 and RSRS for the racemic ligands in 3, 6, 11, and 12). The steric hindrance effects of the methyl group bonded to one of the chiral carbon atoms of camphoric diamine units are believed to play important roles in the formation of the acyclic [1 + 1] trinuclear complex 11 and [1 + 2] dinuclear and pentanuclear complexes 6 and 12. In dinuclear cadmium(II), zinc(II), and manganese(II) complexes 1-10, the sequence of separations between the metal centers is consistent with that of the ionic radii shortened from cadmium(II) to manganese(II) to zinc(II) ions. Furthermore, UV-vis, circular dichroism, (1)H NMR, and fluorescence spectra have been used to characterize and compare the structural

  12. Synthesis of mononuclear copper(II) complexes of acyclic Schiff's base ligands: Spectral, structural, electrochemical, antibacterial, DNA binding and cleavage activity

    NASA Astrophysics Data System (ADS)

    Jayamani, Arumugam; Thamilarasan, Vijayan; Sengottuvelan, Nallathambi; Manisankar, Paramasivam; Kang, Sung Kwon; Kim, Young-Inn; Ganesan, Vengatesan

    2014-03-01

    The mononuclear copper(II) complexes (1&2) of ligands L1 [N,N";-bis(2-hydroxy-5-methylbenzyl)-1,4-bis(3-iminopropyl)piperazine] or L2 [N,N";-bis(2-hydroxy-5-bromobenzyl)-1,4-bis(3-iminopropyl) piperazine] have been synthesized and characterised. The single crystal X-ray study had shown that ligands L1 and L2 crystallize in a monoclinic crystal system with P21/c space group. The mononuclear copper(II) complexes show one quasireversible cyclic voltammetric response near cathodic region (-0.77 to -0.85 V) in DMF assignable to the Cu(II)/Cu(I) couple. Binding interaction of the complexes with calf thymus DNA (CT DNA) investigated by absorption studies and fluorescence spectral studies show good binding affinity to CT DNA, which imply both the copper(II) complexes can strongly interact with DNA efficiently. The copper(II) complexes showed efficient oxidative cleavage of plasmid pBR322 DNA in the presence of 3-mercaptopropionic acid as reducing agent through a mechanistic pathway involving formation of singlet oxygen as the reactive species. The Schiff bases and their Cu(II) complexes have been screened for antibacterial activities which indicates that the complexes exhibited higher antimicrobial activity than the free ligands.

  13. Synthesis of mononuclear copper(II) complexes of acyclic Schiff's base ligands: spectral, structural, electrochemical, antibacterial, DNA binding and cleavage activity.

    PubMed

    Jayamani, Arumugam; Thamilarasan, Vijayan; Sengottuvelan, Nallathambi; Manisankar, Paramasivam; Kang, Sung Kwon; Kim, Young-Inn; Ganesan, Vengatesan

    2014-03-25

    The mononuclear copper(II) complexes (1&2) of ligands L(1) [N,N'-bis(2-hydroxy-5-methylbenzyl)-1,4-bis(3-iminopropyl)piperazine] or L(2) [N,N'-bis(2-hydroxy-5-bromobenzyl)-1,4-bis(3-iminopropyl) piperazine] have been synthesized and characterised. The single crystal X-ray study had shown that ligands L(1) and L(2) crystallize in a monoclinic crystal system with P21/c space group. The mononuclear copper(II) complexes show one quasireversible cyclic voltammetric response near cathodic region (-0.77 to -0.85 V) in DMF assignable to the Cu(II)/Cu(I) couple. Binding interaction of the complexes with calf thymus DNA (CT DNA) investigated by absorption studies and fluorescence spectral studies show good binding affinity to CT DNA, which imply both the copper(II) complexes can strongly interact with DNA efficiently. The copper(II) complexes showed efficient oxidative cleavage of plasmid pBR322 DNA in the presence of 3-mercaptopropionic acid as reducing agent through a mechanistic pathway involving formation of singlet oxygen as the reactive species. The Schiff bases and their Cu(II) complexes have been screened for antibacterial activities which indicates that the complexes exhibited higher antimicrobial activity than the free ligands.

  14. Application of the Ugi four-component reaction to the synthesis of ditopic bifunctional chelating agents.

    PubMed

    Tei, Lorenzo; Gugliotta, Giuseppe; Avedano, Stefano; Giovenzana, Giovanni B; Botta, Mauro

    2009-11-07

    The Ugi four-component reaction (Ugi 4CR) was exploited for the first time to obtain in a single synthetic step bifunctional ditopic chelators by using DOTA monoamide (DOTAMA) derivatives as amino and acid components. A number of ditopic systems in which the two DOTAMA units are connected by a central alpha-acylaminoamide group were synthesized by reacting different aldehydes, isocyanides and two DOTAMA chelates containing amino and acid functionalities. Variation of the components allows the insertion of another functional group into the alpha-acylaminoamide skeleton for further conjugation to biomolecules. The optimal reaction conditions were found by using methanol as solvent and ultrasound irradiation at a power of 60 W (20 kHz) for 3 h. The Gd(III) complexes of the dimeric ligands L1 and L2 (bearing a cyclohexyl ring and an octadecyl chain on the central alpha-acylaminoamide moiety, respectively) were fully characterized in aqueous media by relaxometric techniques with varying temperature and magnetic field strength. The relaxivity of Gd(2)L1 and Gd(2)L2 (in the aggregated form), at 20 MHz and 310 K, are 5.6 and 20.0 mM(-1) s(-1), respectively. The enhanced value found for Gd(2)L2 indicates that this lipophilic complex forms micelles at concentrations <0.1 mM. Finally, the binding of Gd(2)L2 to human serum albumin (HSA) was investigated by proton relaxometry, and the affinity constant of the complex and the relaxivity of the macromolecular adduct (r(1p)(b) = 38.1 mM(-1) s(-1); 20 MHz and 310 K) derived.

  15. Contrasting coordination behavior of Group 12 perchlorate salts with an acyclic N3O2 donor ligand by X-ray crystallography and (1)H NMR.

    PubMed

    Tice, Daniel B; Pike, Robert D; Bebout, Deborah C

    2016-08-09

    An unbranched N3O2 ligand 2,6-bis[((2-pyridinylmethyl)oxy)methyl]pyridine (L1) was used to prepare new mononuclear heteroleptic Group 12 perchlorate complexes characterized by IR, (1)H NMR and X-ray crystallography. Racemic complexes with pentadentate L1 and one to four oxygens from either water or perchlorate bound to a metal ion were structurally characterized. Octahedral [Zn(L1)(OH2)](ClO4)2 (1) and pentagonal bipyramidal [Cd(L1)(OH2)(OClO3)]ClO4 (2) structures were found with lighter congeners. The polymorphic forms of [Hg(L1)(ClO4)2] characterized (3 in P1[combining macron] and 4 in P21/c) had a mix of monodentate, anisobidentate and bidentate perchlorates, providing the first examples of a tricapped trigonal prismatic Hg(ii) coordination geometry, as well as additional examples of a rare square antiprismatic Hg(ii) coordination geometry. Solution state (1)H NMR characterization of the Group 12 complexes in CD3CN indicated intramolecular reorganization remained rapid under conditions where intermolecular M-L1 exchange was slow on the chemical shift time scale for Zn(ii) and on the J(M(1)H) time scale for Cd(ii) and Hg(ii). Solution studies with more than one equivalent of ligand also suggested that a complex with a 1 : 2 ratio of M : L1 contributed significantly to solution equilibria with Hg(ii) but not the other metal ions. The behavior of related linear pentadentate ligands with Group 12 perchlorate salts is discussed.

  16. Gas recirculator for acyclic machines

    NASA Astrophysics Data System (ADS)

    Balsa, T. F.

    1985-05-01

    The present invention relates to acyclic machines of the type using liquid metal collectors, and more particularly to an improvement for retaining the liquid metal in such machines. Radial type acyclic motors and generators generally include a metallic disk rotor rotating on a shaft between electromagnetic stator poles excited by field coils wound concentric with the shaft. Instead of solid brush, current collectors at the rotor periphery, liquid metal collectors are sometimes used to close the electrical current loop between the shaft and the rotor, and an inert pressurized cover gas fills the gaps between the rotating components and the stationary housing. A cover has recirculator in an acyclic generator having liquid metal collectors for reducing entrainment of the liquid metal in the gas. Radial passages in the stator housing provide natural recirculating paths for the cover gas to flow radially outward along the sides of the rotor and return inwardly through the passages. Scoops or lips located inward of the liquid metal collector divert the outward gas flow into the passages to minimize contact of the gas with the liquid metal.

  17. Acyclic water pentamer induces novel supramolecular ribbed sheet: Cooperativity and competitiveness of weak and covalent forces?

    NASA Astrophysics Data System (ADS)

    Jana, Atish Dipankar; Saha, Rajat; Mostafa, Golam

    2010-03-01

    The 1D chain complex [{Cu(II)(bpp)(malonate)(H 2O)}(H 2O) 4] n ( 1) (bpp = 1,3-bis(4-pyridyl)propane) self-assembles to form a 2D ribbed sheet stabilized by an acyclic pentameric water cluster, which in turn, influences the conformation of the bpp ligand.

  18. Cardioleader use in acyclic types of sports

    NASA Technical Reports Server (NTRS)

    Bondin, V. I.

    1980-01-01

    The use of the cardioleader method in regulating training loads and tests for athletes in acyclic sports was investigated. It was found that the use of this method increases the effectiveness of the training process.

  19. Acyclic telluroiminium salts: isolation and characterization.

    PubMed

    Mutoh, Yuichiro; Murai, Toshiaki; Yamago, Shigeru

    2004-12-29

    The isolation, structure, and reactions of acyclic telluroiminium salts were disclosed. The delocalization of electrons on the tellurium atom and the partial double-bond character of C-Te bonds in the salts are discussed on the basis of X-ray molecular structure analysis, 13C and 125Te NMR spectroscopy, and molecular orbital calculation.

  20. Refactoring Problem of Acyclic Extended Free-Choice Workflow Nets to Acyclic Well-Structured Workflow Nets

    NASA Astrophysics Data System (ADS)

    Yamaguchi, Shingo

    A workflow net (WF-net for short) is a Petri net which represents a workflow. There are two important subclasses of WF-nets: extended free-choice (EFC for short) and well-structured (WS for short). It is known that most actual workflows can be modeled as EFC WF-nets; Acyclic WS is a subclass of acyclic EFC but has more analysis methods. An acyclic EFC WF-net may be transformed to an acyclic WS WF-net without changing the external behavior of the net. We name such a transformation Acyclic EFC WF-net refactoring. We give a formal definition of acyclic EFC WF-net refactoring problem. We also give a necessary condition and a sufficient condition for solving the problem. Those conditions can be checked in polynomial time. These result in the enhancement of the analysis power of acyclic EFC WF-nets.

  1. Enantioselective Heck arylations of acyclic alkenyl alcohols using a redox-relay strategy.

    PubMed

    Werner, Erik W; Mei, Tian-Sheng; Burckle, Alexander J; Sigman, Matthew S

    2012-12-14

    Progress in the development of asymmetric Heck couplings of arenes and acyclic olefins has been limited by a tenuous understanding of the factors that dictate selectivity in migratory insertion and β-hydride elimination. On the basis of key mechanistic insight recently garnered in the exploration of selective Heck reactions, we report here an enantioselective variant that delivers β-, γ-, or δ-aryl carbonyl products from acyclic alkenol substrates. The catalyst system imparts notable regioselectivity during migratory insertion and promotes the migration of the alkene's unsaturation toward the alcohol to ultimately form the ketone product. The reaction uses aryldiazonium salts as the arene source, yields enantiomeric products from opposite starting alkene configurations, and uses a readily accessible ligand. The racemic nature of the alkenol substrate does not bias the enantioselection.

  2. Pd-Catalyzed N-Arylation of Secondary Acyclic Amides: Catalyst Development, Scope, and Computational Study

    PubMed Central

    Hicks, Jacqueline D.; Hyde, Alan M.; Cuezva, Alberto Martinez; Buchwald, Stephen L.

    2009-01-01

    We report the efficient N-arylation of acyclic secondary amides and related nucleophiles with aryl nonaflates, triflates, and chlorides. This method allows for easy variation of the aromatic component in tertiary aryl amides. A new biaryl phosphine with P-bound 3,5-(bis)trifluoromethylphenyl groups was found to be uniquely effective for this amidation. The critical aspects of the ligand were explored through synthetic, mechanistic, and computational studies. Systematic variation of the ligand revealed the importance of (1) a methoxy group on the aromatic carbon of the “top ring” ortho to the phosphorus and (2) two highly electron-withdrawing P-bound 3,5-(bis)trifluoromethylphenyl groups. Computational studies suggest the electron-deficient nature of the ligand is important in facilitating amide binding to the LPd(II)(Ph)(X) intermediate. PMID:19886610

  3. Acyclic archaebacterial ether lipids in swamp sediments

    NASA Astrophysics Data System (ADS)

    Pauly, George G.; Van Vleet, Edward S.

    1986-06-01

    Acyclic phytanyl diether glycerol and biphytanyl ether lipids have been quantified in two modern swamp sediment cores in concentrations ranging up to 360 μg/ml porewater. Methanogenic bacteria are the only known source organisms which can inhabit the swamp sediments. Variations in relative abundance between these lipids may reflect taxonomic changes in methanogen populations or the stage of growth. Maxima in methanogen lipid concentrations coincide with local maxima of 13C of organic matter, possibly the result of a pool effect on CO 2 or acetate. Methane production estimates calculated from lipid concentrations in swamp sediments range from 0.1 to 1.3 mmol cm -2 yr -1, values which are consistent with published methane fluxes.

  4. Community detection in directed acyclic graphs

    NASA Astrophysics Data System (ADS)

    Speidel, Leo; Takaguchi, Taro; Masuda, Naoki

    2015-08-01

    Some temporal networks, most notably citation networks, are naturally represented as directed acyclic graphs (DAGs). To detect communities in DAGs, we propose a modularity for DAGs by defining an appropriate null model (i.e., randomized network) respecting the order of nodes. We implement a spectral method to approximately maximize the proposed modularity measure and test the method on citation networks and other DAGs. We find that the attained values of the modularity for DAGs are similar for partitions that we obtain by maximizing the proposed modularity (designed for DAGs), the modularity for undirected networks and that for general directed networks. In other words, if we neglect the order imposed on nodes (and the direction of links) in a given DAG and maximize the conventional modularity measure, the obtained partition is close to the optimal one in the sense of the modularity for DAGs. Contribution to the Topical Issue "Temporal Network Theory and Applications", edited by Petter Holme.

  5. Ditopic receptors containing urea groups for solvent extraction of Cu(ii) salts.

    PubMed

    Carreira-Barral, Israel; Mato-Iglesias, Marta; de Blas, Andrés; Platas-Iglesias, Carlos; Tasker, Peter A; Esteban-Gómez, David

    2017-02-21

    The ditopic receptor L3 [1-(2-((7-(4-(tert-butyl)benzyl)-1,4,7,10-tetraazacyclododecan-1-yl)methyl)phenyl)-3-(3-nitrophenyl)urea] containing a macrocyclic cyclen unit for Cu(ii)-coordination and a urea moiety for anion binding was designed for recognition of metal salts. The X-ray structure of [CuL3(SO4)] shows that the sulfate anion is involved in cooperative binding via coordination to the metal ion and hydrogen-bonding to the urea unit. This behaviour is similar to that observed for the related receptor L1 [1-(2-((bis(pyridin-2-ylmethyl)amino)methyl)phenyl)-3-(3-nitrophenyl)urea], which forms a dimeric [CuL1(μ-SO4)]2 structure in the solid state. In contrast, the single crystal X-ray structure of [ZnL3(NO3)2] contains a 1 : 2 complex (metal : anion) where one anion coordinates to the metal and the other is hydrogen-bonded to the urea group. Spectrophotometric titrations performed for the [CuL3(OSMe2)](2+) complex indicate that this system is able to bind a wide range of anions with an affinity sequence: MeCO2(-) > Cl(-) > H2PO4(-) > Br(-) > NO2(-) > HSO4(-) > NO3(-). Lipophilic analogues of L1 and L3 extract CuSO4 and CuCl2 from water into chloroform with high selectivity over the corresponding Co(ii), Ni(ii) and Zn(ii) salts.

  6. Auto-assembling of ditopic macrocyclic lanthanide chelates with transition-metal ions. Rigid multimetallic high relaxivity contrast agents for magnetic resonance imaging.

    PubMed

    Paris, Jérôme; Gameiro, Cristiana; Humblet, Valérie; Mohapatra, Prasanta K; Jacques, Vincent; Desreux, Jean F

    2006-06-26

    PhenHDO3A is a ditopic ligand featuring a tetraazacyclododecane unit substituted by three acetate arms and one 6-hydroxy-5,6-dihydro-1,10-phenanthroline group (PhenHDO3A = rel-10-[(5R,6R)-5,6-dihydro-6-hydroxy-1,10-phenantholin-5-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid). This ligand was specially designed so as to obtain highly stable heteropolymetallic assemblies. PhenHDO3A has been prepared starting from phenanthroline epoxide and either a triprotected tetraazacyclododecane or tert-butyl triester of N,N',N' '-tetraazacyclododecane-triacetic acid. The latter yields PhenHDO3A in a single step. PhenHDO3A forms kinetically stable lanthanide complexes (acid-catalyzed kinetic constant kH = (1.2 +/- 0.2) x 10(-3) s(-1) M(-1)) whose solution structure has been deduced from a quantitative analysis of the paramagnetic shifts and the longitudinal relaxation times of the proton nuclei of YbPhenHDO3A. The alcohol group of the dihydro-phenanthroline unit remains coordinated to the encapsulated metal ion despite the steric crowding brought about by this group. Furthermore, the complexes are monohydrated, as shown by luminescence lifetime measurements on EuPhenHDO3A solutions. Relaxivity titrations at 20 MHz clearly indicate that the phenanthroline unit of GdPhenHDO3A is available for the spontaneous formation of highly stable tris complexes with the Fe2+ and Ni2+ ions. The water-exchange times and the rotational correlation times of GdPhenHDO3A and Fe(GdPhenHDO3A)32+ have been deduced from variable temperature 17O NMR studies and from nuclear relaxation dispersion curves. Despite rather slow water-exchange rates (taum0 = 1.0-1.2 x 10(-6) s), relaxivity gains of 90% have been observed upon the formation of the heterometallic tris complexes. The latter rotate about four times more slowly (taur0= 398 ps) than the monomeric unit (taur0 = 105 ps) and their relaxivity is, accordingly, twice as high. The relaxivity of the tris complexes between 10 and 50 MHz is

  7. [Application of directed acyclic graphs in control of confounding].

    PubMed

    Xiang, R; Dai, W J; Xiong, Y; Wu, X; Yang, Y F; Wang, L; Dai, Z H; Li, J; Liu, A Z

    2016-07-01

    Observational study is a method most commonly used in the etiology study of epidemiology, but confounders, always distort the true causality between exposure and outcome when local inferencing. In order to eliminate these confounding, the determining of variables which need to be adjusted become a key issue. Directed acyclic graph(DAG)could visualize complex causality, provide a simple and intuitive way to identify the confounding, and convert it into the finding of the minimal sufficient adjustment for the control of confounding. On the one hand, directed acyclic graph can choose less variables, which increase statistical efficiency of the analysis. On the other hand, it could help avoiding variables that is not measured or with missing values. In a word, the directed acyclic graph could facilitate the reveal of the real causality effectively.

  8. On the acyclicity of the solution sets of operator equations

    NASA Astrophysics Data System (ADS)

    Gel'man, Boris D.

    2010-12-01

    A parameter-dependent completely continuous map is considered. The acyclicity of the set of fixed points of this map is proved for some fixed value of the parameter under the assumption that for close values of the parameter the map has a unique fixed point. The results obtained are used to prove the acyclicity of the set of fixed points of a 'nonscattering' map, as well as to study the topological structure of the set of fixed points of an abstract Volterra map. Bibliography: 13 titles.

  9. Synthesis of some novel hydrazono acyclic nucleoside analogues

    PubMed Central

    Khalafi-Nezhad, Ali; Behrouz, Somayeh

    2010-01-01

    Summary The syntheses of novel hydrazono acyclic nucleosides similar to miconazole scaffolds are described. In this series of acyclic nucleosides, pyrimidine as well as purine and other azole derivatives replaced the imidazole function in miconazole and the ether group was replaced with a hydrazone moiety using phenylhydrazine. To interpret the dominant formation of (E)-hydrazone derivatives rather than (Z)-isomers, PM3 semiempirical quantum mechanic calculations were carried out which indicated that the (E)-isomers had the lower heats of formation. PMID:20563270

  10. Acyclic glycosidopyrroles analogues of ganciclovir: synthesis and biological activity.

    PubMed

    Diana, P; Barraja, P; Almerico, A M; Dattolo, G; Mingoia, F; Loi, A G; Congeddu, E; Musiu, C; Putzolu, M; La Colla, P

    1997-05-01

    Acyclic glycosidopyrroles of type 3 were synthetized in good overall yields, according to the Scheme. When evaluated for antiviral activity against DNA and RNA viruses, only compound in which R1 = R2 = Ph, R3 = NH2 was found to inhibit the HIV-1 replication at concentrations that were not cytotoxic for MT-4 cells.

  11. New acyclic diterpenic acids from yacon (Smallanthus sonchifolius) leaves.

    PubMed

    Mercado, María I; Coll Aráoz, María V; Grau, Alfredo; Catalán, César A N

    2010-11-01

    Two new acyclic diterpenoids, smaditerpenic acid E (1a) and F (2a), along with nineteen melampolide-type sesquiterpene lactones, six of them not previously reported in yacon, were isolated from the methylene chloride leaf rinse extract. Their structures were elucidated from 1D and 2D NMR experiments and gas chromatography coupled to mass spectrometry.

  12. Synthesis, spectroscopic and biological activities studies of acyclic and macrocyclic mono and binuclear metal complexes containing a hard-soft Schiff base

    NASA Astrophysics Data System (ADS)

    Abou-Hussein, Azza A. A.; Linert, Wolfgang

    Mono- and bi-nuclear acyclic and macrocyclic complexes with hard-soft Schiff base, H2L, ligand derived from the reaction of 4,6-diacetylresorcinol and thiocabohydrazide, in the molar ratio 1:2 have been prepared. The H2L ligand reacts with Co(II), Ni(II), Cu(II), Zn(II), Mn(II) and UO2(VI) nitrates, VO(IV) sulfate and Ru(III) chloride to get acyclic binuclear complexes except for VO(IV) and Ru(III) which gave acyclic mono-nuclear complexes. Reaction of the acyclic mono-nuclear VO(IV) and Ru(III) complexes with 4,6-diacetylresorcinol afforded the corresponding macrocyclic mono-nuclear VO(IV) and Ru(IIII) complexes. Template reactions of the 4,6-diacetylresorcinol and thiocarbohydrazide with either VO(IV) or Ru(III) salts afforded the macrocyclic binuclear VO(IV) and Ru(III) complexes. The Schiff base, H2L, ligand acts as dibasic with two NSO-tridentate sites and can coordinate with two metal ions to form binuclear complexes after the deprotonation of the hydrogen atoms of the phenolic groups in all the complexes, except in the case of the acyclic mononuclear Ru(III) and VO(IV) complexes, where the Schiff base behaves as neutral tetradentate chelate with N2S2 donor atoms. The ligands and the metal complexes were characterized by elemental analysis, IR, UV-vis 1H-NMR, thermal gravimetric analysis (TGA) and ESR, as well as the measurements of conductivity and magnetic moments at room temperature. Electronic spectra and magnetic moments of the complexes indicate the geometries of the metal centers are either tetrahedral, square planar or octahedral. Kinetic and thermodynamic parameters were calculated using Coats-Redfern equation, for the different thermal decomposition steps of the complexes. The ligands and the metal complexes were screened for their antimicrobial activity against Staphylococcus aureus as Gram-positive bacteria, and Pseudomonas fluorescens as Gram-negative bacteria in addition to Fusarium oxysporum fungus. Most of the complexes exhibit mild

  13. Calix[4]tetrahydrothiophenopyrrole: a ditopic receptor displaying a split personality for ion recognition.

    PubMed

    Saha, Indrajit; Park, Kyung Hwa; Han, Mina; Kim, Sung Kuk; Lynch, Vincent M; Sessler, Jonathan L; Lee, Chang-Hee

    2014-10-17

    A calix[4]pyrrole fused with 2,5-dihydrothiophene, possessing both a deep, π-electron-rich pocket upon anion binding and chelating ligands on the periphery, was developed. The receptor selectively forms an ion-pair complex with CsF through H-bonding and a cation-π interaction. In the process, it adopt a conformationally fixed cone conformation. The receptor displays exceptionally high affinity toward the Hg(II) ion and forms stable complexes while maintaining a rigid 1,3-alternate conformation. This metal ion-induced conformational locking is unprecedented in calix[4]pyrrole chemistry.

  14. The a-cycle problem for transverse Ising ring

    NASA Astrophysics Data System (ADS)

    Dong, Jian-Jun; Li, Peng; Chen, Qi-Hui

    2016-11-01

    Traditionally, the transverse Ising model is mapped to the fermionic c-cycle problem, which neglects the boundary effect due to thermodynamic limit. If persisting on a perfect periodic boundary condition, we can get a so-called a-cycle problem that has not been treated seriously so far (Lieb et al 1961 Ann. Phys. 16 407). In this work, we show a little surprising but exact result in this respect. We find the odevity of the number of lattice sites, N, in the a-cycle problem plays an unexpected role even in the thermodynamic limit, N\\to ∞ , due to the boundary constraint. We pay special attention to the system with N(\\in Odd)\\to ∞ , which is in contrast to the one with N(\\in Even)\\to ∞ , because the former suffers a ring frustration. As a new effect, we find the ring frustration induces a low-energy gapless spectrum above the ground state. By proving a theorem for a new type of Toeplitz determinant, we demonstrate that the ground state in the gapless region exhibits a peculiar longitudinal spin-spin correlation. The entangled nature of the ground state is also disclosed by the evaluation of its entanglement entropy. At low temperature, new behavior of specific heat is predicted. We also propose an experimental protocol for observing the new phenomenon due to the ring frustration.

  15. Catabolism of citronellol and related acyclic terpenoids in pseudomonads.

    PubMed

    Förster-Fromme, Karin; Jendrossek, Dieter

    2010-07-01

    Terpenes are a huge group of natural compounds characterised by their predominantly pleasant smell. They are built up by isoprene units in cyclic or acyclic form and can be functionalised by carbonyl, hydroxyl or carboxyl groups and by presence of additional carbon-carbon double bonds (terpenoids). Currently, much more than 10,000 terpenoid compounds are known, and many thereof are present in different iso- and stereoforms. Terpenoids are secondary metabolites and can have important biological functions in living organisms. In many cases, the biological functions of terpenoids are not known at all. Nevertheless, terpenoids are used in large quantities as perfumes and aroma compounds for food additives. Terpenoids can be also precursors and building blocks for synthesis of complex chiral compounds in chemical and pharmaceutical industry. Unfortunately, only few terpenoids are available in large quantities at reasonable costs. Therefore, characterisation of suited biocatalysts specific for terpenoid compounds and development of biotransformation processes of abundant terpenoids to commercially interesting derivates becomes more and more important. This minireview summarises knowledge on catabolic pathways and biotransformations of acyclic monoterpenes that have received only little attention. Terpenoids with 20 or more carbon atoms are not a subject of this study.

  16. Quaternary Stereogenic Centers through Enantioselective Heck Arylation of Acyclic Olefins with Aryldiazonium Salts: Application in a Concise Synthesis of (R)-Verapamil.

    PubMed

    Oliveira, Caio C; Pfaltz, Andreas; Correia, Carlos Roque Duarte

    2015-11-16

    We describe herein a highly regio- and enantioselective Pd-catalyzed Heck arylation of unactivated trisubstituted acyclic olefins to provide all-carbon quaternary stereogenic centers. Chiral N,N ligands of the pyrimidine- and pyrazino-oxazoline class were developed for that purpose, providing the desired products in good to high yields with enantiomeric ratios up to >99:1. Both linear and branched substituents on the olefins were well-tolerated. The potential of this new method is demonstrated by the straightforward synthesis of several O-methyl lactols and lactones containing quaternary stereocenters, together with a concise enantioselective total synthesis of the calcium channel blocker verapamil.

  17. Delay estimation in a two-node acyclic network

    PubMed Central

    2009-01-01

    Linear measures such as cross-correlation have been used successfully to determine time delays from the given processes. Such an analysis often precedes identifying possible causal relationships between the observed processes. The present study investigates the impact of a positively correlated driver whose correlation function decreases monotonically with lag on the delay estimation in a two-node acyclic network with one and two-delays. It is shown that cross-correlation analysis of the given processes can result in spurious identification of multiple delays between the driver and the dependent processes. Subsequently, delay estimation of increment process as opposed to the original process under certain implicit constraints is explored. Short-range and long-range correlated driver processes along with those of their coarse-grained counterparts are considered. PMID:19214240

  18. Graphical presentation of confounding in directed acyclic graphs.

    PubMed

    Suttorp, Marit M; Siegerink, Bob; Jager, Kitty J; Zoccali, Carmine; Dekker, Friedo W

    2015-09-01

    Since confounding obscures the real effect of the exposure, it is important to adequately address confounding for making valid causal inferences from observational data. Directed acyclic graphs (DAGs) are visual representations of causal assumptions that are increasingly used in modern epidemiology. They can help to identify the presence of confounding for the causal question at hand. This structured approach serves as a visual aid in the scientific discussion by making underlying relations explicit. This article explains the basic concepts of DAGs and provides examples in the field of nephrology with and without presence of confounding. Ultimately, these examples will show that DAGs can be preferable to the traditional methods to identify sources of confounding, especially in complex research questions.

  19. Estimation of Sparse Directed Acyclic Graphs for Multivariate Counts Data

    PubMed Central

    Han, Sung Won; Zhong, Hua

    2016-01-01

    Summary The next-generation sequencing data, called high throughput sequencing data, are recorded as count data, which is generally far from normal distribution. Under the assumption that the count data follow the Poisson log-normal distribution, this paper provides an L1-penalized likelihood framework and an efficient search algorithm to estimate the structure of sparse directed acyclic graphs (DAGs) for multivariate counts data. In searching for the solution, we use iterative optimization procedures to estimate the adjacency matrix and the variance matrix of the latent variables. The simulation result shows that our proposed method outperforms the approach which assumes multivariate normal distributions, and the log-transformation approach. It also shows that the proposed method outperforms the rank-based PC method under sparse network or hub network structures. As a real data example, we demonstrate the efficiency of the proposed method in estimating the gene regulatory networks of the ovarian cancer study. PMID:26849781

  20. Ligand directed self-assembly vs. metal ion coordination algorithm-when does the ligand or the metal take control?

    PubMed

    Shuvaev, Konstantin V; Abedin, Tareque S M; McClary, Corey A; Dawe, Louise N; Collins, Julie L; Thompson, Laurence K

    2009-04-28

    Polyfunctional hydrazone ligands with multidentate terminal donor groups offer metal ions many donor choices, and the coordination outcome depends mainly on the identity of the metal ion. Co(ii) and Ni(ii) prefer to adopt largely undistorted, six-coordinate geometries, while Cu(ii) can easily adapt to a variety of coordination situations (e.g. CN 4-6), and will optimize its coordination number and stereochemistry based on all the available donors. Ni(ii) and Co(ii) form simple [2 x 2] [M(4)-(micro(2)-O)(4)] square grids with such ditopic hydrazone ligands, and ignore other coordination options, while Cu(ii) tries to bind to all the available donors, and forms extended and 2D structures based on linked Cu(ii) triads rather than grids. Ni(ii) is also reluctant to compromise its desire to maximize its crystal field stabilization energy (CFSE) by binding to 'weak' ligands, and with a tetratopic pyrazole bis-hydrazone ligand it ignores the oxygen donors in favour of nitrogen, forming a novel trinuclear, triangular cluster. Also, reaction of a linear Ni(ii)(3) complex of a tetratopic pyridazine bis-hydrazone ligand with NiN(6) coordination spheres with Cu(ii), leads exclusively to a square Cu(12) grid based complex, and complete displacement of nickel. Structural and magnetic properties are highlighted, and metal-ligand interactions are discussed in detail.

  1. Enantioselective Pd-catalyzed allylation of acyclic α-fluorinated ketones.

    PubMed

    Wang, Wengui; Shen, Haiming; Wan, Xiao-Long; Chen, Qing-Yun; Guo, Yong

    2014-07-03

    Significant synthetic challenges remain for the asymmetric synthesis of tertiary α-fluoro ketones, which are potentially useful molecules for the development of drugs, agrochemicals, and functional materials. Herein, we describe the development of a method for the catalytic enantioselective synthesis of tertiary α-fluoro ketones via the Tsuji-Trost reaction of racemic acyclic α-fluorinated ketones. Enantioenriched acyclic α-cabonyl tertiary fluorides can be produced with the aid of a palladium/phosphinooxazoline catalyst.

  2. Differences between the Interactions of Linear and Tetrahedron-like Ditopic Guests with Cucurbit[8]uril: Steric Hindrance and Molecular Structure Play Dominant Roles.

    PubMed

    Hou, Shengzhen; Chen, Hao; Ma, Haili; Tan, Yebang

    2017-02-16

    A tetrahedron-like guest molecule (THV) with four ditopic arms, consisting of viologen (V) and hexylene moieties, was synthesized, and its interaction with cucurbit[8]uril (CB[8]) was investigated. As a reference, the interaction between CB[8] and an analogue of the arm of the linear ditopic guest (LHV) was first explored by (1) H NMR and UV/Vis spectroscopy. In this case, CB[8] was located on the hexylene moiety and resulted in the formation of a binary complex. However, when THV interacted with CB[8], despite having four arms with four hexylene moieties, only two CB[8] molecules were identified as located on the hexylene moieties; the other two CB[8] molecules resided on the V moieties. Great steric hindrance among the arms played a dominant role in the interaction between THV and CB[8]. Regardless of whether the guest molecule was THV or LHV, CB[8] moved to its V moiety (electron-deficient part) to form the charge-transfer complex upon the addition of a stopper containing a naphthol residue (electron-rich part). Guests LHV and THV were reduced to LHV(+(+.)) and THV(+4(+.)) upon the addition of sodium dithionite. Dimerization of LHV(+(+.)) was enhanced when CB[8] was present in less than 0.5 equivalents. In contrast, dimerization was suppressed when CB[8] was present in more than 0.5 equivalents. However, the V(+.) units of THV(+4(+.)) stacked intramolecularly because of the tetrahedron-like molecular structure of THV. The influence of CB[8] on the dimerization of THV(+4(+.)) was weaker than that on LHV(+(+.)) .

  3. Structural Interactions within Lithium Salt Solvates. Acyclic Carbonates and Esters

    SciTech Connect

    Afroz, Taliman; Seo, D. M.; Han, Sang D.; Boyle, Paul D.; Henderson, Wesley A.

    2015-03-06

    Solvate crystal structures serve as useful models for the molecular-level interactions within the diverse solvates present in liquid electrolytes. Although acyclic carbonate solvents are widely used for Li-ion battery electrolytes, only three solvate crystal structures with lithium salts are known for these and related solvents. The present work, therefore, reports six lithium salt solvate structures with dimethyl and diethyl carbonate: (DMC)2:LiPF6, (DMC)1:LiCF3SO3, (DMC)1/4:LiBF4, (DEC)2:LiClO4, (DEC)1:LiClO4 and (DEC)1:LiCF3SO3 and four with the structurally related methyl and ethyl acetate: (MA)2:LiClO4, (MA)1:LiBF4, (EA)1:LiClO4 and (EA)1:LiBF4.

  4. PQQ-dependent alcohol dehydrogenase (QEDH) of Pseudomonas aeruginosa is involved in catabolism of acyclic terpenes.

    PubMed

    Chattopadhyay, Ava; Förster-Fromme, Karin; Jendrossek, Dieter

    2010-04-01

    Growth of Pseudomonas aeruginosa on acyclic terpene alcohols such as geraniol depends on the presence of the atuRABCDEFGH gene cluster and a functional acyclic terpene utilisation (Atu) pathway. The proteins encoded by the atu gene cluster are necessary but not sufficient for growth on acyclic terpenes. Comparative 2-dimensional polyacrylamide gel electrophoresis of soluble P. aeruginosa proteins revealed the presence of an additional spot (besides Atu proteins) that is specifically expressed in geraniol cells but is absent in isovalerate-grown cells. The spot was identified as PA1982 gene product a pyrroloquinoline quinone (PQQ) dependent ethanol oxidoreductase (QEDH). Inactivation of PA1982 by insertion mutagenesis resulted in inability of the mutant to utilise ethanol and in reduced growth on geraniol. Growth on ethanol was restored by transferring an intact copy of the PA1982 gene into the mutant. The PA1982 gene product was purified from recombinant Escherichia coli and revealed PQQ-dependent oxidoreductase activity with a variety of substrates including acyclic terpene derivates at comparable V(max)-values. Our results show that QEDH participates in oxidation of acyclic terpene derivates in addition to the well-known function in ethanol metabolism.

  5. Acyclic cucurbit[n]uril molecular containers enhance the solubility and bioactivity of poorly soluble pharmaceuticals

    NASA Astrophysics Data System (ADS)

    Ma, Da; Hettiarachchi, Gaya; Nguyen, Duc; Zhang, Ben; Wittenberg, James B.; Zavalij, Peter Y.; Briken, Volker; Isaacs, Lyle

    2012-06-01

    The solubility characteristics of 40-70% of new drug candidates are so poor that they cannot be formulated on their own, so new methods for increasing drug solubility are highly prized. Here, we describe a new class of general-purpose solubilizing agents—acyclic cucurbituril-type containers—which increase the solubility of ten insoluble drugs by a factor of between 23 and 2,750 by forming container-drug complexes. The containers exhibit low in vitro toxicity in human liver, kidney and monocyte cell lines, and outbred Swiss Webster mice tolerate high doses of the container without sickness or weight loss. Paclitaxel solubilized by the acyclic cucurbituril-type containers kills cervical and ovarian cancer cells more efficiently than paclitaxel alone. The acyclic cucurbituril-type containers preferentially bind cationic and aromatic drugs, but also solubilize neutral drugs such as paclitaxel, and represent an attractive extension of cyclodextrin-based technology for drug solubilization and delivery.

  6. Some biochemical properties of an acyclic oligonucleotide analogue. A plausible ancestor of the DNA?

    NASA Astrophysics Data System (ADS)

    Merle, Liliane; Spach, Gérard; Merle, Yves; Sági, János; Szemzö, Attila

    1993-04-01

    As acyclic oligonucleotides have been suggested as a primitive model of DNA or RNA in prebiotic times, we compared some biochemical properties of these analogues to that of natural ones. Firstly, an acyclic analogue of deoxyribonucleoside triphosphates was tested as a potential substrate of enzymes intervening in nucleic acids synthesis. GlyTTP, a dTTP analogue with a missing 2'-methylene group is notaccepted as a substrate by either DNA polymerase or deoxynucleotidyl terminal transferase (TdT). Secondly, themodified dodecathymidylate (GlyT)12, the racemic acyclic sugar analogue of (dT)12, proved to be anefficient primer for DNA polymerase and TdT, though the associative properties of (GlyT)12 are very weak as shown by UV spectroscopy in phosphate buffer without magnesium chloride. But (GlyT)12 has the advantage to be 500-times more stable against hydrolysis by snake venom phosphodiesterase than the corresponding oligothymidylate.

  7. Acyclic monoterpenes in tree essential oils as a shrinking agent for waste-expanded polystyrene.

    PubMed

    Shimotori, Yasutaka; Hattori, Kazuyuki; Aoyama, Masakazu; Miyakoshi, Tetsuo

    2011-01-01

    We examined the dissolution of polystyrene (PS) into acyclic monoterpenes present in tree essential oils, to develop an environmentally friendly shrinking agent for waste-expanded polystyrene (EPS). The dissolving powers of geranyl acetate, geranylacetone, and geranyl formate [221.8-241.2 g PS (100 g solvent)(-1)] compared favorably with that of (R)-limonene [181.7 g PS (100 g solvent)(-1)]. Their favorable dissolving powers for PS can be explained by their flexible linear structures, which may be more accessible to the inside of bulk PS compared with cyclic monoterpenes. These acyclic monoterpenes and PS were recovered almost quantitatively by simple steam distillation of the PS solution.

  8. Synthesis of antisense oligonucleotides containing acyclic alkynyl nucleoside analogs and their biophysical and biological properties.

    PubMed

    Ogata, Aya; Maeda, Yusuke; Ueno, Yoshihito

    2017-04-01

    The synthesis of oligonucleotide (ON) analogs, which can be used as antisense molecules, has recently gained much attention. Here, we report the synthesis and properties of an ON analog containing acyclic thymidine and cytidine analogs with a 4-pentyl-1,2-diol instead of the d-ribofuranose moiety. The incorporation of these analogs into the ON improved its nuclease resistance to 3'-exonucleases. Furthermore, it was found that the incorporation of the acyclic thymidine analog into a DNA/RNA duplex accelerates the RNA cleavage of a DNA/RNA duplex by Escherichia coli RNase H.

  9. Solution and Structural Investigations of Ligand Preorganization in Trivalent Lanthanide Complexes of Bicyclic Malonamides

    SciTech Connect

    Parks, Bevin W.; Gilbertson, Robert D.; Hutchison, J. E.; Rather Healey, Elisabeth; Weakley, Timothy J R; Rapko, Brian M.; Hay, Benjamin P.; Sinkov, Sergei I.; Broker, Grant A.; Rogers, Robin D.

    2006-02-20

    This report describes an investigation into the coordination chemistry of trivalentlanthanides in solution and the solid state with acyclic and preorganized bicyclic malonamide ligands. Two experimental investigations were performed: solution bindingaffinities were determined through single-phase spectrophotometric titrations and the extent of conformational change upon binding was investigated with single-crystal X-raycrystallography. Both experimental methods compare the bicyclic malonamide (BMA), which is designed to be preorganized for binding trivalent lanthanides, to an analogousacyclic malonamide. Results from the spectrophotometric titrations indicate that BMA exhibits a 10-100 times increase in binding affinity to Ln(III) over acyclic malonamide.In addition, BMA forms compounds with high ligand-metal ratios, even when competing with water and nitrate ligands for binding sites. The crystal structures exhibit nosignificant differences in the nature of the binding between Ln(III) and the BMA or acyclic malonamide. These results support the conclusion that rational ligand design canlead to compounds that enhance the binding affinities within a ligand class.

  10. Acyclic and star colorings of joins of graphs and an algorithm for cographs.

    SciTech Connect

    Lyons, A.; Mathematics and Computer Science; Univ. of Chicago

    2009-01-01

    An acyclic coloring of a graph is a proper vertex coloring such that the subgraph induced by the union of any two color classes is a disjoint collection of trees. The more restricted notion of star coloring requires that the union of any two color classes induces a disjoint collection of stars. The acyclic and star chromatic numbers of a graph G are defined analogously to the chromatic number {chi}(G) and are denoted by {chi}{sub a}(G) and {chi}{sub s}(G), respectively. In this paper, we consider acyclic and star colorings of graphs that are decomposable with respect to the join operation, which builds a new graph from a collection of two or more disjoint graphs by adding all possible edges between them. In particular, we present a recursive formula for the acyclic chromatic number of joins of graphs and show that a similar formula holds for the star chromatic number. We also demonstrate the algorithmic implications of our results for the cographs, which have the unique property that they are recursively decomposable with respect to the join and disjoint union operations.

  11. Some acyclic analogues of nucleotides and their template-directed reactions

    NASA Technical Reports Server (NTRS)

    Tohidi, Mahrokh; Orgel, Leslie E.

    1989-01-01

    Bismonophosphoimidazolides of acyclic analogues of guanosine IV and adenosine V were synthesized. They undergo oligomerization in the presence of complementary polynucleotide templates. Details of their synthesis and their subsequent template- and nontemplate-directed reactions are described, and their possible relevance to the origin of life is discussed.

  12. Evidence for halogen bond covalency in acyclic and interlocked halogen-bonding receptor anion recognition

    DOE PAGES

    Robinson, Sean W.; Mustoe, Chantal L.; White, Nicholas G.; ...

    2014-12-05

    The synthesis and anion binding properties of novel halogen-bonding (XB) bis-iodotriazole-pyridinium-containing acyclic and [2]catenane anion host systems are described. The XB acyclic receptor displays selectivity for acetate over halides with enhanced anion recognition properties compared to the analogous hydrogen-bonding (HB) acyclic receptor. A reversal in halide selectivity is observed in the XB [2]catenane, in comparison to the acyclic XB receptor, due to the interlocked host’s unique three-dimensional binding cavity, and no binding is observed for oxoanions. Notable halide anion association constant values determined for the [2]catenane in competitive organic–aqueous solvent mixtures demonstrate considerable enhancement of anion recognition as compared tomore » the HB catenane analogue. X-ray crystallographic analysis of a series of halide catenane complexes reveal strong XB interactions in the solid state. These interactions were studied using Cl and Br K-edge X-ray Absorption Spectroscopy (XAS) indicating intense pre-edge features characteristic of charge transfer from the halide to its bonding partner (σAX←X–* ← X1s), and providing a direct measure of the degree of covalency in the halogen bond(s). Lastly, the data reveal that the degree of covalency is similar to that which is observed in transition metal coordinate covalent bonds. These results are supported by DFT results, which correlate well with the experimental data.« less

  13. Evidence for halogen bond covalency in acyclic and interlocked halogen-bonding receptor anion recognition

    SciTech Connect

    Robinson, Sean W.; Mustoe, Chantal L.; White, Nicholas G.; Brown, Asha; Thompson, Amber L.; Kennepohl, Pierre; Beer, Paul D.

    2014-12-05

    The synthesis and anion binding properties of novel halogen-bonding (XB) bis-iodotriazole-pyridinium-containing acyclic and [2]catenane anion host systems are described. The XB acyclic receptor displays selectivity for acetate over halides with enhanced anion recognition properties compared to the analogous hydrogen-bonding (HB) acyclic receptor. A reversal in halide selectivity is observed in the XB [2]catenane, in comparison to the acyclic XB receptor, due to the interlocked host’s unique three-dimensional binding cavity, and no binding is observed for oxoanions. Notable halide anion association constant values determined for the [2]catenane in competitive organic–aqueous solvent mixtures demonstrate considerable enhancement of anion recognition as compared to the HB catenane analogue. X-ray crystallographic analysis of a series of halide catenane complexes reveal strong XB interactions in the solid state. These interactions were studied using Cl and Br K-edge X-ray Absorption Spectroscopy (XAS) indicating intense pre-edge features characteristic of charge transfer from the halide to its bonding partner (σAX←X–* ← X1s), and providing a direct measure of the degree of covalency in the halogen bond(s). Lastly, the data reveal that the degree of covalency is similar to that which is observed in transition metal coordinate covalent bonds. These results are supported by DFT results, which correlate well with the experimental data.

  14. Acyclic sulfides, garlicnins L-1-L-4, E, and F, from Allium sativum.

    PubMed

    Nohara, Toshihiro; Fujiwara, Yukio; Ikeda, Tsuyoshi; Yamaguchi, Koki; Manabe, Hideyuki; Murakami, Kotaro; Ono, Masateru; Nakano, Daisuke; Kinjo, Junei

    2014-01-01

    Six novel acyclic sulfides, named garlicnins L-1-L-4 (1-4), E (5), and F (6), were isolated from the acetone extracts, with the ability to suppress M2 macrophage activation, of the bulbs of garlic (Allium sativum L.), and their chemical structures were characterized.

  15. Study on follicular characteristics, hormonal and biochemical profile in norgestomet+PMSG treated acyclic buffaloes

    PubMed Central

    Jerome, A.; Srivastava, S. K.; Sharma, R. K.

    2016-01-01

    This research was conducted to study the follicular dynamics, hormonal, biochemical profile and fertility response in acyclic and norgestomet+PMSG treated acyclic buffaloes in summer. The study animals were divided into two groups: group I [control (n=8): no treatment] and II [treatment group (n=15)]. In group II, seven animals were used for follicular biochemical and hormonal profile and eight animals for fertility studies following Crestar® (Intervet, France) treatment (day 0: Crestar® insertion; day 8: 500 IU PMSG; day 9: Crestar® removal; day 11 AI). Follicular fluid stradiol (E2) and progesterone (P4) in acyclic and pre-ovulatory follicle in study groups was significantly (P<0.01) higher than peripheral level. Peripheral E2 concentration, during pre-ovulatory period in group II was higher (P<0.05) than group I. Significant correlation between serum and follicular E2 was deduced (r=0.888; P<0.01) as significant difference in serum cholesterol content was shown between groups. Lower follicular total protein (P<0.05) in acyclic animals and higher follicular glucose (P<0.05) in treated group were concluded. Significant correlation (r=-0.770; P<0.05) was observed between follicular cholesterol and triglycerides. Follicular characteristics, post PMSG administration, differed significantly (0.83 ± 0.20 vs 1.32 ± 0.12; P<0.01) in all buffaloes exhibiting estrus, out of which four conceived. In conclusion, follicular hormonal and biochemical profile exhibits alteration in protein and glucose level between summer acyclic and treated buffaloes. However, peripheral E2 along with fertility response showed significant difference (P<0.01) between the study groups with significant correlation in E2, cholesterol and triglycerides between peripheral and follicular compartment. PMID:28224008

  16. Evidence that hyperprolactinaemia is associated with ovarian acyclicity in female zoo African elephants.

    PubMed

    Dow, T L; Brown, J L

    2012-01-01

    African elephants of reproductive age in zoos are experiencing high rates of ovarian cycle problems (>40%) and low reproductive success. Previously, our laboratory found that 1/3 of acyclic females exhibit hyperprolactinaemia, a likely cause of ovarian dysfunction. This follow-up study re-examined hyperprolactinaemia in African elephants and found the problem has increased significantly to 71% of acyclic females. Circulating serum progestagens and prolactin were analysed in 31 normal cycling, 13 irregular cycling and 31 acyclic elephants for 12 months. In acyclic females, overall mean prolactin concentrations differed from cycling females (P < 0.05), with concentrations being either higher (n = 22; 54.90 ± 13.31 ngmL(-1)) or lower (n = 9; 6.47 ± 1.73 ngmL(-1)) than normal. No temporal patterns of prolactin secretion were evident in elephants that lacked progestagen cycles. In cycling females, prolactin was secreted in a cyclical manner, with higher concentrations observed during nonluteal (34.38 ± 1.77 and 32.75 ± 2.61 ngmL(-1)) than luteal (10.51 ± 0.30 and 9.67 ± 0.42 ngmL(-1)) phases for normal and irregular females, respectively. Of most concern was that over two-thirds of acyclic females now are hyperprolactinemic, a dramatic increase over that observed 7 years earlier. Furthermore, females of reproductive age constituted 45% of elephants with hyperprolactinaemia. Until the cause of this problem is identified and a treatment is developed, reproductive rates will remain suboptimal and the population nonsustaining.

  17. Unusual Recognition and Separation of Hydrated Metal Sulfates [M2(μ-SO4)2(H2O)n, M = Zn(II), Cd(II), Co(II), Mn(II)] by a Ditopic Receptor.

    PubMed

    Ghosh, Tamal Kanti; Dutta, Ranjan; Ghosh, Pradyut

    2016-04-04

    A ditopic receptor L1, having metal binding bis(2-picolyl) donor and anion binding urea group, is synthesized and explored toward metal sulfate recognition via formation of dinuclear assembly, (L1)2M2(SO4)2. Mass spectrometric analysis, (1)H-DOSY NMR, and crystal structure analysis reveal the existence of a dinuclear assembly of MSO4 with two units of L1. (1)H NMR study reveals significant downfield chemical shift of -NH protons of urea moiety of L1 selectively with metal sulfates (e.g., ZnSO4, CdSO4) due to second-sphere interactions of sulfate with the urea moiety. Variable-temperature (1)H NMR studies suggest the presence of intramolecular hydrogen bonding interaction toward metal sulfate recognition in solution state, whereas intermolecular H-bonding interactions are observed in solid state. In contrast, anions in their tetrabutylammonium salts fail to interact with the urea -NH probably due to poor acidity of the tertiary butyl urea group of L1. Metal sulfate binding selectivity in solution is further supported by isothermal titration calorimetric studies of L1 with different Zn salts in dimethyl sulfoxide (DMSO), where a binding affinity is observed for ZnSO4 (Ka = 1.23 × 10(6)), which is 30- to 50-fold higher than other Zn salts having other counteranions in DMSO. Sulfate salts of Cd(II)/Co(II) also exhibit binding constants in the order of ∼1 × 10(6) as in the case of ZnSO4. Positive role of the urea unit in the selectivity is confirmed by studying a model ligand L2, which is devoid of anion recognition urea unit. Structural characterization of four MSO4 [M = Zn(II), Cd(II), Co(II), Mn(II)] complexes of L1, that is, complex 1, [(L1)2(Zn)2(μ-SO4)2]; complex 2, [(L1)2(H2O)2(Cd)2(μ-SO4)2]; complex 3, [(L1)2(H2O)2(Co)2(μ-SO4)2]; and complex 4, [(L1)2(H2O)2(Mn)2(μ-SO4)2], reveal the formation of sulfate-bridged eight-membered crownlike binuclear complexes, similar to one of the concentration-dependent dimeric forms of MSO4 as observed in solid state

  18. Highly π electron-rich macro-aromatics: bis(p-aminophenyl)-carbo-benzenes and their DBA acyclic references.

    PubMed

    Rives, Arnaud; Baglai, Iaroslav; Malytskyi, Volodymyr; Maraval, Valérie; Saffon-Merceron, Nathalie; Voitenko, Zoia; Chauvin, Remi

    2012-09-11

    A series of stable quadrupolar bis(p-aminophenyl)-carbo-benzenes, featuring both donor-donor-donor π-frustration and central macro-aromaticity, is described and compared to the acyclic dibutatrienylacetylene (DBA) reference series.

  19. One-pot synthesis of acyclic nucleosides from carbohydrate derivatives, by combination of tandem and sequential reactions.

    PubMed

    Boto, Alicia; Hernández, Dácil; Hernández, Rosendo; Alvarez, Eleuterio

    2007-12-07

    The design of processes which combine tandem and sequential reactions allows the transformation of readily available precursors into high-profit products. This strategy is illustrated by the one-pot synthesis of acyclic nucleosides, which are potential antiviral compounds, from readily available carbohydrates. The reaction conditions are mild, compatible with most functional groups. Depending on the starting sugar, both common and uncommon acyclic chains can be prepared. These polyhydroxylated chains can be combined with different bases to generate diversity.

  20. Screening of a minimal enriched P450 BM3 mutant library for hydroxylation of cyclic and acyclic alkanes.

    PubMed

    Weber, Evelyne; Seifert, Alexander; Antonovici, Mihaela; Geinitz, Christopher; Pleiss, Jürgen; Urlacher, Vlada B

    2011-01-21

    A minimal enriched P450 BM3 library was screened for the ability to oxidize inert cyclic and acyclic alkanes. The F87A/A328V mutant was found to effectively hydroxylate cyclooctane, cyclodecane and cyclododecane. F87V/A328F with high activity towards cyclooctane hydroxylated acyclic n-octane to 2-(R)-octanol (46% ee) with high regioselectivity (92%).

  1. Alterations in follicular fluid estradiol, progesterone and insulin concentrations during ovarian acyclicity in water buffalo (Bubalus bubalis).

    PubMed

    Khan, F A; Das, G K; Pande, Megha; Sarkar, M; Mahapatra, R K; Shankar, Uma

    2012-01-01

    Ovarian acyclicity is one of the most important causes of infertility in water buffalo. Recent studies have indicated alterations in the composition of follicular fluid during the condition. The aim of this study was to determine the changes in follicular fluid concentrations of estradiol, progesterone and insulin during ovarian acyclicity in water buffalo. Ovaries were collected from 50 acyclic and 95 cyclic (control) buffaloes and follicular fluid was aspirated from small (5.0-6.9 mm), medium (7.0-9.9 mm) and large (≥10.0 mm) sized follicles. Estradiol concentration was lower (P<0.0001) in acyclic (1.4 ± 0.09 ng/ml) than in cyclic (3.3 ± 0.18 ng/ml) buffaloes. Regardless of the ovarian cyclic status, there was an increase (P<0.01) in estradiol concentration with the increase in follicle size; the mean concentrations were 2.4 ± 0.16 ng/ml, 2.8 ± 0.29 ng/ml and 3.5 ± 0.41 ng/ml in small, medium and large follicles, respectively. A higher (P<0.001) progesterone concentration was recorded in acyclic (24.3 ± 2.61 ng/ml) compared to the cyclic (7.6 ± 0.79 ng/ml) group. Furthermore, acyclic buffaloes had a lower (P<0.05) concentration of insulin in the follicular fluid than that of cyclic buffaloes (15.2 ± 1.55 μIU/ml versus 25.9 ± 2.78 μIU/ml, respectively). In conclusion, acyclic buffaloes have lower concentrations of estradiol and insulin concurrent with higher concentrations of progesterone in the follicular fluid. These hormonal changes in the follicular microenvironment are possibly a manifestation of the disturbances in the normal follicular development leading to anovulation and anestrus in acyclic buffaloes.

  2. Acyclic ketones in the defensive secretion of a "daddy longlegs" (Leiobunum vittatum).

    PubMed

    Meinwald, J; Kluge, A F; Carrel, J E; Eisner, T

    1971-07-01

    The defensive secretion of the "daddy longlegs" Leiobunum vittatum was analyzed and found to contain the acyclic ketones 4-methylheptan-3-one and E-4,6-dimethyl-6-octen-3-one as its major organic components. Although 4-methylheptan-3-one has been found previously as an alarm substance in certain ant genera, the second component, whose structure is confirmed by synthesis, is new.

  3. Follicular characteristics and intrafollicular concentrations of nitric oxide and ascorbic acid during ovarian acyclicity in water buffalo (Bubalus bubalis).

    PubMed

    Khan, Firdous Ahmad; Das, Goutam Kumar

    2012-01-01

    The objective of this study was to examine the follicular characteristics and intrafollicular concentrations of nitric oxide and ascorbic acid during ovarian acyclicity in buffaloes. Ovaries were collected from 56 acyclic and 95 cyclic buffaloes at slaughter, surface follicle number was counted and follicles were classified into small (5.0-6.9 mm), medium (7.0-9.9 mm), and large (≥ 10.0 mm) size categories based on their diameter. Follicular fluid was aspirated and assayed for nitric oxide, ascorbic acid, estradiol, and progesterone. Acyclic buffaloes had a higher (P<0.05) number of medium-sized follicles and a lower (P<0.001) number of large follicles than the cyclic ones. In acyclic animals, the number of large follicles was lower (P<0.01) than in medium size category which in turn was lower (P<0.001) than the number of small follicles. In contrast, the number of medium and large follicles was not different (P>0.05) in the cyclic control. However, the number of small-sized follicles was higher (P<0.001) compared to the other two categories. The incidence of large-sized follicles was lower (P<0.05) in acyclic buffalo population compared to the cyclic control. Evaluation of estrogenic status demonstrated that all the follicles of acyclic buffaloes are estrogen-inactive (E (2)/P (4) ratio<1). Small- and medium-sized follicles of acyclic buffaloes had higher concentrations of nitric oxide (P<0.05 and P<0.001, respectively) and lower concentrations of ascorbic acid (P<0.05 and P<0.01, respectively) than the corresponding size estrogen-active follicles of their cyclic counterparts. In conclusion, this study indicates that follicular development continues during acyclicity in buffaloes. Although follicles in some acyclic buffaloes attain a size corresponding to morphological dominance, they are unable to achieve functional dominance, perhaps due to an altered balance of intrafollicular nitric oxide and ascorbic acid and, as a result, these follicles instead of

  4. Next generation macrocyclic and acyclic cationic lipids for gene transfer: Synthesis and in vitro evaluation.

    PubMed

    Jubeli, Emile; Maginty, Amanda B; Abdul Khalique, Nada; Raju, Liji; Abdulhai, Mohamad; Nicholson, David G; Larsen, Helge; Pungente, Michael D; Goldring, William P D

    2015-10-01

    Previously we reported the synthesis and in vitro evaluation of four novel, short-chain cationic lipid gene delivery vectors, characterized by acyclic or macrocyclic hydrophobic regions composed of, or derived from, two 7-carbon chains. Herein we describe a revised synthesis of an expanded library of related cationic lipids to include extended chain analogues, their formulation with plasmid DNA (pDNA) and in vitro delivery into Chinese hamster ovarian (CHO-K1) cells. The formulations were evaluated against each other based on structural differences in the hydrophobic domain and headgroup. Structurally the library is divided into four sets based on lipids derived from two 7- or two 11-carbon hydrophobic chains, C7 and C11 respectively, which possess either a dimethylamine or a trimethylamine derived headgroup. Each set includes four cationic lipids based on an acyclic or macrocyclic, saturated or unsaturated hydrophobic domain. All lipids were co-formulated with the commercial cationic lipid 1,2-dimyristoyl-sn-glycero-3-ethylphosphocholine (EPC) in a 1:1 molar ratio, along with one of two distinct neutral co-lipids, cholesterol or 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) in an overall cationic-to-neutral lipid molar ratio of 3:2. Binding of lipid formulations with DNA, and packing morphology associated with the individual lipid-DNA complexes were characterized by gel electrophoresis and small angle X-ray diffraction (SAXD), respectively. As a general trend, lipoplex formulations based on mismatched binary cationic lipids, composed of a shorter C7 lipid and the longer lipid EPC (C14), were generally associated with higher transfection efficiency and lower cytotoxicity than their more closely matched C11/EPC binary lipid formulation counterparts. Furthermore, the cyclic lipids gave transfection levels as high as or greater than their acyclic counterparts, and formulations with cholesterol exhibited higher transfection and lower cytotoxicity than those

  5. Acyclic phosph(on)ate inhibitors of Plasmodium falciparum hypoxanthine-guanine-xanthine phosphoribosyltransferase

    PubMed Central

    Clinch, Keith; Crump, Douglas R.; Evans, Gary B.; Hazleton, Keith Z.; Mason, Jennifer M.; Schramm, Vern L.

    2013-01-01

    The pathogenic protozoa responsible for malaria lack enzymes for the de novo synthesis of purines and rely on purine salvage from the host. In Plasmodium falciparum (Pf), hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT) converts hypoxanthine to inosine monophosphate and is essential for purine salvage making the enzyme an anti-malarial drug target. We have synthesized a number of simple acyclic aza-C- nucleosides and shown that some are potent inhibitors of Pf HGXPRT while showing excellent selectivity for the Pf versus the human enzyme. PMID:23810424

  6. Neutral losses: a type of important variables in prediction of branching degree for acyclic alkenes from mass spectra.

    PubMed

    Zhang, Liangxiao; Fan, Wei; Cao, Dongsheng; Zeng, Maomao; Xiao, Hongbin; Liang, Yizeng

    2012-03-30

    Neutral losses are a type of important variables in mass spectral interpretation. Since it is hard to calculate or extract neutral losses from mass spectra, they are usually discarded. In this study, dissimilarity analysis was employed to extract mass spectral characteristics for predicting branching degree of acyclic alkenes. The relationships between branching degree and neutral loss were constructed under direction of experimental observation and mass spectral fragmentations. A branching degree predictor of acyclic alkenes was subsequently built based on the above relationships. After tested by the experimental data in previous studies, the predictor could correctly provide the branching degree from abundant ions of mass spectra. More importantly, this predictor was able to point out which acyclic alkenes could be predicted correctly or not.

  7. A novel acyclic oligomycin A derivative formed via retro-aldol rearrangement of oligomycin A.

    PubMed

    Lysenkova, Lyudmila N; Turchin, Konstantin F; Korolev, Alexander M; Bykov, Evgenyi E; Danilenko, Valery N; Bekker, Olga B; Trenin, Alexey S; Elizarov, Sergei M; Dezhenkova, Lyubov G; Shtil, Alexander A; Preobrazhenskaya, Maria N

    2012-08-01

    The antibiotic oligomycin A in the presence of K(2)CO(3) and n-Bu(4)NHSO(4) in chloroform in phase-transfer conditions afforded a novel derivative through the initial retro-aldol fragmentation of the 8,9 bond, followed by further transformation of the intermediate aldehyde. NMR, MS and quantum chemical calculations showed that the novel compound is the acyclic oligomycin A derivative, in which the 8,9 carbon bond is disrupted and two polyfunctional branches are connected with spiroketal moiety in positions C-23 and C-25. The tri-O-acetyl derivative of the novel derivative was prepared. The acyclic oligomycin A derivative retained the ability to induce apoptosis in tumor cells at low micromolar concentrations, whereas its antimicrobial potencies decreased substantially. The derivative virtually lost the inhibitory activity against F(0)F(1) ATP synthase-containing proteoliposomes, strongly suggesting the existence of the target(s) beyond F(0)F(1) ATP synthase that is important for the antitumor potency of oligomycin A.

  8. Drude polarizable force field for aliphatic ketones and aldehydes, and their associated acyclic carbohydrates

    NASA Astrophysics Data System (ADS)

    Small, Meagan C.; Aytenfisu, Asaminew H.; Lin, Fang-Yu; He, Xibing; MacKerell, Alexander D.

    2017-02-01

    The majority of computer simulations exploring biomolecular function employ Class I additive force fields (FF), which do not treat polarization explicitly. Accordingly, much effort has been made into developing models that go beyond the additive approximation. Development and optimization of the Drude polarizable FF has yielded parameters for selected lipids, proteins, DNA and a limited number of carbohydrates. The work presented here details parametrization of aliphatic aldehydes and ketones (viz. acetaldehyde, propionaldehyde, butaryaldehyde, isobutaryaldehyde, acetone, and butanone) as well as their associated acyclic sugars (uc(d)-allose and uc(d)-psicose). LJ parameters are optimized targeting experimental heats of vaporization and molecular volumes, while the electrostatic parameters are optimized targeting QM water interactions, dipole moments, and molecular polarizabilities. Bonded parameters are targeted to both QM and crystal survey values, with the models for ketones and aldehydes shown to be in good agreement with QM and experimental target data. The reported heats of vaporization and molecular volumes represent a compromise between the studied model compounds. Simulations of the model compounds show an increase in the magnitude and the fluctuations of the dipole moments in moving from gas phase to condensed phases, which is a phenomenon that the additive FF is intrinsically unable to reproduce. The result is a polarizable model for aliphatic ketones and aldehydes including the acyclic sugars uc(d)-allose and uc(d)-psicose, thereby extending the available biomolecules in the Drude polarizable FF.

  9. Seven-coordinate iron and manganese complexes with acyclic and rigid pentadentate chelates and their superoxide dismutase activity.

    PubMed

    Liu, Gao-Feng; Filipović, Milos; Heinemann, Frank W; Ivanović-Burmazović, Ivana

    2007-10-15

    The reactions of seven-coordinate [Fe(III)(dapsox)(H(2)O)(2)]ClO(4).H(2)O (1), [Fe(II)(H(2)dapsox)(H(2)O)(2)](NO(3))(2).H(2)O (2), and [Mn(II)(H(2)dapsox)(CH(3)OH)(H(2)O)](ClO4)2(H2O) (3) complexes of the acyclic and rigid pentadentate H(2)dapsox ligand [H2dapsox = 2,6-diacetylpyridinebis(semioxamazide)] with superoxide have been studied spectrophotometrically, electrochemically, and by a submillisecond mixing UV/vis stopped-flow in dimethyl sulfoxide (DMSO). The same studies were performed on the seven-coordinate [Mn(II)(Me(2)[15]pyridinaneN(5))(H(2)O)(2)]Cl(2).H(2)O (4) complex with the flexible macrocyclic Me(2)[15]pyridinaneN(5) ligand (Me(2)[15]pyridinaneN(5) = trans-2,13-dimethyl-3,6,9,12,18-pentaazabicyclo[12.3.1]octadeca-1(18),14,16-triene), which belongs to the class of proven superoxide dismutase (SOD) mimetics. The X-ray crystal structures of 2-4 were determined. All complexes possess pentagonal-bipyramidal geometry with the pentadentate ligand in the equatorial plane and solvent molecules in the axial positions. The stopped-flow experiments in DMSO (0.06% of water) reveal that all four metal complexes catalyze the fast disproportionation of superoxide under the applied experimental conditions, and the catalytic rate constants are found to be (3.7 +/- 0.5) x 10(6), (3.9 +/- 0.5) x 10(6), (1.2 +/- 0.3) x 10(7), and (5.3 +/- 0.8) x 10(6) M(-1) s(-1) for 1-4, respectively. The cytochrome c McCord-Fridovich (McCF) assay in an aqueous solution at pH = 7.8 resulted in the IC(50) values (and corresponding kMcCF constants) for 3 and 4, 0.013 +/- 0.001 microM (1.9 +/- 0.2 x 10(8) M(-1) s(-1)) and 0.024 +/- 0.001 microM (1.1 +/- 0.3 x 10(8) M(-1) s(-1)), respectively. IC(50) values from a nitroblue tetrazolium assay are found to be 6.45 +/- 0.02 and 1.36 +/- 0.03 microM for 1 and 4, respectively. The data have been compared with those obtained by direct stopped-flow measurements and discussed in terms of the side reactions that occur under the conditions of

  10. Ether lipid-ester prodrugs of acyclic nucleoside phosphonates: activity against adenovirus replication in vitro.

    PubMed

    Hartline, Caroll B; Gustin, Kortney M; Wan, William B; Ciesla, Stephanie L; Beadle, James R; Hostetler, Karl Y; Kern, Earl R

    2005-02-01

    The acyclic nucleoside phosphonate cidofovir (CDV) and its closely related analogue (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)-adenine ([S]-HPMPA) have been reported to have activity against many adenovirus (AdV) serotypes. A new series of orally active ether lipid-ester prodrugs of CDV and of (S)-HPMPA that have slight differences in the structure of their lipid esters were evaluated, in tissue-culture cells, for activity against 5 AdV serotypes. The results indicated that, against several AdV serotypes, the most active compounds were 15-2500-fold more active than the unmodified parent compounds and should be evaluated further for their potential to treat AdV infections in humans.

  11. Halogen bonding in water results in enhanced anion recognition in acyclic and rotaxane hosts

    NASA Astrophysics Data System (ADS)

    Langton, Matthew J.; Robinson, Sean W.; Marques, Igor; Félix, Vítor; Beer, Paul D.

    2014-12-01

    Halogen bonding (XB), the attractive interaction between an electron-deficient halogen atom and a Lewis base, has undergone a dramatic development as an intermolecular force analogous to hydrogen bonding (HB). However, its utilization in the solution phase remains underdeveloped. Furthermore, the design of receptors capable of strong and selective recognition of anions in water remains a significant challenge. Here we demonstrate the superiority of halogen bonding over hydrogen bonding for strong anion binding in water, to the extent that halide recognition by a simple acyclic mono-charged receptor is achievable. Quantification of iodide binding by rotaxane hosts reveals the strong binding by the XB-rotaxane is driven exclusively by favourable enthalpic contributions arising from the halogen-bonding interactions, whereas weaker association with the HB-rotaxanes is entropically driven. These observations demonstrate the unique nature of halogen bonding in water as a strong alternative interaction to the ubiquitous hydrogen bonding in molecular recognition and assembly.

  12. Acyclic Immucillin Phosphonates. Second-Generation Inhibitors of Plasmodium falciparum Hypoxanthine- Guanine-Xanthine Phosphoribosyltransferase

    SciTech Connect

    Hazelton, Keith Z.; Ho, Meng-Chaio; Cassera, Maria B.; Clinch, Keith; Crump, Douglas R.; Rosario Jr., Irving; Merino, Emilio F.; Almo, Steve C.; Tyler, Peter C.; Schramm, Vern L.

    2012-06-22

    We found that Plasmodium falciparum is the primary cause of deaths from malaria. It is a purine auxotroph and relies on hypoxanthine salvage from the host purine pool. Purine starvation as an antimalarial target has been validated by inhibition of purine nucleoside phosphorylase. Hypoxanthine depletion kills Plasmodium falciparum in cell culture and in Aotus monkey infections. Hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT) from P. falciparum is required for hypoxanthine salvage by forming inosine 5'-monophosphate, a branchpoint for all purine nucleotide synthesis in the parasite. We present a class of HGXPRT inhibitors, the acyclic immucillin phosphonates (AIPs), and cell permeable AIP prodrugs. The AIPs are simple, potent, selective, and biologically stable inhibitors. The AIP prodrugs block proliferation of cultured parasites by inhibiting the incorporation of hypoxanthine into the parasite nucleotide pool and validates HGXPRT as a target in malaria.

  13. The Acyclic Retinoid Peretinoin Inhibits Hepatitis C Virus Replication and Infectious Virus Release in Vitro

    NASA Astrophysics Data System (ADS)

    Shimakami, Tetsuro; Honda, Masao; Shirasaki, Takayoshi; Takabatake, Riuta; Liu, Fanwei; Murai, Kazuhisa; Shiomoto, Takayuki; Funaki, Masaya; Yamane, Daisuke; Murakami, Seishi; Lemon, Stanley M.; Kaneko, Shuichi

    2014-04-01

    Clinical studies suggest that the oral acyclic retinoid Peretinoin may reduce the recurrence of hepatocellular carcinoma (HCC) following surgical ablation of primary tumours. Since hepatitis C virus (HCV) infection is a major cause of HCC, we assessed whether Peretinoin and other retinoids have any effect on HCV infection. For this purpose, we measured the effects of several retinoids on the replication of genotype 1a, 1b, and 2a HCV in vitro. Peretinoin inhibited RNA replication for all genotypes and showed the strongest antiviral effect among the retinoids tested. Furthermore, it reduced infectious virus release by 80-90% without affecting virus assembly. These effects could be due to reduced signalling from lipid droplets, triglyceride abundance, and the expression of mature sterol regulatory element-binding protein 1c and fatty acid synthase. These negative effects of Peretinoin on HCV infection may be beneficial in addition to its potential for HCC chemoprevention in HCV-infected patients.

  14. New acyclic secondary metabolites from the biologically active fraction of Albizia lebbeck flowers.

    PubMed

    Al-Massarani, Shaza M; El Gamal, Ali A; Abd El Halim, Mohamed F; Al-Said, Mansour S; Abdel-Kader, Maged S; Basudan, Omer A; Alqasoumi, Saleh I

    2017-01-01

    The total extract of Albizia lebbeck flowers was examined in vivo for its possible hepatoprotective activity in comparison with the standard drug silymarin at two doses. The higher dose expressed promising activity especially in reducing the levels of AST, ALT and bilirubin. Fractionation via liquid-liquid partition and reexamination of the fractions revealed that the n-butanol fraction was the best in improving liver biochemical parameters followed by the n-hexane fraction. However, serum lipid parameters were best improved with CHCl3 fraction. The promising biological activity results initiated an intensive chromatographic purification of A. lebbeck flowers fractions. Two compounds were identified from natural source for the first time, the acyclic farnesyl sesquiterpene glycoside1-O-[6-O-α-l-arabinopyranosyl-β-d-glucopyranoside]-(2E,6E-)-farnesol (6) and the squalene derivative 2,3-dihydroxy-2,3-dihydrosqualene (9), in addition to eight compounds reported here for the first time from the genus Albizia; two benzyl glycosides, benzyl 1-O-β-d-glucopyranoside (1) and benzyl 6-O-α-l-arabinopyranosyl β-d-glucopyranoside (2); three acyclic monoterpene glycosides, linalyl β-d-glucopyranoside (3) and linalyl 6-O-α-l-arabinopyranosyl-β-d-glucopyranoside (4); (2E)-3,7-dimethylocta-2,6-dienoate-6-O-α-l arabinopyranosyl-β-d-glucopyranoside (5), two oligoglycosides, n-hexyl-α-l arabinopyranosyl-(1 → 6)-β-d-glucopyranoside (creoside) (7) and n-octyl α-l-arabinopyranosyl-(1 → 6)-β-d-glucopyranoside (rhodiooctanoside) (8); and ethyl fructofuranoside (10). The structures of the isolated compounds were elucidated based on extensive examination of their spectroscopic 1D and 2D-NMR, MS, UV, and IR data. It is worth mentioning that, some of the isolated linalol glycoside derivatives were reported as aroma precursors.

  15. Formation of dinuclear, macrocyclic, and chain structures from HgI(2) and a semirigid benzimidazole-based bridging ligand: an example of ring-opening supramolecular isomerism.

    PubMed

    Su, Cheng-Yong; Goforth, Andrea M; Smith, Mark D; zur Loye, Hans-Conrad

    2003-09-08

    The reactions of HgI(2) with the semirigid ditopic ligand 1,3-bis(benzimidazol-1-ylmethyl)-2,4,6-trimethylbenzene (bbimms) afforded three new complexes, [Hg(2)(mu-I)(2)I(2)(bbimms)] (1), [Hg(2)I(4)(bbimms)(2)] (2), and catena-poly[HgI(2)(bbimms)] (3). The ligand and all complexes have been structurally characterized by single-crystal X-ray diffraction. 1 is a triply bridged dinuclear complex comprised of two Hg(II) ions, one bridging ligand, two bridging I(-) anions, and two terminal I(-) anions. 2 is a dinuclear metallamacrocycle comprised of two Hg(II) ions, two bridging ligands, and four terminal I(-) anions, while 3 is a helical chain with the repeating unit of HgI(2)(bbimms). 2 and 3 can be classified as supramolecular isomers, and both are related to the triply bridged precursor 1 via the addition of one more ligand in a ring-opening process.

  16. Synergistic effects of acyclic retinoid and OSI-461 on growth inhibition and gene expression in human hepatoma cells.

    PubMed

    Shimizu, Masahito; Suzui, Masumi; Deguchi, Atsuko; Lim, Jin T E; Xiao, Danhua; Hayes, Julia H; Papadopoulos, Kyriakos P; Weinstein, I Bernard

    2004-10-01

    Hepatoma is one of the most frequently occurring cancers worldwide. However, effective chemotherapeutic agents for this disease have not been developed. Acyclic retinoid, a novel synthetic retinoid, can reduce the incidence of postsurgical recurrence of hepatoma and improve the survival rate. OSI-461, a potent derivative of exisulind, can increase intracellular levels of cyclic GMP, which leads to activation of protein kinase G and induction of apoptosis in cancer cells. In the present study, we examined the combined effects of acyclic retinoid plus OSI-461 in the HepG2 human hepatoma cell line. We found that the combination of as little as 1.0 micromol/L acyclic retinoid and 0.01 micromol/L OSI-461 exerted synergistic inhibition of the growth of HepG2 cells. Combined treatment with low concentrations of these two agents also acted synergistically to induce apoptosis in HepG2 cells through induction of Bax and Apaf-1, reduction of Bcl-2 and Bcl-xL, and activation of caspase-3, -8, and -9. OSI-461 enhanced the G0-G1 arrest caused by acyclic retinoid, and the combination of these agents caused a synergistic decrease in the levels of expression of cyclin D1 protein and mRNA, inhibited cyclin D1 promoter activity, decreased the level of hyperphosphorylated forms of the Rb protein, induced increased cellular levels of the p21(CIP1) protein and mRNA, and stimulated p21(CIP1) promoter activity. Moreover, OSI-461 enhanced the ability of acyclic retinoid to induce increased cellular levels of retinoic acid receptor beta and to stimulate retinoic acid response element-chloramphenicol acetyltransferase activity. A hypothetical model involving concerted effects on p21(CIP1) and retinoic acid receptor beta expression is proposed to explain these synergistic effects. Our results suggest that the combination of acyclic retinoid plus OSI-461 might be an effective regimen for the chemoprevention and chemotherapy of human hepatoma and possibly other malignancies.

  17. Copper-Catalyzed Enantioselective Allyl-Allyl Coupling between Allylic Boronates and Phosphates with a Phenol/N-Heterocyclic Carbene Chiral Ligand.

    PubMed

    Yasuda, Yuto; Ohmiya, Hirohisa; Sawamura, Masaya

    2016-08-26

    Copper-catalyzed enantioselective allyl-allyl coupling between allylboronates and either Z-acyclic or cyclic allylic phosphates using a new chiral N-heterocyclic carbene ligand, bearing a phenolic hydroxy, is reported. This reaction occurs with exceptional SN 2'-type regioselectivities and high enantioselectivities to deliver chiral 1,5-diene derivatives with a tertiary stereogenic center at the allylic/homoallylic position.

  18. The preparation and intra- and intermolecular addition reactions of acyclic N-acylimines: application to the synthesis of (+/-)-sertraline.

    PubMed

    DeNinno, M P; Eller, C; Etienne, J B

    2001-10-19

    Intramolecular endo-cyclization reactions of N-acyliminium ions have seen wide application for the synthesis of heterocyclic compounds. The corresponding exocyclic variant, which would provide 1-aminotetralin derivatives, for example, has little precedent. We have discovered that acyclic N-acylcarbamates can be readily reduced to the corresponding N-acylhemiaminal derivatives in high yield using DIBAL as the reducing agent. These intermediates are remarkably stable and, if desired, can be purified and stored. The acyclic N-acylhemiaminals undergo both intra- and intermolecular nucleophilic addition reactions mediated by strong Lewis acids, such as TiCl(4). Diastereoselectivity, induced either by a substituent on the newly formed ring, or by utilizing a chiral ester on the carbamic acid, was disappointingly low. This methodology was successfully applied to the synthesis of the racemic form of the marketed antidepressant sertraline.

  19. Eu-MOFs with 2-(4-carboxyphenyl)imidazo[4,5-f]-1,10-phenanthroline and ditopic carboxylates as coligands: synthesis, structure, high thermostability, and luminescence properties.

    PubMed

    Zhang, Sheng; Yang, Yang; Xia, Zheng-Qiang; Liu, Xiang-Yu; Yang, Qi; Wei, Qing; Xie, Gang; Chen, San-Ping; Gao, Sheng-Li

    2014-10-20

    Hydrothermal reactions of europium(III) salt with 2-(4-carboxyphenyl)imidazo[4,5-f]-1,10-phenanthroline and dicarboxylic acid as coligands-benzene-1,4-dicarboxylic acid, 4,4'-biphenyldicarboxylic acid, 2,5-dibromoterephthalic acid, and naphthalene-1,4-dicarboxylic acid-lead to four europium fluorescent materials (1-4). Structural analyses reveal that 1-4 have binuclear 3D metal-organic frameworks with different channels, void volumes, and conjugated structures tuned by ditopic carboxylates. There are no latticed and coordinated water molecules occurring in 1-3, while the free water molecules fill in 1D channels of 4. 4' was readily obtained via water removal of 4. Thermal analyses of all compounds show the high thermal stability of the main framework up to 450 °C. Optical studies indicate that 1-4 and 4' show the characteristic red luminescence emission of the Eu(III) ion in the visible regions at room temperature. On the basis of emission spectra, their luminescence lifetimes were determined. In particular, compound 4' shows a longer lifetime (τ = 0.942 ms) and significantly enhanced quantum yield (39%) compared with those of 1 (11%, 0.770 ms), 2 (4%, 0.414 ms), 3 (18%, 0.807 ms), and 4 (26%, 0.858 ms).

  20. Structural and thermodiffractometric analysis of coordination polymers. Part II: zinc and cadmium derivatives of the Bim ligand [Bim = bis(1-imidazolyl)methane].

    PubMed

    Masciocchi, Norberto; Pettinari, Claudio; Alberti, Enrica; Pettinari, Riccardo; Nicola, Corrado Di; Albisetti, Alessandro Figini; Sironi, Angelo

    2007-12-10

    New polynuclear coordination species containing the ditopic bis(1-imidazolyl)methane (Bim) ligand have been prepared as microcrystalline powders and structurally characterized by ab initio X-ray powder diffraction methods. [Zn(CH3COO)2(Bim)]n contains 1D chains with tetrahedral metal atoms bridged by Bim ligands; [CdBr2(Bim)]n shows a dense packing with hexacoordinated Cd(II) ions and mu-Br and mu-Bim bridges; at variance, the isomorphous [ZnCl2(Bim)]n and [ZnBr2(Bim)]n species contain cyclic dimers based on tetrahedral Zn(II) ions. Thermodiffractometric analysis allowed estimation of the linear thermal expansion coefficients and strain tensors derived there from. Bim-rich phases, with 2:1 ligand-to-metal ratio, were also isolated: ZnBr2(Bim)2(H2O)3 and [Cd(CH3COO)2(Bim)2]n containing cis and trans MN4O2 chromophores, respectively, show 1D polymers built upon M2Bim2 cycles, hinged on the metal ions. In all species the conformation of the Bim ligands is Cs (or nearly so), while in the few sparse reports of similar coordination polymers the alternative C2 one was preferentially observed.

  1. Enzymatic study on AtCCD4 and AtCCD7 and their potential to form acyclic regulatory metabolites

    PubMed Central

    Bruno, Mark; Koschmieder, Julian; Wuest, Florian; Schaub, Patrick; Fehling-Kaschek, Mirjam; Timmer, Jens; Beyer, Peter; Al-Babili, Salim

    2016-01-01

    The Arabidopsis carotenoid cleavage dioxygenase 4 (AtCCD4) is a negative regulator of the carotenoid content of seeds and has recently been suggested as a candidate for the generation of retrograde signals that are thought to derive from the cleavage of poly-cis-configured carotene desaturation intermediates. In this work, we investigated the activity of AtCCD4 in vitro and used dynamic modeling to determine its substrate preference. Our results document strict regional specificity for cleavage at the C9–C10 double bond in carotenoids and apocarotenoids, with preference for carotenoid substrates and an obstructing effect on hydroxyl functions, and demonstrate the specificity for all-trans-configured carotenes and xanthophylls. AtCCD4 cleaved substrates with at least one ionone ring and did not convert acyclic carotene desaturation intermediates, independent of their isomeric states. These results do not support a direct involvement of AtCCD4 in generating the supposed regulatory metabolites. In contrast, the strigolactone biosynthetic enzyme AtCCD7 converted 9-cis-configured acyclic carotenes, such as 9-cis-ζ-carotene, 9'-cis-neurosporene, and 9-cis-lycopene, yielding 9-cis-configured products and indicating that AtCCD7, rather than AtCCD4, is the candidate for forming acyclic retrograde signals. PMID:27811075

  2. Invited commentary: the perils of birth weight--a lesson from directed acyclic graphs.

    PubMed

    Wilcox, Allen J

    2006-12-01

    The strong association of birth weight with infant mortality is complicated by a paradoxical finding: Small babies in high-risk populations usually have lower risk than small babies in low-risk populations. In this issue of the Journal, Hernández-Díaz et al. (Am J Epidemiol 2006;164:1115-20) address this "birth weight paradox" using directed acyclic graphs (DAGs). They conclude that the paradox is the result of bias created by adjustment for a factor (birth weight) that is affected by the exposure of interest and at the same time shares causes with the outcome (mortality). While this bias has been discussed before, the DAGs presented by Hernández-Díaz et al. provide more firmly grounded criticism. The DAGs demonstrate (as do many other examples) that seemingly reasonable adjustments can distort epidemiologic results. In this commentary, the birth weight paradox is shown to be an illustration of Simpson's Paradox. It is possible for a factor to be protective within every stratum of a variable and yet be damaging overall. Questions remain as to the causal role of birth weight.

  3. Polarizable empirical force field for acyclic polyalcohols based on the classical Drude oscillator.

    PubMed

    He, Xibing; Lopes, Pedro E M; Mackerell, Alexander D

    2013-10-01

    A polarizable empirical force field for acyclic polyalcohols based on the classical Drude oscillator is presented. The model is optimized with an emphasis on the transferability of the developed parameters among molecules of different sizes in this series and on the condensed-phase properties validated against experimental data. The importance of the explicit treatment of electronic polarizability in empirical force fields is demonstrated in the cases of this series of molecules with vicinal hydroxyl groups that can form cooperative intra- and intermolecular hydrogen bonds. Compared to the CHARMM additive force field, improved treatment of the electrostatic interactions avoids overestimation of the gas-phase dipole moments resulting in significant improvement in the treatment of the conformational energies and leads to the correct balance of intra- and intermolecular hydrogen bonding of glycerol as evidenced by calculated heat of vaporization being in excellent agreement with experiment. Computed condensed phase data, including crystal lattice parameters and volumes and densities of aqueous solutions are in better agreement with experimental data as compared to the corresponding additive model. Such improvements are anticipated to significantly improve the treatment of polymers in general, including biological macromolecules.

  4. Flotation properties of some oxygen-containing compounds of the acyclic series

    SciTech Connect

    Shreider, E.M.; Para, S.F.; Galanov, M.E.; Trachik, T.L.; Lagutina, L.V.

    1981-01-01

    In the monatomic alcohols series, maximum flotation activity is reached at 6 to 8 carbon atoms in the radical. It was decided to investigate the reagent properties of some other substances containing hydroxyl radicals which have not previously been considered. Oxygen-containing compounds in the acyclic series were examined, including alcohols: I - ethanol, ethylene-glycol, glycerol, pentaerythrytol, D-mannitol; II - dulcitol, D-sorbitol, D-mannitol, xylitol; glycols - monoethyleneglycol, diethyleneglycol, triethyleneglycol, polyethyleneglycol; and ethanolamines - ethanolamine, triethanolamine. The flotation properties of the reagents were determined in a Mekhanobr laboratory flotation machine with a chamber volume of 1.5 liter and an impeller speed of 1800 rpm. The materials tested were the <1 mm size fractions from run-of-plant charge and slurry from the radial thickeners. The samples were first dried and averaged. The pulp density was 200 g/l. The reagent conditions were kept constant throughout (50% of the total added at the start of a test, 25% after 2 min and 25% after 4 min from the start). The reagent additions were 1.0 to 1.4 kg/ton. All of these compounds had a very weak flotation activity.

  5. A multiple testing method for hypotheses structured in a directed acyclic graph.

    PubMed

    Meijer, Rosa J; Goeman, Jelle J

    2015-01-01

    We present a novel multiple testing method for testing null hypotheses that are structured in a directed acyclic graph (DAG). The method is a top-down method that strongly controls the familywise error rate and can be seen as a generalization of Meinshausen's procedure for tree-structured hypotheses. Just as Meinshausen's procedure, our proposed method can be used to test for variable importance, only the corresponding variable clusters can be chosen more freely, because the method allows for multiple parent nodes and partially overlapping hypotheses. An important application of our method is in gene set analysis, in which one often wants to test multiple gene sets as well as individual genes for their association with a clinical outcome. By considering the genes and gene sets as nodes in a DAG, our method enables us to test both for significant gene sets as well as for significant individual genes within the same multiple testing procedure. The method will be illustrated by testing Gene Ontology terms for evidence of differential expression in a survival setting and is implemented in the R package cherry.

  6. Robust causal inference using directed acyclic graphs: the R package 'dagitty'.

    PubMed

    Textor, Johannes; van der Zander, Benito; Gilthorpe, Mark S; Liśkiewicz, Maciej; Ellison, George T H

    2017-01-15

    Directed acyclic graphs (DAGs), which offer systematic representations of causal relationships, have become an established framework for the analysis of causal inference in epidemiology, often being used to determine covariate adjustment sets for minimizing confounding bias. DAGitty is a popular web application for drawing and analysing DAGs. Here we introduce the R package 'dagitty', which provides access to all of the capabilities of the DAGitty web application within the R platform for statistical computing, and also offers several new functions. We describe how the R package 'dagitty' can be used to: evaluate whether a DAG is consistent with the dataset it is intended to represent; enumerate 'statistically equivalent' but causally different DAGs; and identify exposure-outcome adjustment sets that are valid for causally different but statistically equivalent DAGs. This functionality enables epidemiologists to detect causal misspecifications in DAGs and make robust inferences that remain valid for a range of different DAGs. The R package 'dagitty' is available through the comprehensive R archive network (CRAN) at [https://cran.r-project.org/web/packages/dagitty/]. The source code is available on github at [https://github.com/jtextor/dagitty]. The web application 'DAGitty' is free software, licensed under the GNU general public licence (GPL) version 2 and is available at [http://dagitty.net/].

  7. Amino acids of the Murchison meteorite. I - Six carbon acyclic primary alpha-amino alkanoic acids

    NASA Technical Reports Server (NTRS)

    Cronin, J. R.; Gandy, W. E.; Pizzarello, S.

    1981-01-01

    Six of the seven chain isomers of six-carbon acyclic primary alpha-amino alkanoic acids (leucine isomers) have been either identified or confirmed in hot-water extracts of the Murchison meteorite using combined gas chromatography-mass spectrometry (GC-MS) and ion exchange chromatography. 2-Amino-2-ethylbutyric acid, 2-amino-2,3-dimethylbutyric acid, pseudoleucine, and 2-methylnorvaline were positively identified by GC-MS. These amino acids have not been previously reported to occur in natural materials and may be uniquely meteoritic in origin. The presence of leucine and isoleucine (including the diastereoisomer, alloisoleucine) was confirmed. Peaks corresponding to norleucine were seen by ion-exchange and gas chromatography but characteristic mass spectra were not obtained. The alpha-branched chain isomers in this series are quantitatively the most significant. These results are compared with literature data on amino acid synthesis by electrical discharge and Fischer-Tropsch-type catalysis. Neither model system produces an amino acid suite that is completely comparable to that found in the Murchison meteorite.

  8. Amino acids of the Murchison meteorite. III - Seven carbon acyclic primary alpha-amino alkanoic acids

    NASA Technical Reports Server (NTRS)

    Cronin, John R.; Pizzarello, Sandra

    1986-01-01

    All of the eighteen possible seven-carbon acyclic primary alpha-amino alkanoic acids have been positively identified in a hot-water extract of the Murchison meteorite by the combined use of gas chromatography-mass spectrometry, ion exchange chromatography and reversed-phase chromatography. None of these amino acids has previously been found in meteorites or in any other natural material. They range in concentration from less than or equal to 0.5 to 5.3 nmol/g. Configuration assignments were made for 2-amino-3,4-dimethylpentanoic acid and allo-2-amino-3,4-dimethylpentanoic acid and the diasteromer ratio was determined. Fifty-five amino acids have now been positively identified in the Murchison meteorite, 36 of which are unknown in terrestrial materials. This unique suite of amino acids is characterized by the occurrence of all structural isomers within the two major classes of amino acids represented, by the predominance of branched chain isomers, and by an exponential decline in amount with increasing carbon chain length within homologous series. These characteristics of the Murchison amino acids are suggestive of synthesis before incorporation into a parent body.

  9. Solution-phase parallel synthesis of acyclic nucleoside libraries of purine, pyrimidine, and triazole acetamides.

    PubMed

    Pathak, Ashish K; Pathak, Vibha; Reynolds, Robert C

    2014-09-08

    Molecular diversity plays a pivotal role in modern drug discovery against phenotypic or enzyme-based targets using high throughput screening technology. Under the auspices of the Pilot Scale Library Program of the NIH Roadmap Initiative, we produced and report herein a diverse library of 181 purine, pyrimidine, and 1,2,4-triazole-N-acetamide analogues which were prepared in a parallel high throughput solution-phase reaction format. A set of assorted amines were reacted with several nucleic acid N-acetic acids utilizing HATU as the coupling reagent to produce diverse acyclic nucleoside N-acetamide analogues. These reactions were performed using 24 well reaction blocks and an automatic reagent-dispensing platform under inert atmosphere. The targeted compounds were purified on an automated purification system using solid sample loading prepacked cartridges and prepacked silica gel columns. All compounds were characterized by NMR and HRMS, and were analyzed for purity by HPLC before submission to the Molecular Libraries Small Molecule Repository (MLSMR) at NIH. Initial screening through the Molecular Libraries Probe Production Centers Network (MLPCN) program, indicates that several analogues showed diverse and interesting biological activities.

  10. Terahertz vibrations of crystalline acyclic and cyclic diglycine: benchmarks for London force correction models.

    PubMed

    Juliano, Thomas R; Korter, Timothy M

    2013-10-10

    Terahertz spectroscopy provides direct information concerning weak intermolecular forces in crystalline molecular solids and therefore acts as an excellent method for calibrating and evaluating computational models for noncovalent interactions. In this study, the low-frequency vibrations of two dipeptides were compared, acyclic diglycine and cyclic diglycine, as benchmark systems for gauging the performance of semiempirical London force correction approaches. The diglycine samples were investigated using pulsed terahertz spectroscopy from 10 to 100 cm(-1) and then analyzed using solid-state density functional theory (DFT) augmented with existing London force corrections, as well as a new parametrization (DFT-DX) based on known experimental values. The two diglycine molecules provide a useful test for the applied models given their similarities, but more importantly the differences in the intermolecular forces displayed by each. It was found that all of the considered London force correction models were able to generate diglycine crystal structures of similar accuracy, but considerable variation occurred in their abilities to predict terahertz frequency vibrations. The DFT-DX parametrization was particularly successful in this investigation and shows promise for the improved analysis of low-frequency spectra.

  11. "Toward a clearer definition of confounding" revisited with directed acyclic graphs.

    PubMed

    Howards, Penelope P; Schisterman, Enrique F; Poole, Charles; Kaufman, Jay S; Weinberg, Clarice R

    2012-09-15

    In a 1993 paper (Am J Epidemiol. 1993;137(1):1-8), Weinberg considered whether a variable that is associated with the outcome and is affected by exposure but is not an intermediate variable between exposure and outcome should be considered a confounder in etiologic studies. As an example, she examined the common practice of adjusting for history of spontaneous abortion when estimating the effect of an exposure on the risk of spontaneous abortion. She showed algebraically that such an adjustment could substantially bias the results even though history of spontaneous abortion would meet some definitions of a confounder. Directed acyclic graphs (DAGs) were introduced into epidemiology several years later as a tool with which to identify confounders. The authors now revisit Weinberg's paper using DAGs to represent scenarios that arise from her original assumptions. DAG theory is consistent with Weinberg's finding that adjusting for history of spontaneous abortion introduces bias in her original scenario. In the authors' examples, treating history of spontaneous abortion as a confounder introduces bias if it is a descendant of the exposure and is associated with the outcome conditional on exposure or is a child of a collider on a relevant undirected path. Thoughtful DAG analyses require clear research questions but are easily modified for examining different causal assumptions that may affect confounder assessment.

  12. Executive Summary of Ares V: Lunar Capabilities Concept Review Through Phase A-Cycle 3

    NASA Technical Reports Server (NTRS)

    Holladay, J. B.; Baggett, K. E.; Feldman, S. M.

    2011-01-01

    This Technical Memorandum (TM) was generated as an overall Ares V summary from the Lunar Capabilities Concept Review (LCCR) through Phase A-Cycle 3 (PA-C3) with the intent that it may be coupled with separately published appendices for a more detailed, integrated narrative. The Ares V has evolved from the initial point of departure (POD) 51.00.48 LCCR configuration to the current candidate POD, PA-C3D, and the family of vehicles concept that contains vehicles PA-C3A through H. The logical progression from concept to POD vehicles is summarized in this TM and captures the trade space and performance of each. The family-of-vehicles concept was assessed during PA-C3 and offered flexibility in the path forward with the ability to add options deemed appropriate. A description of each trade space is given in addition to a summary of each Ares V element. The Ares V contributions to a Mars campaign are also highlighted with the goal of introducing Ares V capabilities within the trade space. The assessment of the Ares V vehicle as it pertains to Mars missions remained locked to the architecture presented in Mars Design Reference Authorization 5.0 using the PA-C3D vehicle configuration to assess Mars transfer vehicle options, in-space EDS capabilities, docking adaptor and propellant transfer assessments, and lunar and Mars synergistic potential.

  13. Alteration in substrate specificity of horse liver alcohol dehydrogenase by an acyclic nicotinamide analog of NAD(+).

    PubMed

    Malver, Olaf; Sebastian, Mina J; Oppenheimer, Norman J

    2014-11-01

    A new, acyclic NAD-analog, acycloNAD(+) has been synthesized where the nicotinamide ribosyl moiety has been replaced by the nicotinamide (2-hydroxyethoxy)methyl moiety. The chemical properties of this analog are comparable to those of β-NAD(+) with a redox potential of -324mV and a 341nm λmax for the reduced form. Both yeast alcohol dehydrogenase (YADH) and horse liver alcohol dehydrogenase (HLADH) catalyze the reduction of acycloNAD(+) by primary alcohols. With HLADH 1-butanol has the highest Vmax at 49% that of β-NAD(+). The primary deuterium kinetic isotope effect is greater than 3 indicating a significant contribution to the rate limiting step from cleavage of the carbon-hydrogen bond. The stereochemistry of the hydride transfer in the oxidation of stereospecifically deuterium labeled n-butanol is identical to that for the reaction with β-NAD(+). In contrast to the activity toward primary alcohols there is no detectable reduction of acycloNAD(+) by secondary alcohols with HLADH although these alcohols serve as competitive inhibitors. The net effect is that acycloNAD(+) has converted horse liver ADH from a broad spectrum alcohol dehydrogenase, capable of utilizing either primary or secondary alcohols, into an exclusively primary alcohol dehydrogenase. This is the first example of an NAD analog that alters the substrate specificity of a dehydrogenase and, like site-directed mutagenesis of proteins, establishes that modifications of the coenzyme distance from the active site can be used to alter enzyme function and substrate specificity. These and other results, including the activity with α-NADH, clearly demonstrate the promiscuity of the binding interactions between dehydrogenases and the riboside phosphate of the nicotinamide moiety, thus greatly expanding the possibilities for the design of analogs and inhibitors of specific dehydrogenases.

  14. Methoxymethyl (MOM) group nitrogen protection of pyrimidines bearing C-6 acyclic side-chains.

    PubMed

    Kraljević, Tatjana Gazivoda; Petrović, Martina; Krištafor, Svjetlana; Makuc, Damjan; Plavec, Janez; Ross, Tobias L; Ametamey, Simon M; Raić-Malić, Silvana

    2011-06-20

    Novel N-methoxymethylated (MOM) pyrimidine (4-13) and pyrimidine-2,4-diones (15-17) nucleoside mimetics in which an isobutyl side-chain is attached at the C-6 position of the pyrimidine moiety were synthesized. Synthetic methods via O-persilylated or N-anionic uracil derivatives have been evaluated for the synthesis of N-1- and/or N-3-MOM pyrimidine derivatives with C-6 acyclic side-chains. A synthetic approach using an activated N-anionic pyrimidine derivative afforded the desired N,N-1,3-diMOM and N-1-MOM pyrimidines 4 and 5 in good yield. Introduction of fluorine into the side-chain was performed with DAST as the fluorinating reagent to give a N,N-1,3-diMOM pyrimidine 13 with a 1-fluoro-3-hydroxyisobutyl moiety at C-6. Conformational study of the monotritylated N-1-MOM pyrimidine 12 by the use of the NOE experiments revealed the predominant conformation of the compound to be one where the hydroxymethyl group in the C-6 side-chain is close to the N-1-MOM moiety, while the OMTr is in proximity to the CH(3)-5 group. Contrary to this no NOE enhancements between the N-1-MOM group and hydroxymethyl or fluoromethyl protons in 13 were observed, which suggested a nonrestricted rotation along the C-6 side-chain. Fluorinated N,N-1,3-diMOM pyrimidine 13 emerged as a model compound for development of tracer molecules for non-invasive imaging of gene expression using positron emission tomography (PET).

  15. A ditopic O(4)S(2) macrocycle and its hard, soft, and hard/soft metal complexes exhibiting endo-, exo-, or endo/exocyclic coordination: synthesis, crystal structures, NMR titration, and physical properties.

    PubMed

    Ryu, Hyunsoo; Park, Ki-Min; Ikeda, Mari; Habata, Yoichi; Lee, Shim Sung

    2014-04-21

    A 20-membered O4S2 macrocycle (L(2)) was synthesized as a ditopic ligating system toward hard and soft metal ions simultaneously. Five complexes (3-7) of L(2) with different structures and coordination modes, including discrete to infinite forms, mono- to heteronuclear, and endo- to exo- and endo/exocoordination, were prepared and structurally characterized. First, the reaction of L(2) with Pb(ClO4)2·3H2O afforded a typical endocyclic mononuclear perchlorato complex [Pb(L(2))(ClO4)2] (3) in which one lead(II) is surrounded by the macrocycle adopting a "tight and bent" conformation. Meanwhile, the reaction with a softer metal salt AgNO3 resulted in the formation of the dinuclear bis(macrocycle) complex [Ag2(L(2))2(NO3)2] (4) in which two exocyclic silver(I) ions are doubly linked by two nitrate ions. The treatment of L(2) with CuI gave a mixture of the exocyclic monomer complex [Cu(L(2))I] (5) and the exocyclic dimer complex [(Cu2I2)(L(2))2] (6), which were separated manually because of their brick and rhomboid shapes of the crystals, respectively. Furthermore, the reaction of L(2) with a mixture of CuI and NaI afforded a photoluminescent heteronuclear complex [Na2(Cu6I8)(L(2))2(CH3CN)4]n (7) in the endo/exocyclic coordination mode. In this case, the endocyclic sodium(I) complex units are linked by the double-open cubanes-type cluster Cu6I8, yielding a two-dimensional network. The structural and binding properties of the complex of L(2) with silver(I) nitrate in solution were monitored by the NMR titration. Photophysical and thermal properties for complex 7 were also investigated and discussed.

  16. Acyclic phosphonate nucleotides and human adenylate kinases: impact of a borano group on alpha-P position.

    PubMed

    Topalis, D; Alvarez, K; Barral, K; Munier-Lehmann, H; Schneider, B; Véron, M; Guerreiro, C; Mulard, L; El-Amri, C; Canard, B; Deville-Bonne, D

    2008-04-01

    Adenylate kinases are involved in the activation of antiviral drugs such as the acyclic phosphonates analogs PMEA and (R)PMPA. We examine the in vitro phosphorylation of PMEA and PMPA bearing a borano- or a H- group on the phosphorus atom. The alpha-borano or alpha-H on PMEA and PMPA were detrimental to the activity of recombinant human AMP kinases 1 and 2. Docking PMEA to the active site of AMP kinase 1 indicated that the borano group may prevent two conserved critical Arg interactions with the alpha-phosphate, resulting in substrate bad positioning.

  17. Amino acids of the Murchison meteorite. II - Five carbon acyclic primary beta-, gamma-, and delta-amino alkanoic acids

    NASA Technical Reports Server (NTRS)

    Cronin, J. R.; Pizzarello, S.; Yuen, G. U.

    1985-01-01

    The five-carbon acyclic primary beta, gamma, and delta amino alkanoic acids of the Murchison meteorite are studied using gas chromatography-mass spectrometry and ion exchange chromatography. The chromatograms reveal that alpha is the most abundant monoamino alkanoic acid followed by gamma and beta, and an exponential increase in the amount of amino acid is observed as the carbon number increases in the homologous series. The influence of frictional heating, spontaneous thermal decomposition, and radiation of the synthesis of amino acids is examined. The data obtained support an amino acid synthesis process involving random combination of single-carbon precursors.

  18. Zirconocene-assisted remote cleavage of C-C and C-O bonds: application to acyclic stereodefined metalated hydrocarbons.

    PubMed

    Bruffaerts, J; Pierrot, D; Marek, I

    2016-11-08

    The molding of molecules through remote functionalisation has increasingly become popular as it provides original and flexible synthetic alternatives to classical retrosynthetic analysis. In this Perspective article, we summarise more than a decade of studies in the specific field of remote activation of inert C-C and C-O bonds using the unique abilities of organozirconocene species mainly from our own research group. By demonstrating that these reactions represent novel and powerful entries towards acyclic stereodefined reactive organometallic species, we aim to show the vast opportunities this concept-driven methodology discovery offers.

  19. New Proton-Ionizable, Calixarene-Based Ligands for Selective Metal Ion Separations

    SciTech Connect

    Bartsch, Richard A.

    2012-06-04

    The project objective was the discovery of new ligands for performing metal ion separations. The research effort entailed the preparation of new metal ion complexing agents and polymers and their evaluation in metal ion separation processes of solvent extraction, synthetic liquid membrane transport, and sorption. Structural variations in acyclic, cyclic, and bicyclic organic ligands were used to probe their influence upon the efficiency and selectivity with which metal ion separations can be performed. A unifying feature of the ligand structures is the presence of one (or more) side arm with a pendent acidic function. When a metal ion is complexed within the central cavity of the ligand, ionization of the side arm(s) produces the requisite anion(s) for formation of an overall electroneutral complex. This markedly enhances extraction/transport efficiency for separations in which movement of aqueous phase anions of chloride, nitrate, or sulfate into an organic medium would be required. Through systematic structural variations, new ligands have been developed for efficient and selective separations of monovalent metal ions (e.g., alkali metal, silver, and thallium cations) and of divalent metal ion species (e.g., alkaline earth metal, lead, and mercury cations). Research results obtained in these fundamental investigations provide important insight for the design and development of ligands suitable for practical metal ion separation applications.

  20. GRASr2 evaluation of aliphatic acyclic and alicyclic terpenoid tertiary alcohols and structurally related substances used as flavoring ingredients.

    PubMed

    Marnett, Lawrence J; Cohen, Samuel M; Fukushima, Shoji; Gooderham, Nigel J; Hecht, Stephen S; Rietjens, Ivonne M C M; Smith, Robert L; Adams, Timothy B; Bastaki, Maria; Harman, Christie L; McGowen, Margaret M; Taylor, Sean V

    2014-04-01

    This publication is the 1st in a series of publications by the Expert Panel of the Flavor and Extract Manufacturers Assoc. summarizing the Panel's 3rd re-evaluation of Generally Recognized as Safe (GRAS) status referred to as the GRASr2 program. In 2011, the Panel initiated a comprehensive program to re-evaluate the safety of more than 2700 flavor ingredients that have previously met the criteria for GRAS status under conditions of intended use as flavor ingredients. Elements that are fundamental to the safety evaluation of flavor ingredients include exposure, structural analogy, metabolism, pharmacokinetics, and toxicology. Flavor ingredients are evaluated individually and in the context of the available scientific information on the group of structurally related substances. Scientific data relevant to the safety evaluation of the use of aliphatic acyclic and alicyclic terpenoid tertiary alcohols and structurally related substances as flavoring ingredients are evaluated. The group of aliphatic acyclic and alicyclic terpenoid tertiary alcohols and structurally related substances was reaffirmed as GRAS (GRASr2) based, in part, on their rapid absorption, metabolic detoxication, and excretion in humans and other animals; their low level of flavor use; the wide margins of safety between the conservative estimates of intake and the no-observed-adverse effect levels determined from subchronic studies and the lack of significant genotoxic and mutagenic potential.

  1. Synthesis, spectroscopic, coordination and biological activities of some organometallic complexes derived from thio-Schiff base ligands

    PubMed Central

    Abou-Hussein, Azza A.; Linert, Wolfgang

    2014-01-01

    Two series of mono- and binuclear complexes cyclic or acyclic thio-ferocine Schiff base ligands, derived from the condensation of 2-aminobenzenthiol (L) with monoacetyl ferrocene in the molar ratio 1:1 or in the molar ratio 1:2 for diacetyl ferocine have been prepared. The condensation reactions yield the corresponding Schiff Base ligands, HLa-Maf and H2Lb-Daf. The chelation of the ligands to metal ions occurs through the sulfur of the thiol group as well as the nitrogen atoms of the azomethine group of the ligands. HLa-Maf acts as monobasic bidentate or dibasic tetradentate, while H2Lb-Daf behaves as twice negatively cargend tetradentate ligand. The structures of these ligands were elucidated by elemental analysis, infrared, ultraviolet–visible spectra, as well as 1H NMR spectra. Reactions of the Schiff bases ligands with ruthenium(III), oxovanadium(IV) and dioxouranium(VI) afforded the corresponding transition metal complexes. The properties of the newly prepared complexes were analyse by elemental analyses, infrared, electronic spectra, 1H NMR as well as the magnetic susceptibility and conductivity measurement. The metal complexes exhibits different geometrical arrangements such as octahedral and square pyramidal coordination. Schiff base ligands and their metal complexes were tested against two pathogenic bacteria as Gram-positive and Gram-negative bacteria as well as one kind of fungi to study their biological activity. All the complexes exhibit antibacterial and antifungal activities against these organisms. PMID:24070648

  2. Synthesis, spectroscopic, coordination and biological activities of some organometallic complexes derived from thio-Schiff base ligands

    NASA Astrophysics Data System (ADS)

    Abou-Hussein, Azza A.; Linert, Wolfgang

    2014-01-01

    Two series of mono- and binuclear complexes cyclic or acyclic thio-ferocine Schiff base ligands, derived from the condensation of 2-aminobenzenthiol (L) with monoacetyl ferrocene in the molar ratio 1:1 or in the molar ratio 1:2 for diacetyl ferocine have been prepared. The condensation reactions yield the corresponding Schiff Base ligands, HLa-Maf and H2Lb-Daf. The chelation of the ligands to metal ions occurs through the sulfur of the thiol group as well as the nitrogen atoms of the azomethine group of the ligands. HLa-Maf acts as monobasic bidentate or dibasic tetradentate, while H2Lb-Daf behaves as twice negatively cargend tetradentate ligand. The structures of these ligands were elucidated by elemental analysis, infrared, ultraviolet-visible spectra, as well as 1H NMR spectra. Reactions of the Schiff bases ligands with ruthenium(III), oxovanadium(IV) and dioxouranium(VI) afforded the corresponding transition metal complexes. The properties of the newly prepared complexes were analyse by elemental analyses, infrared, electronic spectra, 1H NMR as well as the magnetic susceptibility and conductivity measurement. The metal complexes exhibits different geometrical arrangements such as octahedral and square pyramidal coordination. Schiff base ligands and their metal complexes were tested against two pathogenic bacteria as Gram-positive and Gram-negative bacteria as well as one kind of fungi to study their biological activity. All the complexes exhibit antibacterial and antifungal activities against these organisms.

  3. Palladium(II)-catalyzed enantioselective C(sp³)-H activation using a chiral hydroxamic acid ligand.

    PubMed

    Xiao, Kai-Jiong; Lin, David W; Miura, Motofumi; Zhu, Ru-Yi; Gong, Wei; Wasa, Masayuki; Yu, Jin-Quan

    2014-06-04

    An enantioselective method for Pd(II)-catalyzed cross-coupling of methylene β-C(sp(3))-H bonds in cyclobutanecarboxylic acid derivatives with arylboron reagents is described. High yields and enantioselectivities were achieved through the development of chiral mono-N-protected α-amino-O-methylhydroxamic acid (MPAHA) ligands, which form a chiral complex with the Pd(II) center. This reaction provides an alternative approach to the enantioselective synthesis of cyclobutanecarboxylates containing α-chiral quaternary stereocenters. This new class of chiral catalysts also show promises for enantioselective β-C(sp(3))-H activation of acyclic amides.

  4. Structural and thermodiffractometric analysis of coordination polymers. Part I: tin derivatives of the Bim ligand [Bim = Bis(1-imidazolyl)methane]).

    PubMed

    Masciocchi, Norberto; Pettinari, Claudio; Alberti, Enrica; Pettinari, Riccardo; Nicola, Corrado Di; Albisetti, Alessandro Figini; Sironi, Angelo

    2007-12-10

    New polynuclear coordination species containing the ditopic bis(1-imidazolyl)methane (Bim) ligand have been prepared as microcrystalline powders and structurally characterized by ab initio X-ray powder diffraction methods. [Bim(Me2SnCl2)]n (1), [Bim(nBu2SnCl2)]n (3), [Bim(Ph2SnCl2)]n (4), [Bim(MeSnCl3)]n (5), and [Bim(PhSnCl3)]n (6) all contain 1D chains with octahedral tin atoms with trans N-Sn-N linkages (but 4, which displays a cis N-Sn-N linkage). Their thermodiffractometric analysis allowed the estimation of the linear thermal expansion coefficients and strain tensors derived there from. The potential-energy surface of the free Bim ligand (as defined by two torsional degrees of freedom about the two N-CH2 bonds), eventually controlling the length of the repeating unit (polymer elongation), has been estimated using molecular mechanics and correlated with experimental observations.

  5. Recurrence of hyperprolactinemia and continuation of ovarian acyclicity in captive African elephants (Loxodonta africana) treated with cabergoline.

    PubMed

    Morfeld, Kari A; Ball, Ray L; Brown, Janine L

    2014-09-01

    Hyperprolactinemia is associated with reproductive acyclicity in zoo African elephants (Loxodonta africana) and may contribute to the non-self-sustainability of the captive population in North America. It is a common cause of infertility in women and other mammals and can be treated with the dopamine agonist cabergoline. The objectives of this study were to assess prolactin responses to cabergoline treatment in hyperprolactinemic, acyclic African elephants and to determine the subsequent impact on ovarian cyclic activity. Five elephants, diagnosed as hyperprolactinemic (>11 ng/ml prolactin) and acyclic (maintenance of baseline progestagens for at least 1 yr), were treated with 1-2 mg cabergoline orally twice weekly for 16-82 wk. Cabergoline reduced (P < 0.05) serum prolactin concentrations during the treatment period compared to pretreatment levels in four of five elephants (11.5 +/- 3.2 vs. 9.1 +/- 3.4 ng/ml; 20.3 +/- 16.7 vs. 7.9 +/- 9.8 ng/ml; 26.4 +/- 15.0 vs. 6.8 +/- 1.5 ng/ml; 42.2 +/- 22.6 vs. 18.6 +/- 8.9 ng/ml). However, none of the females resumed ovarian cyclicity based on serum progestagen analyses up to 1 yr posttreatment. In addition, within 1 to 6 wk after cessation of oral cabergoline, serum prolactin concentrations returned to concentrations that were as high as or higher than before treatment (P < 0.05). One elephant that exhibited the highest pretreatment prolactin concentration (75.2 +/- 10.5 ng/ml) did not respond to cabergoline and maintained elevated levels throughout the study. Thus, oral cabergoline administration reduced prolactin concentrations in elephants with hyperprolactinemia, but there was no resumption of ovarian cyclicity, and a significant prolactin rebound effect was observed. It is possible that higher doses or longer treatment intervals may be required for cabergoline treatment to result in permanent suppression of prolactin secretion and to mitigate associated ovarian cycle problems.

  6. The role of minerals in the thermal alteration of organic matter--IV. Generation of n-alkanes, acyclic isoprenoids, and alkenes in laboratory experiments.

    PubMed

    Huizinga, B J; Tannenbaum, E; Kaplan, I R

    1987-01-01

    A series of pyrolysis experiments, utilizing two different immature oil-prone kerogens ("type I": Green River Formation kerogen; "Type II": Monterey Formation kerogen) mixed with common sedimentary minerals (calcite, illite, or Na-montmorillonite), was conducted to study the effects of minerals on the generation of n-alkanes, acyclic isoprenoids, and alkenes during laboratory-simulated catagenesis of kerogen. The influence of clay minerals on the aliphatic hydrocarbons is critically dependent on the water concentration during laboratory thermal maturation. Under extremely low contents of water (i.e., dry pyrolysis, where only pyrolysate water is present), C12(+) -range n-alkanes and acyclic isoprenoids are mostly destroyed by montmorillonite but undergo only minor alteration with illite. Both clay minerals significantly reduce alkene formation during dry pyrolysis. Under hydrous conditions (mineral/water = 2:1), the effects of the clay minerals are substantially reduced. In addition, the dry pyrolysis experiments show that illite and montmorillonite preferentially retain large amounts of the polar constituents of bitumen, but not n-alkanes or acyclic isoprenoids. Therefore, bitumen fractionation according to polarity differences occurs in the presence of these clay minerals. By this process, n-alkanes and acyclic isoprenoids are concentrated in the bitumen fraction that is not strongly adsorbed on the clay matrices. The extent of these concentrations effects is greatly diminished during hydrous pyrolysis. In contrast, calcite has no significant influence on the thermal evolution of the hydrocarbons. In addition, calcite is incapable of retaining bitumen. Therefore, the fractionation of n-alkanes or acyclic isoprenoids relative to the polar constituents of bitumen is insignificant in the presence of calcite.

  7. Enantioselective Lewis acid-catalyzed Mukaiyama-Michael reactions of acyclic enones. Catalysis by allo-threonine-derived oxazaborolidinones.

    PubMed

    Wang, Xiaowei; Adachi, Shinya; Iwai, Hiroyoshi; Takatsuki, Hiroshi; Fujita, Katsuhiro; Kubo, Mikako; Oku, Akira; Harada, Toshiro

    2003-12-26

    allo-Threonine-derived O-aroyl-B-phenyl-N-tosyl-1,3,2-oxazaborolidin-5-ones 1g,n catalyze the asymmetric Mukaiyama-Michael reaction of acyclic enones with a trimethylsilyl ketene S,O-acetal in high enantioselectivity. A range of alkenyl methyl ketones is successfully employed as Michael acceptors affording ee values of 85-90% by using 10 mol % of the catalyst. The use of 2,6-diisopropylphenol and tert-butyl methyl ether as additives is found to be essential to achieve high enantioselectivity in these reactions. The effects of the additives are discussed in terms of the retardation of an Si(+)-catalyzed racemic pathway, which seriously deteriorates the enantioselectivity of asymmetric Mukaiyama-Michael reactions. A working model for asymmetric induction is proposed based on correlation between catalyst structures and enantioselectivities.

  8. Identification and geochemical significance of cyclic di-and trisulphides with linear and acyclic isoprenoid carbon skeletons in immature sediments

    NASA Astrophysics Data System (ADS)

    Kohnen, Math E. L.; Sinninghe Damsté, Jaap S.; ten Haven, H. L.; Van Dalen, A. C. Kock; Schouten, Stefan; De Leeuw, Jan W.

    1991-12-01

    Homologous series (C 15-C 24) of novel 3- n-alkyl-1,2-dithianes and 3- n-alkyl-6-methyl-1,2-di-thianes have been identified in immature sediments. The identification of these compounds was based on comparison of mass spectra and Chromatographie data with those of synthesized 3-methyl-6-tridecyll, 2-dithiane. In addition, 4-methyl-3-(3,7,11-trimethyldodecyl)-1,2-dithiane, 4-(4,8,12-trimethyltridecyl)-1,2-dithiane, 5-methyl-4-(3,7,11-trimethyldodecyl)-1,2,3-trithiepane, and a 1,2-dithiane possessing a pentakishomohopane carbon skeleton were tentatively assigned on the basis of mass spectral characteristics, selective chemolysis, and desulphurisation. The occurrence of these cyclic di-and trisulphides with linear, acyclic isoprenoid and hopanoid carbon skeletons in thermally immature sediments indicates that inorganic polysulphides are incorporated into functionalised lipids during the early stages of diagenesis.

  9. Design, synthesis and evaluation of a series of acyclic fleximer nucleoside analogues with anti-coronavirus activity.

    PubMed

    Peters, Hannah L; Jochmans, Dirk; de Wilde, Adriaan H; Posthuma, Clara C; Snijder, Eric J; Neyts, Johan; Seley-Radtke, Katherine L

    2015-08-01

    A series of doubly flexible nucleoside analogues were designed based on the acyclic sugar scaffold of acyclovir and the flex-base moiety found in the fleximers. The target compounds were evaluated for their antiviral potential and found to inhibit several coronaviruses. Significantly, compound 2 displayed selective antiviral activity (CC50 >3× EC50) towards human coronavirus (HCoV)-NL63 and Middle East respiratory syndrome-coronavirus, but not severe acute respiratory syndrome-coronavirus. In the case of HCoV-NL63 the activity was highly promising with an EC50 <10 μM and a CC50 >100 μM. As such, these doubly flexible nucleoside analogues are viewed as a novel new class of drug candidates with potential for potent inhibition of coronaviruses.

  10. Wavelet Entropy and Directed Acyclic Graph Support Vector Machine for Detection of Patients with Unilateral Hearing Loss in MRI Scanning

    PubMed Central

    Wang, Shuihua; Yang, Ming; Du, Sidan; Yang, Jiquan; Liu, Bin; Gorriz, Juan M.; Ramírez, Javier; Yuan, Ti-Fei; Zhang, Yudong

    2016-01-01

    Highlights We develop computer-aided diagnosis system for unilateral hearing loss detection in structural magnetic resonance imaging.Wavelet entropy is introduced to extract image global features from brain images. Directed acyclic graph is employed to endow support vector machine an ability to handle multi-class problems.The developed computer-aided diagnosis system achieves an overall accuracy of 95.1% for this three-class problem of differentiating left-sided and right-sided hearing loss from healthy controls. Aim: Sensorineural hearing loss (SNHL) is correlated to many neurodegenerative disease. Now more and more computer vision based methods are using to detect it in an automatic way. Materials: We have in total 49 subjects, scanned by 3.0T MRI (Siemens Medical Solutions, Erlangen, Germany). The subjects contain 14 patients with right-sided hearing loss (RHL), 15 patients with left-sided hearing loss (LHL), and 20 healthy controls (HC). Method: We treat this as a three-class classification problem: RHL, LHL, and HC. Wavelet entropy (WE) was selected from the magnetic resonance images of each subjects, and then submitted to a directed acyclic graph support vector machine (DAG-SVM). Results: The 10 repetition results of 10-fold cross validation shows 3-level decomposition will yield an overall accuracy of 95.10% for this three-class classification problem, higher than feedforward neural network, decision tree, and naive Bayesian classifier. Conclusions: This computer-aided diagnosis system is promising. We hope this study can attract more computer vision method for detecting hearing loss. PMID:27807415

  11. Wavelet Entropy and Directed Acyclic Graph Support Vector Machine for Detection of Patients with Unilateral Hearing Loss in MRI Scanning.

    PubMed

    Wang, Shuihua; Yang, Ming; Du, Sidan; Yang, Jiquan; Liu, Bin; Gorriz, Juan M; Ramírez, Javier; Yuan, Ti-Fei; Zhang, Yudong

    2016-01-01

    Highlights We develop computer-aided diagnosis system for unilateral hearing loss detection in structural magnetic resonance imaging.Wavelet entropy is introduced to extract image global features from brain images. Directed acyclic graph is employed to endow support vector machine an ability to handle multi-class problems.The developed computer-aided diagnosis system achieves an overall accuracy of 95.1% for this three-class problem of differentiating left-sided and right-sided hearing loss from healthy controls. Aim: Sensorineural hearing loss (SNHL) is correlated to many neurodegenerative disease. Now more and more computer vision based methods are using to detect it in an automatic way. Materials: We have in total 49 subjects, scanned by 3.0T MRI (Siemens Medical Solutions, Erlangen, Germany). The subjects contain 14 patients with right-sided hearing loss (RHL), 15 patients with left-sided hearing loss (LHL), and 20 healthy controls (HC). Method: We treat this as a three-class classification problem: RHL, LHL, and HC. Wavelet entropy (WE) was selected from the magnetic resonance images of each subjects, and then submitted to a directed acyclic graph support vector machine (DAG-SVM). Results: The 10 repetition results of 10-fold cross validation shows 3-level decomposition will yield an overall accuracy of 95.10% for this three-class classification problem, higher than feedforward neural network, decision tree, and naive Bayesian classifier. Conclusions: This computer-aided diagnosis system is promising. We hope this study can attract more computer vision method for detecting hearing loss.

  12. The role of minerals in the thermal alteration of organic matter. IV - Generation of n-alkanes, acyclic isoprenoids, and alkenes in laboratory experiments

    NASA Technical Reports Server (NTRS)

    Huizinga, Bradley J.; Tannenbaum, Eli; Kaplan, Isaac R.

    1987-01-01

    The effect of common sedimentary minerals (illite, Na-montmorillonite, or calcite) under different water concentrations on the generation and release of n-alkanes, acyclic isoprenoids, and select alkenes from oil-prone kerogens was investigated. Matrices containing Green River Formation kerogen or Monterey Formation kerogen, alone or in the presence of minerals, were heated at 200 or 300 C for periods of up to 1000 hours, and the pyrolysis products were analyzed. The influence of the first two clay minerals was found to be critically dependent on the water content. Under the dry pyrolysis conditions, both minerals significantly reduced alkene formation; the C12+ n-alkanes and acyclic isoprenoids were mostly destroyed by montmorillonite, but underwent only minor alteration with illite. Under hydrous conditions (mineral/water of 2/1), the effects of both minerals were substantially reduced. Calcite had no significant effect on the thermal evolution of the hydrocarbons.

  13. The role of minerals in the thermal alteration of organic matter. IV - Generation of n-alkanes, acyclic isoprenoids, and alkenes in laboratory experiments

    NASA Astrophysics Data System (ADS)

    Huizinga, Bradley J.; Tannenbaum, Eli; Kaplan, Isaac R.

    1987-05-01

    The effect of common sedimentary minerals (illite, Na-montmorillonite, or calcite) under different water concentrations on the generation and release of n-alkanes, acyclic isoprenoids, and select alkenes from oil-prone kerogens was investigated. Matrices containing Green River Formation kerogen or Monterey Formation kerogen, alone or in the presence of minerals, were heated at 200 or 300 C for periods of up to 1000 hours, and the pyrolysis products were analyzed. The influence of the first two clay minerals was found to be critically dependent on the water content. Under the dry pyrolysis conditions, both minerals significantly reduced alkene formation; the C12+ n-alkanes and acyclic isoprenoids were mostly destroyed by montmorillonite, but underwent only minor alteration with illite. Under hydrous conditions (mineral/water of 2/1), the effects of both minerals were substantially reduced. Calcite had no significant effect on the thermal evolution of the hydrocarbons.

  14. Ligand modeling and design

    SciTech Connect

    Hay, B.P.

    1997-10-01

    The purpose of this work is to develop and implement a molecular design basis for selecting organic ligands that would be used in the cost-effective removal of specific radionuclides from nuclear waste streams. Organic ligands with metal ion specificity are critical components in the development of solvent extraction and ion exchange processes that are highly selective for targeted radionuclides. The traditional approach to the development of such ligands involves lengthy programs of organic synthesis and testing, which in the absence of reliable methods for screening compounds before synthesis, results in wasted research effort. The author`s approach breaks down and simplifies this costly process with the aid of computer-based molecular modeling techniques. Commercial software for organic molecular modeling is being configured to examine the interactions between organic ligands and metal ions, yielding an inexpensive, commercially or readily available computational tool that can be used to predict the structures and energies of ligand-metal complexes. Users will be able to correlate the large body of existing experimental data on structure, solution binding affinity, and metal ion selectivity to develop structural design criteria. These criteria will provide a basis for selecting ligands that can be implemented in separations technologies through collaboration with other DOE national laboratories and private industry. The initial focus will be to select ether-based ligands that can be applied to the recovery and concentration of the alkali and alkaline earth metal ions including cesium, strontium, and radium.

  15. PenPC: A Two-step Approach to Estimate the Skeletons of High Dimensional Directed Acyclic Graphs

    PubMed Central

    Ha, Min Jin; Sun, Wei; Xie, Jichun

    2015-01-01

    Summary Estimation of the skeleton of a directed acyclic graph (DAG) is of great importance for understanding the underlying DAG and causal e ects can be assessed from the skeleton when the DAG is not identifiable. We propose a novel method named PenPC to estimate the skeleton of a high-dimensional DAG by a two-step approach. We first estimate the non-zero entries of a concentration matrix using penalized regression, and then fix the difference between the concentration matrix and the skeleton by evaluating a set of conditional independence hypotheses. For high dimensional problems where the number of vertices p is in polynomial or exponential scale of sample size n, we study the asymptotic property of PenPC on two types of graphs: traditional random graphs where all the vertices have the same expected number of neighbors, and scale-free graphs where a few vertices may have a large number of neighbors. As illustrated by extensive simulations and applications on gene expression data of cancer patients, PenPC has higher sensitivity and specificity than the state-of-the-art method, the PC-stable algorithm. PMID:26406114

  16. H4octapa-Trastuzumab: Versatile Acyclic Chelate System for 111In and 177Lu Imaging and Therapy

    PubMed Central

    Price, Eric W.; Zeglis, Brian M.; Cawthray, Jacqueline F.; Ramogida, Caterina F.; Ramos, Nicholas

    2013-01-01

    A bifunctional derivative of the versatile acyclic chelator H4octapa, p-SCNBn- H4octapa, has been synthesized for the first time. The chelator was conjugated to the HER2/neu-targeting antibody trastuzumab and labeled in high radiochemical purity and specific activity with the radioisotopes 111In and 177Lu. The in vivo behavior of the resulting radioimmunoconjugates was investigated in mice bearing ovarian cancer xenografts and compared to analogous radioimmunoconjugates employing the ubiquitous chelator DOTA. The H4octapa-trastuzumab conjugates displayed faster radiolabeling kinetics with more reproducible yields under milder conditions (15 min, RT, ~94–95%) than those based on DOTA-trastuzumab (60 min, 37 °C ~50–88%). Further, antibody integrity was better preserved in the 111In- and 177Lu-octapatrastuzumab constructs, with immunoreactive fractions of 0.99 for each compared to 0.93–0.95 for 111In- and 177Lu-DOTA-trastuzumab. These results translated to improved in vivo biodistribution profiles and SPECT imaging results for 111In- and 177Lu-octapa-trastuzumab compared to 111In- and 177Lu-DOTA-trastuzumab, with increased tumor uptake and higher tumor-to-tissue activity ratios. PMID:23901833

  17. Molecular mechanism by which acyclic retinoid induces nuclear localization of transglutaminase 2 in human hepatocellular carcinoma cells

    PubMed Central

    Shrestha, R; Tatsukawa, H; Shrestha, R; Ishibashi, N; Matsuura, T; Kagechika, H; Kose, S; Hitomi, K; Imamoto, N; Kojima, S

    2015-01-01

    Nuclear accumulation of transglutaminase 2 (TG2) is an important step in TG2-dependent cell death. However, the underlying molecular mechanisms for nuclear translocation of TG2 are still poorly understood. In this study, we demonstrated that acyclic retinoid (ACR) induced nuclear accumulation of TG2 in JHH-7 cells, a hepatocellular carcinoma (HCC) leading to their apoptosis. We further demonstrated molecular mechanism in nuclear-cytoplasmic trafficking of TG2 and an effect of ACR on it. We identified a novel 14-amino acid nuclear localization signal (NLS) 466AEKEETGMAMRIRV479 in the ‘C' domain and a leucine-rich nuclear export signal (NES) 657LHMGLHKL664 in the ‘D' domain that allowed TG2 to shuttle between the nuclear and cytosolic milieu. Increased nuclear import of GAPDH myc-HIS fused with the identified NLS was observed, confirming its nuclear import ability. Leptomycin B, an inhibitor of exportin-1 as well as point mutation of all leucine residues to glutamine residues in the NES of TG2 demolished its nuclear export. TG2 formed a trimeric complex with importin-α and importin-β independently from transamidase activity which strongly suggested the involvement of a NLS-based translocation of TG2 to the nucleus. ACR accelerated the formation of the trimeric complex and that may be at least in part responsible for enhanced nuclear localization of TG2 in HCC cells treated with ACR. PMID:26633708

  18. Clinical Potential of the Acyclic Nucleoside Phosphonates Cidofovir, Adefovir, and Tenofovir in Treatment of DNA Virus and Retrovirus Infections

    PubMed Central

    De Clercq, Erik

    2003-01-01

    The acyclic nucleoside phosphonates HPMPC (cidofovir), PMEA (adefovir), and PMPA (tenofovir) have proved to be effective in vitro (cell culture systems) and in vivo (animal models and clinical studies) against a wide variety of DNA virus and retrovirus infections: cidofovir against herpesvirus (herpes simplex virus types 1 and 2 varicella-zoster virus, cytomegalovirus [CMV], Epstein-Barr virus, and human herpesviruses 6, 7, and 8), polyomavirus, papillomavirus, adenovirus, and poxvirus (variola virus, cowpox virus, vaccinia virus, molluscum contagiosum virus, and orf virus) infections; adefovir against herpesvirus, hepadnavirus (human hepatitis B virus), and retrovirus (human immunodeficiency virus types 1 [HIV-1] and 2 [HIV-2], simian immunodeficiency virus, and feline immunodeficiency virus) infections; and tenofovir against both hepadnavirus and retrovirus infections. Cidofovir (Vistide) has been officially approved for the treatment of CMV retinitis in AIDS patients, tenofovir disoproxil fumarate (Viread) has been approved for the treatment of HIV infections (i.e., AIDS), and adefovir dipivoxil (Hepsera) has been approved for the treatment of chronic hepatitis B. Nephrotoxicity is the dose-limiting side effect for cidofovir (Vistide) when used intravenously (5 mg/kg); no toxic side effects have been described for adefovir dipivoxil and tenofovir disoproxil fumarate, at the approved doses (Hepsera at 10 mg orally daily and Viread at 300 mg orally daily). PMID:14557287

  19. Ligand modeling and design

    SciTech Connect

    Hay, B.

    1996-10-01

    The purpose of this work is to develop and implement a molecular design basis for selecting organic ligands that would be used tin applications for the cost-effective removal of specific radionuclides from nuclear waste streams.

  20. Bis(methylpyridine)-EDTA derivative as a potential ligand for PET imaging: synthesis, complexation, and biological evaluation.

    PubMed

    Singh, Pooja; Aggarwal, Swati; Tiwari, Anjani K; Kumar, Vikas; Pratap, Ramendra; Chuttani, Krishna; Mishra, Anil K

    2014-12-01

    A novel transitional metal ligand derivatized from EDTA-conjugated 2-amino-4-methyl pyridine, an acyclic vehicle (EDTA-Mepy2 ) was designed, synthesized, and characterized for PET imaging with ⁶⁸Ga. The drug likeliness and appropriate lipophilicity were first analyzed by molecular docking studies which shows interactive property of ligand with serum albumin protein (HSA: PDB 1E78), at Lys199, Arg257, and His242 residues, which make it more appropriate in transportation as a specific ligand for PET imaging. As a confirmation, binding constant of the ligand with human serum albumin was calculated at λex = 350 nm which was found to be 4.9 × 10³ m⁻¹. The pharmacokinetics of (68) Ga-EDTA-Mepy2 was analyzed by blood kinetics (t(1/2) slow: 3 h 56 min and t(1/2) fast: 32 min) and biodistribution (maximum % ID/g was found in kidney at 1 h). Further the capability of this ligand was analyzed as optical marker also, by recording λex = 380 nm, RFU = 8000; 710 nm, RFU = 1000 units at fixed λem = 280 nm. Additionally, in physiological conditions where its stability was calculated, suggests 15-20 times selectivity over the endogenously present metal ions (KG aL /KZ nL = 14.3, KG aL /KC uL = 18.1).

  1. Cationic lipids bearing succinic-based, acyclic and macrocyclic hydrophobic domains: Synthetic studies and in vitro gene transfer.

    PubMed

    Jubeli, Emile; Maginty, Amanda B; Khalique, Nada Abdul; Raju, Liji; Nicholson, David G; Larsen, Helge; Pungente, Michael D; Goldring, William P D

    2017-01-05

    In this communication we describe the construction of four succinic-based cationic lipids, their formulation with plasmid DNA (pDNA), and an evaluation of their in vitro gene delivery into Chinese hamster ovarian (CHO-K1) cells. The cationic lipids employed in this work possess either a dimethylamine or trimethylamine headgroup, and a macrocyclic or an acyclic hydrophobic domain composed of, or derived from two 16-atom, succinic-based acyl chains. The synthesized lipids and a co-lipid of neutral charge, either cholesterol or 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), were formulated in an overall 3:2 cationic-to-neutral lipid molar ratio, then complexed with plasmid DNA (pDNA). The relative transfection performance was evaluated via a comparison between matched versus mismatched formulations defined by the rigidity relationship between the lipids employed. Gel electrophoresis was used to characterize the binding of the lipid formulations with plasmid DNA and the relative degree of plasmid degradation using a DNase I degradation assay. Small angle X-ray diffraction (SAXD) was employed to characterize the packing morphology of the lipid-DNA complexes. In general, the succinic unit embedded within the hydrophobic domain of the cationic lipids was found to improve lipid hydration. The transfection assays revealed a general trend in which mismatched formulations that employed a rigid lipid combined with a non-rigid (or flexible) lipid, outperformed the matched formulations. The results from this work suggest that the design of the cationic lipid structure and the composition of the lipoplex formulation play key roles in governing the transfection performance of nonviral gene delivery agents.

  2. New acyclic bis phenylpropanoid and neolignans, from Myristica fragrans Houtt., exhibiting PARP-1 and NF-κB inhibitory effects.

    PubMed

    Muñoz Acuña, Ulyana; Carcache, Peter J Blanco; Matthew, Susan; Carcache de Blanco, Esperanza J

    2016-07-01

    The bioassay-guided fractionation of the aril of Myristica fragrans (mace spice) yielded five phenolic compounds, one new acyclic bis phenylpropanoid (1) and four previously known phenolic compounds: compounds (1) (S) 1-(3,4,5-trimethoxyphenyl)-2-(3-methoxy-5-(prop-1-yl) phenyl)-propan-1-ol, (2) benzenemethanol; α-[1-[2,6-dimethoxy-4-(2-propen-1-yl)phenoxy]ethyl]-3,4-dimethoxy-1-acetate, (3) odoratisol A, phenol, 4-[(2S,3S)-2,3-dihydro-7-methoxy-3-methyl-5-(1E)-1-propenyl-2-benzofuranyl]-2,6-dimethoxy, (4) 1,3-benzodioxate-5-methanol,α-[1-[2,6-dimethoxy-4-(2-propenyl)phenoxy]ethyl]-acetate, (5) licarin C; benzofuran,2,3-dihydro-7-methoxy-3-methyl-5-(1E)-1-yl-2-(3,4,5-trimethoxyphenyl). An NMR tube Mosher ester reaction was used in an approach to characterize and determine the assignment of the absolute configuration of the new isolated chiral alcohol (1). The PARP-1 inhibitory activity was evaluated for compound (1) (IC50=3.04μM), compound (2) (IC50=0.001μM), compound (4) (IC50=22.07μM) and compound (5) (IC50=3.11μM). Furthermore, the isolated secondary metabolites were tested for NF-κB and K-Ras inhibitory activities. When tested in the p65 assay, compounds (2) and (4) displayed potent NF-κB inhibition (IC50=1.5 nM and 3.4nM, respectively).

  3. Acyclic Identification of Aptamers for Human alpha-Thrombin Using Over-Represented Libraries and Deep Sequencing

    PubMed Central

    Kupakuwana, Gillian V.; Crill, James E.; McPike, Mark P.; Borer, Philip N.

    2011-01-01

    Background Aptamers are oligonucleotides that bind proteins and other targets with high affinity and selectivity. Twenty years ago elements of natural selection were adapted to in vitro selection in order to distinguish aptamers among randomized sequence libraries. The primary bottleneck in traditional aptamer discovery is multiple cycles of in vitro evolution. Methodology/Principal Findings We show that over-representation of sequences in aptamer libraries and deep sequencing enables acyclic identification of aptamers. We demonstrated this by isolating a known family of aptamers for human α-thrombin. Aptamers were found within a library containing an average of 56,000 copies of each possible randomized 15mer segment. The high affinity sequences were counted many times above the background in 2–6 million reads. Clustering analysis of sequences with more than 10 counts distinguished two sequence motifs with candidates at high abundance. Motif I contained the previously observed consensus 15mer, Thb1 (46,000 counts), and related variants with mostly G/T substitutions; secondary analysis showed that affinity for thrombin correlated with abundance (Kd = 12 nM for Thb1). The signal-to-noise ratio for this experiment was roughly 10,000∶1 for Thb1. Motif II was unrelated to Thb1 with the leading candidate (29,000 counts) being a novel aptamer against hexose sugars in the storage and elution buffers for Concanavilin A (Kd = 0.5 µM for α-methyl-mannoside); ConA was used to immobilize α-thrombin. Conclusions/Significance Over-representation together with deep sequencing can dramatically shorten the discovery process, distinguish aptamers having a wide range of affinity for the target, allow an exhaustive search of the sequence space within a simplified library, reduce the quantity of the target required, eliminate cycling artifacts, and should allow multiplexing of sequencing experiments and targets. PMID:21625587

  4. Estimation of apparent binding constant of complexes of selected acyclic nucleoside phosphonates with β-cyclodextrin by affinity capillary electrophoresis.

    PubMed

    Šolínová, Veronika; Mikysková, Hana; Kaiser, Martin Maxmilián; Janeba, Zlatko; Holý, Antonín; Kašička, Václav

    2016-01-01

    Affinity capillary electrophoresis (ACE) has been applied to estimation of apparent binding constant of complexes of (R,S)-enantiomers of selected acyclic nucleoside phosphonates (ANPs) with chiral selector β-cyclodextrin (βCD) in aqueous alkaline medium. The noncovalent interactions of five pairs of (R,S)-enantiomers of ANPs-based antiviral drugs and their derivatives with βCD were investigated in the background electrolyte (BGE) composed of 35 or 50 mM sodium tetraborate, pH 10.0, and containing variable concentration (0-25 mM) of βCD. The apparent binding constants of the complexes of (R,S)-enantiomers of ANPs with βCD were estimated from the dependence of effective electrophoretic mobilities of (R,S)-enantiomers of ANPs (measured simultaneously by ACE at constant reference temperature 25°C inside the capillary) on the concentration of βCD in the BGE using different nonlinear and linear calculation methodologies. Nonlinear regression analysis provided more precise and accurate values of the binding constants and a higher correlation coefficient as compared to the regression analysis of the three linearized plots of the effective mobility dependence on βCD concentration in the BGE. The complexes of (R,S)-enantiomers of ANPs with βCD have been found to be relatively weak - their apparent binding constants determined by the nonlinear regression analysis were in the range 13.3-46.4 L/mol whereas the values from the linearized plots spanned the interval 12.3-55.2 L/mol.

  5. Rational Design and Generation of a Bimodal Bifunctional Ligand for Antibody-Targeted Radiation Cancer Therapy

    PubMed Central

    Chong, Hyun-Soon; Ma, Xiang; Le, Thien; Kwamena, Baidoo; Milenic, Diane E.; Brady, Erik D.; Song, Hyun A.; Brechbiel, Martin W.

    2008-01-01

    An antibody-targeted radiation therapy (radioimmunotherapy, RIT) employs a bifunctional ligand that can effectively hold a cytotoxic metal with clinically acceptable complexation kinetics and stability while being attached to a tumor-specific antibody. Clinical exploration of the therapeutic potential of RIT has been challenged by the absence of adequate ligand, a critical component for enhancing the efficacy of the cancer therapy. To address this deficiency, the bifunctional ligand C-NETA in a unique structural class possessing both a macrocyclic cavity and a flexible acyclic moiety was designed. The practical, reproducible, and readily scalable synthetic route to C-NETA was developed, and its potential as the chelator of 212Bi, 213Bi, and 177Lu for RIT was evaluated in vitro and in vivo. C-NETA rapidly binds both Lu(III) and Bi(III), and the respective metal complexes remain extremely stable in serum for 14 days. 177Lu—C-NETA and 205/6Bi—C-NETA possess an excellent or acceptable in vivo biodistribution profile. PMID:18062661

  6. The Role of Ligand Topology in the Decomplexation of Luminescent Lanthanide Complexes by Dipicolinic Acid.

    PubMed

    Mian, Federica; Bottaro, Gregorio; Seraglia, Roberta; Cavazzini, Marco; Quici, Silvio; Armelao, Lidia

    2016-10-18

    In this study, we present the aqueous solution behavior of two luminescent lanthanide antenna complexes (Eu(3+) ⊂1, Dy(3+) ⊂9) with different ligand topologies in the presence of dipicolinic acid (DPA, pyridine-2,6-dicarboxylic acid). Macrocyclic (1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid, DO3A, 9) and acyclic (1,4,7-triazaheptane-1,1,7,7-tetraacetic acid, DTTA, 1) ligands have been selected to form a ratiometric pair in which Dy(3+) ⊂9 acts as a reference and Eu(3+) ⊂1 acts as a probe for the recognition of DPA. The pair of luminescent complexes in water reveals the capability to work as a DPA luminescent sensor. The change of emission intensity of Eu(3+) indicates the occurrence of a new sensitization path for the lanthanide cation through excitation of DPA. NMR evidence implies the presence of free 1 and mass spectrometry shows the formation of emitting [EuDPA2 ](-) as a result of a ligand exchange reaction.

  7. Ruthenium complexes with chiral tetradentate PNNP ligands: asymmetric catalysis from the viewpoint of inorganic chemistry.

    PubMed

    Mezzetti, Antonio

    2010-09-14

    This is a personal account of the application of ruthenium complexes containing chiral tetradentate ligands with a P(2)N(2) ligand set (PNNP) as catalyst precursors for enantioselective "atom transfer" reactions. Therewith are meant reactions that involve bond formation between a metal-coordinated molecule and a free reagent. The reactive fragment (e.g. carbene) is transferred either from the metal to the non-coordinated substrate (e.g. olefin) or from the free reagent (e.g. F(+)) to the metal-bound substrate (e.g.beta-ketoester), depending on the class of catalyst (monocationic, Class A; or dicationic, Class B). The monocationic five-coordinate species [RuCl(PNNP)](+) and the six-coordinate complexes [RuCl(L)(PNNP)](+) (L = Et(2)O, H(2)O) of Class A catalyse asymmetric epoxidation, cyclopropanation (carbene transfer from the metal to the free olefin), and imine aziridination. Alternatively, the dicationic complexes [Ru(L-L)(PNNP)](2+) (Class B), which contain substrates that act as neutral bidentate ligands L-L (e.g., beta-ketoesters), catalyse Michael addition, electrophilic fluorination, and hydroxylation reactions. Additionally, unsaturated beta-ketoesters form dicationic complexes of Class B that catalyse Diels-Alder reactions with acyclic dienes to produce tetrahydro-1-indanones and estrone derivatives. Excellent enantioselectivity has been achieved in several of the catalytic reactions mentioned above. The study of key reaction intermediates (both in the solid state and in solution) has revealed significant mechanistic aspects of the catalytic reactions.

  8. Ligand fitting with CCP4

    PubMed Central

    2017-01-01

    Crystal structures of protein–ligand complexes are often used to infer biology and inform structure-based drug discovery. Hence, it is important to build accurate, reliable models of ligands that give confidence in the interpretation of the respective protein–ligand complex. This paper discusses key stages in the ligand-fitting process, including ligand binding-site identification, ligand description and conformer generation, ligand fitting, refinement and subsequent validation. The CCP4 suite contains a number of software tools that facilitate this task: AceDRG for the creation of ligand descriptions and conformers, Lidia and JLigand for two-dimensional and three-dimensional ligand editing and visual analysis, Coot for density interpretation, ligand fitting, analysis and validation, and REFMAC5 for macromolecular refinement. In addition to recent advancements in automatic carbohydrate building in Coot (LO/Carb) and ligand-validation tools (FLEV), the release of the CCP4i2 GUI provides an integrated solution that streamlines the ligand-fitting workflow, seamlessly passing results from one program to the next. The ligand-fitting process is illustrated using instructive practical examples, including problematic cases such as post-translational modifications, highlighting the need for careful analysis and rigorous validation. PMID:28177312

  9. Flexible Acyclic Polyol-Chloride Anion Complexes and Their Characterization by Photoelectron Spectroscopy and Variable Temperature Binding Constant Determinations

    SciTech Connect

    Shokri, Alireza; Wang, Xue B.; Wang, Yangping; O'Doherty, George A.; Kass, Steven R.

    2016-03-17

    Flexible acyclic alcohols with 1–5 hydroxyl groups were bound to chloride anion and these complexes were interrogated by negative ion photoelectron spectroscopy and companion density functional theory computations. The resulting vertical detachment energies are reproduced on average to 0.10 eV by M06-2X/aug-cc-pVTZ predictions and range from 4.45 – 5.96 eV. These values are 0.84 – 2.35 eV larger than the adiabatic detachment energy of Cl– as a result of the larger hydrogen bond networks in the bigger polyols. Adiabatic detachment energies of the alcohol–Cl– clusters are more difficult to determine both experimentally and computationally. This is due to the large geometry changes that occur upon photodetachment and the large bond dissociation energy of H–Cl which enables the resulting chlorine atom to abstract a hydrogen from any of the methylene (CH2) or methine (CH) positions. Both ionic and non-ionic hydrogen bonds (i.e., OH•••Cl– and OH•••OH•••Cl–) form in the larger polyols complexes, and are found to be energetically comparable. Subtle structural differences, consequently can lead to the formation of different types of hydrogen bonds and maximizing the ionic ones is not always preferred. Solution equilibrium binding constants between the alcohols and tetrrabuylammonium chloride (TBACl) in acetonitrile at -24.2, 22.0, and 53.6 °C were also determined. The free energies of association are nearly identical for all of the substrates (i.e., ΔG° = -2.8 ± 0.7 kcal mol–1). Compensating enthalpy and entropy values reveal, contrary to expectation and the intrinsic gas-phase preferences, that the bigger systems with more hydroxyl groups are entropically favored and enthalpically disfavored relative to the smaller species. This suggests that more solvent molecules are released upon binding TBACl to alcohols with more hydroxyl groups and is consistent with the measured negative heat capacities. These quantities increase with

  10. Acyclic Cucurbit[n]uril-type Molecular Containers: Influence of Aromatic Walls on their Function as Solubilizing Excipients for Insoluble Drugs

    PubMed Central

    2015-01-01

    We studied the influence of the aromatic sidewalls on the ability of acyclic CB[n]-type molecular containers (1a–1e) to act as solubilizing agents for 19 insoluble drugs including the developmental anticancer agent PBS-1086. All five containers exhibit good water solubility and weak self-association (Ks ≤ 624 M–1). We constructed phase solubility diagrams to extract Krel and Ka values for the container·drug complexes. The acyclic CB[n]-type containers generally display significantly higher Ka values than HP-β-CD toward drugs. Containers 1a–1e bind the steroidal ring system and aromatic moieties of insoluble drugs. Compound 1b displays highest affinity toward most of the drugs studied. Containers 1a and 1b are broadly applicable and can be used to formulate a wider variety of insoluble drugs than was previously possible with cyclodextrin technology. For drugs that are solubilized by both HP-β-CD and 1a–1e, lower concentrations of 1a–1e are required to achieve identical [drug]. PMID:25369565

  11. LigandRNA: computational predictor of RNA-ligand interactions.

    PubMed

    Philips, Anna; Milanowska, Kaja; Lach, Grzegorz; Bujnicki, Janusz M

    2013-12-01

    RNA molecules have recently become attractive as potential drug targets due to the increased awareness of their importance in key biological processes. The increase of the number of experimentally determined RNA 3D structures enabled structure-based searches for small molecules that can specifically bind to defined sites in RNA molecules, thereby blocking or otherwise modulating their function. However, as of yet, computational methods for structure-based docking of small molecule ligands to RNA molecules are not as well established as analogous methods for protein-ligand docking. This motivated us to create LigandRNA, a scoring function for the prediction of RNA-small molecule interactions. Our method employs a grid-based algorithm and a knowledge-based potential derived from ligand-binding sites in the experimentally solved RNA-ligand complexes. As an input, LigandRNA takes an RNA receptor file and a file with ligand poses. As an output, it returns a ranking of the poses according to their score. The predictive power of LigandRNA favorably compares to five other publicly available methods. We found that the combination of LigandRNA and Dock6 into a "meta-predictor" leads to further improvement in the identification of near-native ligand poses. The LigandRNA program is available free of charge as a web server at http://ligandrna.genesilico.pl.

  12. Analysis of macromolecules, ligands and macromolecule-ligand complexes

    DOEpatents

    Von Dreele, Robert B.

    2008-12-23

    A method for determining atomic level structures of macromolecule-ligand complexes through high-resolution powder diffraction analysis and a method for providing suitable microcrystalline powder for diffraction analysis are provided. In one embodiment, powder diffraction data is collected from samples of polycrystalline macromolecule and macromolecule-ligand complex and the refined structure of the macromolecule is used as an approximate model for a combined Rietveld and stereochemical restraint refinement of the macromolecule-ligand complex. A difference Fourier map is calculated and the ligand position and points of interaction between the atoms of the macromolecule and the atoms of the ligand can be deduced and visualized. A suitable polycrystalline sample of macromolecule-ligand complex can be produced by physically agitating a mixture of lyophilized macromolecule, ligand and a solvent.

  13. Synthesis and structural characterization of silver(I), copper(I) coordination polymers and a helicate palladium(II) complex of dipyrrolylmethane-based dipyrazole ligands: the effect of meso substituents on structural formation.

    PubMed

    Guchhait, Tapas; Barua, Bhagyasree; Biswas, Aritra; Basak, Biswanath; Mani, Ganesan

    2015-05-21

    A new class of multidentate dipyrrolylmethane based ditopic tecton, 1,9-bis(3,5-dimethylpyrazolylmethyl)dipyrrolylmethane, containing diethyl (L1) or cyclohexylidene (L2) substituents at the meso carbon atom were readily synthesized in 28-45% yields in two different ways starting from dipyrrolylmethanes. A one dimensional coordination polymer structure ([(L2)Ag][BF4])n was obtained when L2 was treated with AgBF4, whereas the analogous reaction between L1 and AgBF4 afforded the dicationic binuclear metallacycle complex [(L1)2Ag2][BF4]2. In addition, yet another coordination polymeric structure [(L1)CuI]n was obtained from the reaction between L1 and CuI. The analogous reaction of L1 with [Pd(PhCN)2Cl2] afforded the binuclear palladium complex [(L1)2Pd2Cl4] having a double-stranded helicate structure. The observed structural differences are attributed to the effects of the substituents present at the meso carbon atom of the ligand, in addition to the nature of the metal centre, coordination number and the preferred geometry.

  14. EGF receptor ligands: recent advances

    PubMed Central

    Singh, Bhuminder; Carpenter, Graham; Coffey, Robert J.

    2016-01-01

    Seven ligands bind to and activate the mammalian epidermal growth factor (EGF) receptor (EGFR/ERBB1/HER1): EGF, transforming growth factor-alpha (TGFA), heparin-binding EGF-like growth factor (HBEGF), betacellulin (BTC), amphiregulin (AREG), epiregulin (EREG), and epigen (EPGN). Of these, EGF, TGFA, HBEGF, and BTC are thought to be high-affinity ligands, whereas AREG, EREG, and EPGN constitute low-affinity ligands. This focused review is meant to highlight recent studies related to actions of the individual EGFR ligands, the interesting biology that has been uncovered, and relevant advances related to ligand interactions with the EGFR. PMID:27635238

  15. Macrocyclic ligands for uranium complexation. Final report, August 1, 1986--March 31, 1993

    SciTech Connect

    Potts, K.T.

    1993-12-31

    Macrocycles, designed for complexation of the uranyl ion by computer modeling studies and utilizing six ligating atoms in the equatorial plane of the uranyl ions, have been prepared and their complexation of the uranyl ions evaluated. The ligating atoms, either oxygen or sulfur, were part of acylurea, biuret or thiobiuret subunits with alkane chains or pyridine units completing the macrocyclic periphery. These macrocycles with only partial preorganization formed uranyl complexes in solution but no crystalline complexes were isolated. Refinement of the cavity diameter by variation of the peripheral functional groups is currently studied to achieve an optimized cavity diameter of 4.7--5.2 {angstrom}. Acyclic ligands containing the same ligating atoms in equivalent functional entities were found to form a crystalline 1:1 uranyl-ligand complex (stability constant log K = 10.7) whose structure was established by X-ray data. This complex underwent a facile, DMSO-induced rearrangement to a 2:1 uranyl-ligand complex whose structure was also established by X-ray data. The intermediates to the macrocycles all behaved as excellent ligands for the complexation of transition metals. Acylthiourea complexes of copper and nickel as well as intermolecular, binuclear copper and nickel complexes of bidentate carbonyl thioureas formed readily and their structures were established in several representative instances by X-ray structural determinations. Tetradentate bis(carbonylthioureas) were found to be very efficient selective reagents for the complexation of copper in the presence of nickel ions. Several preorganized macrocycles were also prepared but in most instances these macrocycles underwent ring-opening under complexation conditions.

  16. Analogues of acyclic nucleosides derived from tris-(hydroxymethyl)phosphine oxide or bis-(hydroxymethyl)phosphinic acid coupled to DNA nucleobases.

    PubMed

    Nawrot, Barbara; Michalak, Olga; De Clercq, Erik; Stec, Wojciech J

    2004-11-01

    A series of novel acyclic nucleoside analogues containing bis-(hydroxymethyl)phosphinic acid (BHPA) or tris(hydroxymethyl)phosphine oxide (THPO) coupled with DNA nucleobases or with 5-fluorouracil were prepared and their antiviral activity was studied against cytomegalovirus (CMV), varicella-zoster virus (VZV), parainfluenza-virus type 3, reovirus-type 1, sindbis, coxsackie B4, punta toro, vesicular stomatitis and respiratory syncytial virus, herpes simplex virus-type 1 (KOS) and type 2 (G), vaccinia virus and herpes simplex virus-1 (TK- KOS ACVr). No specific antiviral effects were noted for any of test compounds against viruses evaluated, except thymine, cytosine and adenine derivatives of BHPA exerting borderline activity against respiratory syncytial virus at the 80 mg/ml concentration.

  17. Acyclic diene metathesis with a monomer from renewable resources: control of molecular weight and one-step preparation of block copolymers.

    PubMed

    Rybak, Anastasiya; Meier, Michael A R

    2008-01-01

    The preparation of a long-chain aliphatic alpha,omega-diene from plant oil derivatives and its subsequent polymerization through acyclic diene metathesis (ADMET) is described. The ADMET bulk polymerization of the thus-obtained monomer, undecyl undecenoate, was investigated and optimized by applying ruthenium-based metathesis catalysts from Grubbs and Hoveyda-Grubbs, leading to high-molecular-weight polyesters. Moreover, by applying different amounts of methyl 10-undecenoate as a chain stopper in this ADMET step growth polymerization, the molecular weight of the resulting polyester could be tuned in a range from approximately 10 to 45 kDa. Finally, the application of a poly(ethylene glycol) methyl ether acrylate as the chain stopper led to the preparation of ABA triblock copolymers in a one-step, one-pot procedure.

  18. Efficacy of the acyclic nucleoside phosphonates (S)-9-(3-fluoro-2-phosphonylmethoxypropyl)adenine (FPMPA) and 9-(2-phosphonylmethoxyethyl)adenine (PMEA) against feline immunodeficiency virus.

    PubMed

    Hartmann, K; Kuffer, M; Balzarini, J; Naesens, L; Goldberg, M; Erfle, V; Goebel, F D; De Clercq, E; Jindrich, J; Holy, A; Bischofberger, N; Kraft, W

    1998-02-01

    The acyclic nucleoside phosphonates (S)-9-(3-fluoro-2-phosphonylmethoxypropyl)adenine (FPMPA) and 9-(2-phosphonylmethoxyethyl)adenine (PMEA) were evaluated for their efficacy and side effects in a double-blind placebo-controlled trial using naturally occurring feline immunodeficiency virus (FIV)-infected cats. This natural retrovirus animal model is considered highly relevant for the pathogenesis and chemotherapy of HIV in humans. Both PMEA and FPMPA proved effective in ameliorating the clinical symptoms of FIV-infected cats, as measured by several clinical parameters including the incidence and severity of stomatitis, Karnofsky's score, immunologic parameters such as relative and absolute CD4+ lymphocyte counts, and virologic parameters including proviral DNA levels in peripheral blood mononuclear cells (PBMC) of drug-treated animals. In contrast with PMEA, FPMPA showed no hematologic side effects at a dose that was 2.5-fold higher than PMEA.

  19. An integrated QSAR-PBK/D modelling approach for predicting detoxification and DNA adduct formation of 18 acyclic food-borne α,β-unsaturated aldehydes

    SciTech Connect

    Kiwamoto, R. Spenkelink, A.; Rietjens, I.M.C.M.; Punt, A.

    2015-01-01

    Acyclic α,β-unsaturated aldehydes present in food raise a concern because the α,β-unsaturated aldehyde moiety is considered a structural alert for genotoxicity. However, controversy remains on whether in vivo at realistic dietary exposure DNA adduct formation is significant. The aim of the present study was to develop physiologically based kinetic/dynamic (PBK/D) models to examine dose-dependent detoxification and DNA adduct formation of a group of 18 food-borne acyclic α,β-unsaturated aldehydes without 2- or 3-alkylation, and with no more than one conjugated double bond. Parameters for the PBK/D models were obtained using quantitative structure–activity relationships (QSARs) defined with a training set of six selected aldehydes. Using the QSARs, PBK/D models for the other 12 aldehydes were defined. Results revealed that DNA adduct formation in the liver increases with decreasing bulkiness of the molecule especially due to less efficient detoxification. 2-Propenal (acrolein) was identified to induce the highest DNA adduct levels. At realistic dietary intake, the predicted DNA adduct levels for all aldehydes were two orders of magnitude lower than endogenous background levels observed in disease free human liver, suggesting that for all 18 aldehydes DNA adduct formation is negligible at the relevant levels of dietary intake. The present study provides a proof of principle for the use of QSAR-based PBK/D modelling to facilitate group evaluations and read-across in risk assessment. - Highlights: • Physiologically based in silico models were made for 18 α,β-unsaturated aldehydes. • Kinetic parameters were determined by in vitro incubations and a QSAR approach. • DNA adduct formation was negligible at levels relevant for dietary intake. • The use of QSAR-based PBK/D modelling facilitates group evaluations and read-across.

  20. Melatonin: functions and ligands.

    PubMed

    Singh, Mahaveer; Jadhav, Hemant R

    2014-09-01

    Melatonin is a chronobiotic substance that acts as synchronizer by stabilizing bodily rhythms. Its synthesis occurs in various locations throughout the body, including the pineal gland, skin, lymphocytes and gastrointestinal tract (GIT). Its synthesis and secretion is controlled by light and dark conditions, whereby light decreases and darkness increases its production. Thus, melatonin is also known as the 'hormone of darkness'. Melatonin and analogs that bind to the melatonin receptors are important because of their role in the management of depression, insomnia, epilepsy, Alzheimer's disease (AD), diabetes, obesity, alopecia, migraine, cancer, and immune and cardiac disorders. In this review, we discuss the mechanism of action of melatonin in these disorders, which could aid in the design of novel melatonin receptor ligands.

  1. Bifunctional DTPA-type ligand

    SciTech Connect

    Gansow, O.A.; Brechbiel, M.W.

    1990-03-26

    The subject matter of the invention relates to bifunctional cyclohexyl DTPA ligands and methods of using these compounds. Specifically, such ligands are useful for radiolabeling proteins with radioactive metals, and can consequently be utilized with respect to radioimmunoimaging and/or radioimmunotherapy.

  2. The development of new molecular tools containing a chemically synthesized carbohydrate ligand for the elucidation of carbohydrate roles via photoaffinity labeling: carbohydrate-protein interactions are affected by the structures of the glycosidic bonds and the reducing-end sugar.

    PubMed

    Ohtsuka, Isao; Sadakane, Yutaka; Hada, Noriyasu; Higuchi, Mari; Atsumi, Toshiyuki; Kakiuchi, Nobuko

    2014-08-01

    Photoaffinity labeling technology is a highly efficient method for cloning carbohydrate-binding proteins. When the carbohydrate probes are synthesized according to conventional methods, however, the reducing terminus of the sugar is opened to provide an acyclic structure. Our continued efforts to solve this problem led to the development of new molecular tools with an oligosaccharide structure that contains a phenyldiazirine group for the elucidation of carbohydrate-protein interactions. We investigated whether carbohydrate-lectin interactions are affected by differences in the glycosidic formation and synthesized three types of molecular tools containing Galp-GlcpNAc disaccharide ligands and a photoreactive group (1, 2, 3). Photoaffinity labeling validated the recognition of the new ligand by different glycosidic bonds. Photoaffinity labeling also demonstrated that both the reducing end sugar and non-reducing end sugar recognized the Erythrina cristagalli agglutinin.

  3. Synthesis and characterization of d{sup 10} metal complexes with mixed 1,3-di(1H-imidazol-4-yl)benzene and multicarboxylate ligands

    SciTech Connect

    Chen, Zhi-Hao; Zhao, Yue; Chen, Shui-Sheng; Wang, Peng; Sun, Wei-Yin

    2013-06-15

    Seven new coordination polymers [Zn(H{sub 2}L)(mbdc)] (1), [Zn(H{sub 3}L)(btc)] (2), [Zn(H{sub 2}L)(Hbtc)] (3), [Zn(H{sub 2}L)(Hbtc)]·H{sub 2}O (4), [Zn{sub 2}(H{sub 2}L)(btc)(μ{sub 2}-OH)] (5), [Cd(H{sub 2}L)(mbdc)] (6) and [Cd{sub 3}(H{sub 2}L){sub 2}(btc){sub 2}(H{sub 2}O)]·5H{sub 2}O (7) were synthesized by reactions of the corresponding metal salt with rigid ligand 1,3-di(1H-imidazol-4-yl)benzene (H{sub 2}L) and different carboxylic acids of 1,3-benzenedicarboxylic acid (H{sub 2}mbdc) and benzene-1,3,5-tricarboxylic acid (H{sub 3}btc), respectively. The results of X-ray crystallographic analysis indicate that complex 1 is 1D chain while 2 is a (3,3)-connected 2D network with Point (Schläfli) symbol of (4,8{sup 2}). Complexes 3 and 6 are 2D networks, 4 is a 3-fold interpenetrating 3D framework with Point (Schläfli) symbol of (6{sup 5},8) and 5 is a (3,8)-connected 2D network with Point (Schläfli) symbol of (3,4{sup 2}){sub 2}(3{sup 4},4{sup 6},5{sup 6},6{sup 8},7{sup 3},8), while 7 is a (3,10)-connected 3D net with Schläfli symbol of (3,4,5){sub 2}(3{sup 4},4{sup 8},5{sup 18},6{sup 12},7{sup 2},8). The thermal stability and photoluminescence of the complexes were investigated. Furthermore, DFT calculations were performed for 2–4 to discuss the temperature controlled self-assembly of the complexes. - Graphical abstract: Seven new coordination polymers with multicarboxylate and rigid ditopic 4-imidazole containing ligands have been obtained and found to show different structures and topologies. - Highlights: • Metal complexes with diverse structures of 1D chain, 2D network and 3D framework. • Mixed ligands of 1,3-di(1H-imidazol-4-yl)benzene and multicarboxylate. • Photoluminescence property.

  4. Sterically-directed consecutive and size-selective self-assembly of palladium diphosphane complexes with an Ar-BIAN ligand: unexpected formation of pentameric and hexameric aggregates.

    PubMed

    Holló-Sitkei, Eszter; Szalontai, Gábor; Lois, Isabella; Gömöry, Agnes; Pollreisz, Ferenc; Párkányi, László; Jude, Hershel; Besenyei, Gábor

    2009-10-12

    The coordination properties of N,N'-bis[4-(4-pyridyl)phenyl]acenaphthenequinonediimine (L(1)) and N,N'-bis[4-(2-pyridyl)phenyl]acenaphthenequinonediimine (L(2)) were investigated in self-assembly with palladium diphosphane complexes [Pd(P;P)(H(2)O)(2)](OTf)(2) (OTf = triflate) by using various analytical techniques, including multinuclear ((1)H, (15)N, and (31)P) NMR spectroscopy and mass spectrometry (P;P = dppp, dppf, dppe; dppp = bis(diphenylphosphanyl)propane, dppf = bis(diphenylphosphanyl)ferrocene, and dppe = bis(diphenylphosphanyl)ethane). Beside the expected trimeric and tetrameric species, the interaction of an equimolar mixture of [Pd(dppp)](2+) ions and L(1) also generates pentameric aggregates. Due to the E/Z isomerism of L(1), a dimeric product was also observed. In all of these species, which correspond to the general formula [Pd(dppp)L(1)](n)(OTf)(2n) (n = 2-5), the L(1) ligand is coordinated to the Pd center only through the terminal pyridyl groups. Introduction of a second equivalent of the [Pd(dppp)](2+) tecton results in coordination to the internal, sterically more encumbered chelating site and induces enhancement of the higher nuclearity components. The presence of higher-order aggregates (n = 5, 6), which were unexpected for the interaction of cis-protected palladium corners with linear ditopic bridging ligands, has been demonstrated both by mass-spectrometric and DOSY NMR spectroscopic analysis. The sequential coordination of the [Pd(dppp)](2+) ion is attributed to the dissimilar steric properties of the two coordination sites. In the self-assembled species formed in a 1:1:1 mixture of [Pd(dppp)](2+)/[Pd(dppe)](2+)/L(1), the sterically more demanding [Pd(dppp)](2+) tectons are attached selectively to the pyridyl groups, whereas the more hindered imino nitrogen atoms coordinate the less bulky dppe complexes, thus resulting in a sterically directed, size-selective sorting of the metal tectons. The propensity of the new ligands to incorporate

  5. Validity of ligand efficiency metrics.

    PubMed

    Murray, Christopher W; Erlanson, Daniel A; Hopkins, Andrew L; Keserü, György M; Leeson, Paul D; Rees, David C; Reynolds, Charles H; Richmond, Nicola J

    2014-06-12

    A recent viewpoint article (Improving the plausibility of success with inefficient metrics. ACS Med. Chem. Lett. 2014, 5, 2-5) argued that the standard definition of ligand efficiency (LE) is mathematically invalid. In this viewpoint, we address this criticism and show categorically that the definition of LE is mathematically valid. LE and other metrics such as lipophilic ligand efficiency (LLE) can be useful during the multiparameter optimization challenge faced by medicinal chemists.

  6. Acyclic diterpene glycosides, capsianosides VIII, IX, X, XIII, XV and XVI from the fruits of Paprika Capsicum annuum L. var. grossum BAILEY and Jalapeño Capsicum annuum L. var. annuum.

    PubMed

    Lee, Jong-Hyun; Kiyota, Naoko; Ikeda, Tsuyoshi; Nohara, Toshihiro

    2006-10-01

    Paprika and Jalapeño are used as vegetables and spices. We have obtained six new acyclic diterpene glycosides, called capsianosides XIII (2), XV (3), IX (4), XVI (5), X (6) and VIII (7) together with known capsianoside II (1) from the fruits of the Paprika and Jalapeño. The structures of these compounds have been elucidated by the (1)H- and (13)C-NMR spectra and two-dimensional NMR methods.

  7. Ligand Identification Scoring Algorithm (LISA)

    PubMed Central

    Zheng, Zheng; Merz, Kenneth M.

    2011-01-01

    A central problem in de novo drug design is determining the binding affinity of a ligand with a receptor. A new scoring algorithm is presented that estimates the binding affinity of a protein-ligand complex given a three-dimensional structure. The method, LISA (Ligand Identification Scoring Algorithm), uses an empirical scoring function to describe the binding free energy. Interaction terms have been designed to account for van der Waals (VDW) contacts, hydrogen bonding, desolvation effects and metal chelation to model the dissociation equilibrium constants using a linear model. Atom types have been introduced to differentiate the parameters for VDW, H-bonding interactions and metal chelation between different atom pairs. A training set of 492 protein-ligand complexes was selected for the fitting process. Different test sets have been examined to evaluate its ability to predict experimentally measured binding affinities. By comparing with other well known scoring functions, the results show that LISA has advantages over many existing scoring functions in simulating protein-ligand binding affinity, especially metalloprotein-ligand binding affinity. Artificial Neural Network (ANN) was also used in order to demonstrate that the energy terms in LISA are well designed and do not require extra cross terms. PMID:21561101

  8. Ligand Identification Scoring Algorithm (LISA).

    PubMed

    Zheng, Zheng; Merz, Kenneth M

    2011-06-27

    A central problem in de novo drug design is determining the binding affinity of a ligand with a receptor. A new scoring algorithm is presented that estimates the binding affinity of a protein-ligand complex given a three-dimensional structure. The method, LISA (Ligand Identification Scoring Algorithm), uses an empirical scoring function to describe the binding free energy. Interaction terms have been designed to account for van der Waals (VDW) contacts, hydrogen bonding, desolvation effects, and metal chelation to model the dissociation equilibrium constants using a linear model. Atom types have been introduced to differentiate the parameters for VDW, H-bonding interactions, and metal chelation between different atom pairs. A training set of 492 protein-ligand complexes was selected for the fitting process. Different test sets have been examined to evaluate its ability to predict experimentally measured binding affinities. By comparing with other well-known scoring functions, the results show that LISA has advantages over many existing scoring functions in simulating protein-ligand binding affinity, especially metalloprotein-ligand binding affinity. Artificial Neural Network (ANN) was also used in order to demonstrate that the energy terms in LISA are well designed and do not require extra cross terms.

  9. Furan-oxidation-triggered inducible DNA cross-linking: acyclic versus cyclic furan-containing building blocks--on the benefit of restoring the cyclic sugar backbone.

    PubMed

    Stevens, Kristof; Claeys, Diederica D; Catak, Saron; Figaroli, Sara; Hocek, Michal; Tromp, Jan M; Schürch, Stefan; Van Speybroeck, Veronique; Madder, Annemieke

    2011-06-14

    Oligodeoxynucleotides incorporating a reactive functionality can cause irreversible cross-linking to the target sequence and have been widely studied for their potential in inhibition of gene expression or development of diagnostic probes for gene analysis. Reactive oligonucleotides further show potential in a supramolecular context for the construction of nanometer-sized DNA-based objects. Inspired by the cytochrome P450 catalyzed transformation of furan into a reactive enal species, we recently introduced a furan-oxidation-based methodology for cross-linking of nucleic acids. Previous experiments using a simple acyclic building block equipped with a furan moiety for incorporation into oligodeoxynucleotides have shown that cross-linking occurs in a very fast and efficient way and that substantial amounts of stable, site-selectively cross-linked species can be isolated. Given the destabilization of duplexes observed upon introduction of the initially designed furan-modified building block into DNA duplexes, we explore here the potential benefits of two new building blocks featuring an extended aromatic system and a restored cyclic backbone. Thorough experimental analysis of cross-linking reactions in a series of contexts, combined with theoretical calculations, permit structural characterization of the formed species and allow assessment of the origin of the enhanced cross-link selectivity. Our experiments clearly show that the modular nature of the furan-modified building blocks used in the current cross-linking strategy allow for fine tuning of both yield and selectivity of the interstrand cross-linking reaction.

  10. First acyclic diene metathesis polymerization under biphasic conditions using a dicationic ruthenium alkylidene: access to high-molecular-weight polymers with very low ruthenium contamination.

    PubMed

    Zhao, Jing; Wang, Dongren; Autenrieth, Benjamin; Buchmeiser, Michael R

    2015-01-01

    The acyclic diene metathesis (ADMET) polymerization of 6-hydroxy-1,10-undecadiene (M1) and 6-acetoxy-1,10-undecadiene (M2) by the action of two different catalysts, i.e., the second-generation Grubbs-Hoveyda system ([RuCl2(IMesH2)(CH-2-(2-PrO-C6H4)]) (1) and the dicationic ruthenium alkylidene [Ru(DMF)3(IMesH2)(CH-2-(2-PrO-C6H4)] (2, IMesH2 = 1,3-dimesitylimidazolin-2-ylidene) is reported. Biphasic conditions using 1-butyl-2,3-dimethylimidazolium tetrafluoroborate ([BDMIM(+)BF4(-)]) and 1,2,4-trichlorobenzene (TCB) are applied. Under the chosen conditions (T = 75 °C, 20 mbar), the use of catalyst 1 results only in the formation of low-molecular-weight polymers (Mn ≤ 10,000 g mol(-1)), while catalyst 2 allows for the high yield synthesis of high-molecular-weight polymers (Mn ≤ 40,000 g mol(-1), yields ≤ 99%). Irrespective of the catalyst used, all polymers display a high trans-content (>95%). Notably, Ru-contamination of the target polymers without any additional purification is as low as 1.2 ppm with catalyst 2. Together with the high yields and high molecular weights, the low Ru-contaminations clearly illustrate the advantages of the biphasic setup.

  11. All-carbon quaternary stereogenic centers in acyclic systems through the creation of several C-C bonds per chemical step.

    PubMed

    Marek, Ilan; Minko, Yury; Pasco, Morgane; Mejuch, Tom; Gilboa, Noga; Chechik, Helena; Das, Jaya P

    2014-02-19

    In the past few decades, it has become clear that asymmetric catalysis is one of the most powerful methods for the construction of carbon-carbon as well as carbon-heteroatom bonds in a stereoselective manner. However, when structural complexity increases (i.e., all-carbon quaternary stereogenic center), the difficulty in reaching the desired adducts through asymmetric catalytic reactions leads to a single carbon-carbon bond-forming event per chemical step between two components. Issues of efficiency and convergence should therefore be addressed to avoid extraneous chemical steps. In this Perspective, we present approaches that tackle the stimulating problem of efficiency while answering interesting synthetic challenges. Ideally, if one could create all-carbon quaternary stereogenic centers via the creation of several new carbon-carbon bonds in an acyclic system and in a single-pot operation from simple precursors, it would certainly open new horizons toward solving the synthetic problems. Even more important for any further design, the presence of polyreactive intermediates in synthesis (bismetalated, carbenoid, and oxenoids species) becomes now an indispensable tool, as it creates consecutively the same number of carbon-carbon bonds as in a multi-step process, but in a single-pot operation.

  12. Mechanism of inhibition of adenovirus DNA replication by the acyclic nucleoside triphosphate analogue (S)-HPMPApp: influence of the adenovirus DNA binding protein.

    PubMed Central

    Mul, Y M; van Miltenburg, R T; De Clercq, E; van der Vliet, P C

    1989-01-01

    The acyclic adenosine analogue (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine [S]-HPMPA) is a potent and selective inhibitor of adenovirus (Ad) replication in cell culture. We studied the mechanism of inhibition using a reconstituted in vitro DNA replication system. The diphosphoryl derivative (S)-HPMPApp, but not (S)-HPMPA, inhibited the DNA replication of origin containing fragments strongly. The inhibitory effect was exerted at the level of elongation, while initiation was resistant to the drug. Remarkably, the elongation of short strands was only slightly impaired, while inhibition was maximal upon synthesis of long DNA fragments. (S)-HPMPApp appeared to be competitive with dATP, suggesting that the Ad DNA polymerase is the prime target for the drug. We purified the Ad DNA polymerase in complex to the precursor terminal protein to homogeneity from cells infected with overproducing recombinant vaccinia viruses. Employing gapped DNA or poly(dT).oligo(dA) templates, only a weak inhibition was observed. However, inhibition was strongly enhanced in the presence of the adenovirus DNA binding protein (DBP). We interpret this to mean that the increased processivity of the polymerization reaction in the presence of DBP leads to increased drug sensitivity. Images PMID:2587248

  13. Rh-catalyzed enantioselective conjugate addition of arylboronic acids with a dynamic library of chiral tropos phosphorus ligands.

    PubMed

    Monti, Chiara; Gennari, Cesare; Piarulli, Umberto

    2007-01-01

    A library of 19 chiral tropos phosphorus ligands, based on a free-to-rotate (tropos) biphenol unit and a chiral P-bonded alcohol (11 phosphites, 1-P(O)(2)O to 11-P(O)(2)O) or secondary amine (8 phosphoramidites, 12-P(O)(2)N to 19-P(O)(2)N), were screened, individually and in combinations of two, in the rhodium-catalyzed asymmetric conjugate addition of arylboronic acids to enones and enoates. High enantioselectivities (up to 99 % ee) and excellent yields were obtained in the addition to either cyclic or acyclic substrates. The flexible biphenolic P ligands outperformed the analogous rigid binaphtholic P ligands. Variable-temperature (31)P NMR studies revealed that the biphenolic ligands are tropos even at low temperature. Only below 190 K was a coalescence observed; upon further cooling, two atropisomers were detected. The Rh homocomplexes ([Rh(L(a))(2)](+)) were also studied: in general, a single doublet (P-Rh coupling) was observed in the case of the biphenolic phosphite ligands, over the temperature range 380-230 K, demonstrating their tropos nature in the rhodium complexes even at low temperatures. On the other hand, the phosphoramidites showed different behaviors depending on the structure of the ligand and on the nature of the rhodium source. The spectrum at 230 K of the mixture of [Rh(acac)(eth)(2)] (eth=C(2)H(4)) with phosphite 6-P(O)(2)O and phosphoramidite 19-P(O)(2)N (the most enantioselective ligand combination in the conjugate addition reaction) revealed the presence of four homocomplexes (total approximately 40 %: [Rh{6-P(O)(2)O}(2)], [Rh{(aR)-19-P(O)(2)N}(2)], [Rh{(aS)-19-P(O)(2)N}(2)], [Rh{(aR)-19-P(O)(2)N}{(aS)-19-P(O)(2)N}]) and one heterocomplex, [Rh{6-P(O)(2)O}{(aR)-19-P(O)(2)N}] (approximately 60 %) In the heterocomplex, the biphenol-derived phosphite is free to rotate (tropos) while the biphenol-derived phosphoramidite shows a temperature-dependent tropos/atropos behavior (coalescence temperature=310 K).

  14. Why mercury prefers soft ligands

    SciTech Connect

    Riccardi, Demian M; Guo, Hao-Bo; Gu, Baohua; Parks, Jerry M; Summers, Anne; Miller, S; Liang, Liyuan; Smith, Jeremy C

    2013-01-01

    Mercury (Hg) is a major global pollutant arising from both natural and anthropogenic sources. Defining the factors that determine the relative affinities of different ligands for the mercuric ion, Hg2+, is critical to understanding its speciation, transformation, and bioaccumulation in the environment. Here, we use quantum chemistry to dissect the relative binding free energies for a series of inorganic anion complexes of Hg2+. Comparison of Hg2+ ligand interactions in the gaseous and aqueous phases shows that differences in interactions with a few, local water molecules led to a clear periodic trend within the chalcogenide and halide groups and resulted in the well-known experimentally observed preference of Hg2+ for soft ligands such as thiols. Our approach establishes a basis for understanding Hg speciation in the biosphere.

  15. What are Nuclear Receptor Ligands?

    PubMed Central

    Sladek, Frances M.

    2010-01-01

    Nuclear receptors (NRs) are a family of highly conserved transcription factors that regulate transcription in response to small lipophilic compounds. They play a role in every aspect of development, physiology and disease in humans. They are also ubiquitous in and unique to the animal kingdom suggesting that they may have played an important role in their evolution. In contrast to the classical endocrine receptors that originally defined the family, recent studies suggest that the first NRs might have been sensors of their environment, binding ligands that were external to the host organism. The purpose of this review is to provide a broad perspective on NR ligands and address the issue of exactly what constitutes a NR ligand from historical, biological and evolutionary perspectives. This discussion will lay the foundation for subsequent reviews in this issue as well as pose new questions for future investigation. PMID:20615454

  16. Molecular Recognition and Ligand Association

    NASA Astrophysics Data System (ADS)

    Baron, Riccardo; McCammon, J. Andrew

    2013-04-01

    We review recent developments in our understanding of molecular recognition and ligand association, focusing on two major viewpoints: (a) studies that highlight new physical insight into the molecular recognition process and the driving forces determining thermodynamic signatures of binding and (b) recent methodological advances in applications to protein-ligand binding. In particular, we highlight the challenges posed by compensating enthalpic and entropic terms, competing solute and solvent contributions, and the relevance of complex configurational ensembles comprising multiple protein, ligand, and solvent intermediate states. As more complete physics is taken into account, computational approaches increase their ability to complement experimental measurements, by providing a microscopic, dynamic view of ensemble-averaged experimental observables. Physics-based approaches are increasingly expanding their power in pharmacology applications.

  17. Ligand-induced Epitope Masking

    PubMed Central

    Mould, A. Paul; Askari, Janet A.; Byron, Adam; Takada, Yoshikazu; Jowitt, Thomas A.; Humphries, Martin J.

    2016-01-01

    We previously demonstrated that Arg-Gly-Asp (RGD)-containing ligand-mimetic inhibitors of integrins are unable to dissociate pre-formed integrin-fibronectin complexes (IFCs). These observations suggested that amino acid residues involved in integrin-fibronectin binding become obscured in the ligand-occupied state. Because the epitopes of some function-blocking anti-integrin monoclonal antibodies (mAbs) lie near the ligand-binding pocket, it follows that the epitopes of these mAbs may become shielded in the ligand-occupied state. Here, we tested whether function-blocking mAbs directed against α5β1 can interact with the integrin after it forms a complex with an RGD-containing fragment of fibronectin. We showed that the anti-α5 subunit mAbs JBS5, SNAKA52, 16, and P1D6 failed to disrupt IFCs and hence appeared unable to bind to the ligand-occupied state. In contrast, the allosteric anti-β1 subunit mAbs 13, 4B4, and AIIB2 could dissociate IFCs and therefore were able to interact with the ligand-bound state. However, another class of function-blocking anti-β1 mAbs, exemplified by Lia1/2, could not disrupt IFCs. This second class of mAbs was also distinguished from 13, 4B4, and AIIB2 by their ability to induce homotypic cell aggregation. Although the epitope of Lia1/2 was closely overlapping with those of 13, 4B4, and AIIB2, it appeared to lie closer to the ligand-binding pocket. A new model of the α5β1-fibronectin complex supports our hypothesis that the epitopes of mAbs that fail to bind to the ligand-occupied state lie within, or very close to, the integrin-fibronectin interface. Importantly, our findings imply that the efficacy of some therapeutic anti-integrin mAbs could be limited by epitope masking. PMID:27484800

  18. Multifunctional Ligands in Transition Metal Catalysis

    SciTech Connect

    Crabtree, Robert H

    2011-01-01

    Sophisticated ligands are now being designed that do far more than just fulfil their traditional spectator roles by binding to the metal and providing a sterically-defined binding pocket for the substrate in homogeneous transition metal catalysis. This Focus review emphasizes selected cases in which ligands carry additional functional groups that change the properties of the ligand as a result of an external stimulus or undergo catalytically-relevant ligand-based reactivity. These include proton responsive ligands capable of gaining or losing one or more protons, ligands having a hydrogen bonding function, electroresponsive ligands capable of gaining or losing one or more electrons, and photoresponsive ligands capable of undergoing a useful change of properties upon irradiation. Molecular recognition ligands and proton coupled electron transfer (PCET) are briefly discussed.

  19. Multicoordinate ligands for actinide/lanthanide separations.

    PubMed

    Dam, Henk H; Reinhoudt, David N; Verboom, Willem

    2007-02-01

    In nuclear waste treatment processes there is a need for improved ligands for the separation of actinides (An(III)) and lanthanides (Ln(III)). Several research groups are involved in the design and synthesis of new An(III) ligands and in the confinement of these and existing An(III) ligands onto molecular platforms giving multicoordinate ligands. The preorganization of ligands considerably improves the An(III) extraction properties, which are largely dependent on the solubility and rigidity of the platform. This tutorial review summarizes the most important An(III) ligands with emphasis on the preorganization strategy using (macrocyclic) platforms.

  20. Kinetics of ligand binding to nucleic acids.

    PubMed

    Arakelyan, V B; Babayan, S Y; Tairyan, V I; Arakelyan, A V; Parsadanyan, M A; Vardevanyan, P O

    2006-02-01

    Ligand binding to nucleic acids (NA) is considered as a stationary Markov process. It is shown that the probabilistic description of ligand-NA binding allows one to describe not only the kinetics of the change of number of bound ligands at arbitrary fillings but also to calculate stationary values of the number of bound ligands and its dispersion. The general analysis of absorption isotherms and kinetics of ligand binding to NA make it possible to determine of rate constants of ligand-NA complex formation and dissociation.

  1. In Vitro Selectivity of an Acyclic Cucurbit[n]uril Molecular Container towards Neuromuscular Blocking Agents Relative to Commonly Used Drugs

    PubMed Central

    Ganapati, Shweta; Zavalij, Peter Y.; Eikermann, Matthias; Isaacs, Lyle

    2015-01-01

    An acyclic cucurbit[n]uril (CB[n]) based molecular container (2, a.k.a. Calabadion 2) binds to both amino-steroidal and benzylisoquinolinium type neuromuscular blocking agents (NMBAs) in vitro, and reverses the effect of these drugs in vivo displaying faster recovery times than placebo and the γ-cyclodextrin (CD) based and clinically used reversal agent Sugammadex. In this study we have assessed the potential for other drugs commonly used during and after surgery (e.g. antibiotics, antihistamines, and antiarrhythmics) to interfere with the ability of 2 to bind NMBAs rocuronium and cisatracurium in vitro. We measured the binding affinities (Ka, M−1) of twenty seven commonly used drugs towards 2 and simulated the equilibrium between 2, NMBA, and drug based on their standard clinical dosages to calculate the equilibrium concentration of 2•NMBA in the presence of the various drugs. We found that none of the 27 drugs studied possess the combination of a high enough binding affinity with 2 and a high enough standard dosage to be able to promote the competitive dissociation (a.k.a. displacement interactions) of the 2•NMBA complex with the formation of the 2•drug complex. Finally, we used the simulations to explore how the potential for displacement interactions is affected by a number of factors including the Ka of the 2•NMBA complex, the Ka of the AChR•NMBA complex, the Ka of the 2•drug complex, and the dosage of the drug. PMID:26648135

  2. Accumulation of acyclic polyols and trehalose as related to growth form and carbohydrate source in the dimorphic fungi Mucor rouxii and Candida albicans.

    PubMed

    Pfyffer, G E; Rast, D M

    1989-01-01

    Yeast (Y) and hyphal (H) cells of Mucor rouxii and Candida albicans were cultivated in liquid media containing different carbon nutrient sources (glucose, fructose, ribose) and their free acyclic polyol and trehalose contents determined using capillary gas liquid chromatography (TMS- and OAc-derivatization). Irrespective of growth form and C-source, the fraction of the water-soluble neutral components of the cellular mass of the cultures - highly homogeneous with regard to the respective cell form produced - contained glycerol, ribitol and arabitol, in addition to trehalose. The polyols contributed 0.5-2% to the biomass of M. rouxii and 1.5-6% to that of C. albicans; the values for trehalose ranged from 0.2-11% in the former and 1-3.5% in the latter species. Mucor contained higher amounts of ribitol and arabitol in H cells and larger quantities of trehalose and glycerol in Y cells. In Candida, too, hyphae always exhibited higher ribitol contents, whereas arabitol attained higher levels in yeasts under almost any conditions - regardless of the type of medium (synthetic vs. complex), stage of culture (early vs. late log-phase) and strain used. Glycerol concentration was not correlated with the growth form; trehalose contents tended to be higher in Y cells. Taking into account the facts that C. albicans and certain Mucor species are agents of opportunistic infections and are invasive mainly in the filamentous form, and that the prospective hosts do not accumulate either of these carbohydrates, the possibility is considered of using trehalose- and polyol-metabolizing enzymes as targets for designing antifungal drugs.

  3. Acyclic Cucurbit[n]uril-Type Molecular Container Enables Systemic Delivery of Effective Doses of Albendazole for Treatment of SK-OV-3 Xenograft Tumors.

    PubMed

    Hettiarachchi, Gaya; Samanta, Soumen K; Falcinelli, Shane; Zhang, Ben; Moncelet, Damien; Isaacs, Lyle; Briken, Volker

    2016-03-07

    Approximately, 40-70% of active pharmaceutical ingredients (API) are severely limited by their extremely poor aqueous solubility, and consequently, there is a high demand for excipients that can be used to formulate clinically relevant doses of these drug candidates. Here, proof-of-concept studies demonstrate the potential of our recently discovered acyclic cucurbit[n]uril-type molecular container Motor1 (M1) as a solubilizing agent for insoluble drugs. M1 did not induce significant rates of mutations in various Salmonella typhimurium test strains during the Ames test, suggesting low genotoxicity. M1 also has low risk of causing cardiac toxicity in humans since it did not inhibit the human Ether-à-go-go-Related Gene channel as tested on transfected CHO cell lines via patch clamp analysis. Albendazole (ABZ) is a widely used antihelminthic agent but that has also shown promising efficacy against cancerous cells in vitro. However, due to its low aqueous solubility (2.7 μM) and poor pharmacokinetics, ABZ is clinically limited as an anticancer agent. Here we investigated the potential of M1 as a solubilizing excipient for ABZ formulation. A pharmacokinetic study indicated that ABZ escapes the peritoneal cavity resulting in 78% absolute bioavailability, while its active intermediate metabolite, albendazole sulfoxide, achieved 43% absolute bioavailability. The daily dosing of 681 mg/kg M1 complexed with 3.2 mg/kg of ABZ for 14 days did not result in significant weight loss or pathology in Swiss Webster mice. In vivo efficacy studies using this M1·ABZ inclusion complex showed significant decreases in tumor growth rates and increases in survival of mice bearing SK-OV-3 xenograft tumors. In conclusion, we provide substantial new evidence demonstrating that M1 is a safe and efficient excipient that enables in vivo parenteral delivery of poorly water-soluble APIs.

  4. Experimental and theoretical investigations of the redox behavior of the heterodichalcogenido ligands [(EP(i)Pr2)(TeP(i)Pr2)N](-) (E = S, Se): cyclic cations and acyclic dichalcogenide dimers.

    PubMed

    Robertson, Stuart D; Chivers, Tristram; Tuononen, Heikki M

    2008-11-17

    The two-electron oxidation of the lithium salts of the heterodichalcogenidoimidodiphosphinate anions [(EP (i)Pr 2)(TeP (i)Pr 2)N] (-) ( 1a, E = S; 1b, E = Se) with iodine yields cyclic cations [(EP (i)Pr 2)(TeP (i)Pr 2)N] (+) as their iodide salts [(SP (i)Pr 2)(TeP (i)Pr 2)N]I ( 2a) and [(SeP (i)Pr 2)(TeP (i)Pr 2)N]I ( 2b). The five-membered rings in 2a and 2b both display an elongated E-Te bond as a consequence of an interaction between tellurium and the iodide anion. One-electron reduction of 2a and 2b with cobaltocene produces the neutral dimers (EP (i)Pr 2NP (i)Pr 2Te-) 2 ( 3a, E = S; 3b, E = Se), which are connected exclusively through a Te-Te bond. Two-electron reduction of 2a and 2b with 2 equiv of cobaltocene regenerates the corresponding dichalcogenidoimidodiphosphinate anions as ion-separated cobaltocenium salts Cp 2Co[(EP (i)Pr 2)(TeP (i)Pr 2)N] ( 4a, E = S; 4b, E = Se). The ditellurido analogue Cp 2Co[(TeP (i)Pr 2) 2N] ( 4c) has been prepared in the same manner for comparison. Density functional theory calculations reveal that the preferential interaction of the iodide anion with tellurium is determined by the polarization of the lowest unoccupied molecular orbital [sigma*(E-Te)] of the cations in 2a and 2b toward tellurium and that the formation of the dimers 3a and 3b with a central Te-Te linkage is energetically more favorable than the structural isomers with either E-Te or E-E bonds. Compounds 2a, 2b, 3a, 3b, 4a, 4b, and 4c have been characterized in solution by multinuclear NMR spectroscopy and in the solid state by X-ray crystallography.

  5. Glyconanomaterials: synthesis, characterization, and ligand presentation.

    PubMed

    Wang, Xin; Ramström, Olof; Yan, Mingdi

    2010-05-04

    Glyconanomaterials, nanomaterials carrying surface-tethered carbohydrate ligands, have emerged and demonstrated increasing potential in biomedical imaging, therapeutics, and diagnostics. These materials combine the unique properties of nanometer-scale objects with the ability to present multiple copies of carbohydrate ligands, greatly enhancing the weak affinity of individual ligands to their binding partners. Critical to the performance of glyconanomaterials is the proper display of carbohydrate ligands, taking into consideration of the coupling chemistry, the type and length of the spacer linkage, and the ligand density. This article provides an overview of the coupling chemistry for attaching carbohydrate ligands to nanomaterials, and discusses the need for thorough characterization of glyconanomaterials, especially quantitative analyses of the ligand density and binding affinities. Using glyconanoparticles synthesized by a versatile photocoupling chemistry, methods for determining the ligand density by colorimetry and the binding affinity with lectins by a fluorescence competition assay are determined. The results show that the multivalent presentation of carbohydrate ligands significantly enhances the binding affinity by several orders of magnitude in comparison to the free ligands in solution. The effect is sizeable even at low surface ligand density. The type and length of the spacer linkage also affect the binding affinity, with the longer linkage promoting the association of bound ligands with the corresponding lectins.

  6. Glyconanomaterials: Synthesis, Characterization, and Ligand Presentation

    PubMed Central

    Wang, Xin

    2010-01-01

    Glyconanomaterials, nanomaterials carrying surface-tethered carbohydrate ligands, have emerged and demonstrated increasing potential in biomedical imaging, therapeutics, and diagnostics. These materials combine the unique properties of nanometer-scale objects with the ability to present multiple copies of carbohydrate ligands, greatly enhancing the weak affinity of individual ligands to their binding partners. Critical to the performance of glyconanomaterials is the proper display of carbohydrate ligands, taking into consideration of the coupling chemistry, the type and length of the spacer linkage, and the ligand density. This article provides an overview of the coupling chemistry for attaching carbohydrate ligands to nanomaterials, and discusses the need for thorough characterization of glyconanomaterials, especially quantitative analyses of the ligand density and binding affinities. Using glyconanoparticles synthesized by a versatile photocoupling chemistry, methods for determining the ligand density by colorimetry and the binding affinity with lectins by a fluorescence competition assay are determined. The results show that the multivalent presentation of carbohydrate ligands significantly enhances the binding affinity by several orders of magnitude in comparison to the free ligands in solution. The effect is sizeable even at low surface ligand density. The type and length of the spacer linkage also affect the binding affinity, with the longer linkage promoting the association of bound ligands with the corresponding lectins. PMID:20301131

  7. Ligand chain length conveys thermochromism.

    PubMed

    Ganguly, Mainak; Panigrahi, Sudipa; Chandrakumar, K R S; Sasmal, Anup Kumar; Pal, Anjali; Pal, Tarasankar

    2014-08-14

    Thermochromic properties of a series of non-ionic copper compounds have been reported. Herein, we demonstrate that Cu(II) ion with straight-chain primary amine (A) and alpha-linolenic (fatty acid, AL) co-jointly exhibit thermochromic properties. In the current case, we determined that thermochromism becomes ligand chain length-dependent and at least one of the ligands (A or AL) must be long chain. Thermochromism is attributed to a balanced competition between the fatty acids and amines for the copper(II) centre. The structure-property relationship of the non-ionic copper compounds Cu(AL)2(A)2 has been substantiated by various physical measurements along with detailed theoretical studies based on time-dependent density functional theory. It is presumed from our results that the compound would be a useful material for temperature-sensor applications.

  8. Presentation of Ligands on Hydroxylapatite

    NASA Technical Reports Server (NTRS)

    Chu, Barbara C. F.; Orgel, Leslie E.

    1997-01-01

    Conjugates of biotin with the decamer of glutamic acid (glu(sub 10)) and the trimer of D,L-2-amino-5-phosphonovaleric acid (I) have been synthesized, and it has been shown that they mediate the binding of avidin to hydroxylapatite. In a similar way a conjugate of methotrexate with glu(sub 10) mediates the binding of dihydrofolate reductase to the mineral. The presentation of ligands on the hydroxylapatite component of bone may find applications in clinical medicine.

  9. Tumor Targeting via Integrin Ligands

    PubMed Central

    Marelli, Udaya Kiran; Rechenmacher, Florian; Sobahi, Tariq Rashad Ali; Mas-Moruno, Carlos; Kessler, Horst

    2013-01-01

    Selective and targeted delivery of drugs to tumors is a major challenge for an effective cancer therapy and also to overcome the side-effects associated with current treatments. Overexpression of various receptors on tumor cells is a characteristic structural and biochemical aspect of tumors and distinguishes them from physiologically normal cells. This abnormal feature is therefore suitable for selectively directing anticancer molecules to tumors by using ligands that can preferentially recognize such receptors. Several subtypes of integrin receptors that are crucial for cell adhesion, cell signaling, cell viability, and motility have been shown to have an upregulated expression on cancer cells. Thus, ligands that recognize specific integrin subtypes represent excellent candidates to be conjugated to drugs or drug carrier systems and be targeted to tumors. In this regard, integrins recognizing the RGD cell adhesive sequence have been extensively targeted for tumor-specific drug delivery. Here we review key recent examples on the presentation of RGD-based integrin ligands by means of distinct drug-delivery systems, and discuss the prospects of such therapies to specifically target tumor cells. PMID:24010121

  10. Tools for ligand validation in Coot

    PubMed Central

    Emsley, Paul

    2017-01-01

    Coot is a molecular-graphics program primarily aimed at model building using X-ray data. Recently, tools for the manipulation and representation of ligands have been introduced. Here, these new tools for ligand validation and comparison are described. Ligands in the wwPDB have been scored by density-fit, distortion and atom-clash metrics. The distributions of these scores can be used to assess the relative merits of the particular ligand in the protein–ligand complex of interest by means of ‘sliders’ akin to those now available for each accession code on the wwPDB websites. PMID:28291755

  11. Ligand identification using electron-density mapcorrelations

    SciTech Connect

    Terwilliger, Thomas C.; Adams, Paul D.; Moriarty, Nigel W.; Cohn,Judith D.

    2006-12-01

    A procedure for the identification of ligands bound incrystal structuresof macromolecules is described. Two characteristics ofthe density corresponding to a ligand are used in the identificationprocedure. One is the correlation of the ligand density with each of aset of test ligands after optimization of the fit of that ligand to thedensity. The other is the correlation of a fingerprint of the densitywith the fingerprint of model density for each possible ligand. Thefingerprints consist of an ordered list of correlations of each the testligands with the density. The two characteristics are scored using aZ-score approach in which the correlations are normalized to the mean andstandard deviation of correlations found for a variety of mismatchedligand-density pairs, so that the Z scores are related to the probabilityof observing a particular value of the correlation by chance. Theprocedure was tested with a set of 200 of the most commonly found ligandsin the Protein Data Bank, collectively representing 57 percent of allligands in the Protein Data Bank. Using a combination of these twocharacteristics of ligand density, ranked lists of ligand identificationswere made for representative (F-o-F-c) exp(i phi(c)) difference densityfrom entries in the Protein Data Bank. In 48 percent of the 200 cases,the correct ligand was at the top of the ranked list of ligands. Thisapproach may be useful in identification of unknown ligands in newmacromolecular structures as well as in the identification of whichligands in a mixture have bound to a macromolecule.

  12. What a Difference a Carbon Makes: H4octapa vs H4C3octapa, Ligands for In-111 and Lu-177 Radiochemistry

    PubMed Central

    2015-01-01

    The acyclic ligands H4C3octapa and p-SCN-Bn-H4C3octapa were synthesized for the first time, using nosyl protection chemistry. These new ligands were compared to the previously studied ligands H4octapa and p-SCN-Bn-H4octapa to determine the extent to which the addition of a single carbon atom to the backbone of the ligand would affect metal coordination, complex stability, and, ultimately, utility for in vivo radiopharmaceutical applications. Although only a single carbon atom was added to H4C3octapa and the metal donor atoms and denticity were not changed, the solution chemistry and radiochemistry properties were drastically altered, highlighting the importance of careful ligand design and radiometal–ligand matching. It was found that [In(C3octapa)]− and [Lu(C3octapa)]− were substantially different from the analogous H4octapa complexes, exhibiting fluxional isomerization and a higher number of isomers, as observed by 1H NMR, VT-NMR, and 2D COSY/HSQC-NMR experiments. Past evaluation of the DFT structures of [In(octapa)]− and [Lu(octapa)]− revealed very symmetric complexes; in contrast, the [In(C3octapa)]− and [Lu(C3octapa)]− complexes were much less symmetric, suggesting lower symmetry and less rigidity than that of the analogous H4octapa complexes. Potentiometric titrations revealed the formation constants (log KML, pM) were ∼2 units lower for the In3+ and Lu3+ complexes of H4C3octapa when compared to that of the more favorable H4octapa ligand (∼2 orders of magnitude less thermodynamically stable). The bifunctional ligands p-SCN-Bn-H4C3octapa and p-SCN-Bn-H4octapa were conjugated to the antibody trastuzumab and radiolabeled with 111In and 177Lu. Over a 5 day stability challenge experiment in blood serum, 111In-octapa– and 111In-C3octapa–trastuzumab immunoconjugates were determined to be ∼91 and ∼24% stable, respectively, and 177Lu-octapa– and 177Lu-C3octapa–trastuzumab, ∼89% and ∼4% stable, respectively. This work suggests that 5

  13. NKG2D ligands as therapeutic targets

    PubMed Central

    Spear, Paul; Wu, Ming-Ru; Sentman, Marie-Louise; Sentman, Charles L.

    2013-01-01

    The Natural Killer Group 2D (NKG2D) receptor plays an important role in protecting the host from infections and cancer. By recognizing ligands induced on infected or tumor cells, NKG2D modulates lymphocyte activation and promotes immunity to eliminate ligand-expressing cells. Because these ligands are not widely expressed on healthy adult tissue, NKG2D ligands may present a useful target for immunotherapeutic approaches in cancer. Novel therapies targeting NKG2D ligands for the treatment of cancer have shown preclinical success and are poised to enter into clinical trials. In this review, the NKG2D receptor and its ligands are discussed in the context of cancer, infection, and autoimmunity. In addition, therapies targeting NKG2D ligands in cancer are also reviewed. PMID:23833565

  14. Synthesis, spectroscopic studies, thermal analyses, biological activity of tridentate coordinated transition metal complexes of bi(pyridyl-2-ylmethyl)amine]ligand

    NASA Astrophysics Data System (ADS)

    Abd El-Halim, Hanan F.; Mohamed, Gehad G.

    2016-01-01

    A new tridentate acyclic pincer ligand, [bi(pyridin-2-methyl)amine] (bpma, HL), was synthesized and reacted to form complexes with copper(II), nickel(II), iron(II), cobalt(II) and zinc(II) ions. Both the ligand and its complexes were characterized using elemental analysis, molar conductance, infrared, 1H-NMR-spectroscopy, mass and thermal analyses. According to the spectroscopic data, all of the complexes share the same coordination environment around the metal atoms, consisting two nitrogen-pyridine entities, one nitrogen-methylamine entity, one/two water molecules and/or one/two chloride or bromide ions. Complexes also showed molar conductivity according to the presence of two halide anions outer the coordination sphere except Co(II) and Zn(II) complexes are non electrolytes. Analysis indicates that the metal ions have trigonal bipyramidal structure. Cu(II), Ni(II), Fe(II), Co(II), and Zn(II) metal complexes were screened for their antibacterial activity against Bacillus subtilis, Staphylococcus aureus (G+) and Escherichia coli, and Pseudomonas aeruginosa (G-) bacteria. They showed remarkable antimicrobial activity.

  15. Novel Ligands for a Purine Riboswitch Discovered by RNA-Ligand Docking

    PubMed Central

    Daldrop, Peter; Reyes, Francis E.; Robinson, David A.; Hammond, Colin M.; Lilley, David M.; Batey, Robert T.; Brenk, Ruth

    2011-01-01

    Summary The increasing number of RNA crystal structures enables a structure-based approach to the discovery of new RNA-binding ligands. To develop the poorly explored area of RNA-ligand docking, we have conducted a virtual screening exercise for a purine riboswitch to probe the strengths and weaknesses of RNA-ligand docking. Using a standard protein-ligand docking program with only minor modifications, four new ligands with binding affinities in the micromolar range were identified, including two compounds based on molecular scaffolds not resembling known ligands. RNA-ligand docking performed comparably to protein-ligand docking indicating that this approach is a promising option to explore the wealth of RNA structures for structure-based ligand design. PMID:21439477

  16. Acyclic peptide inhibitors of amylases.

    PubMed

    Pohl, Nicola

    2005-12-01

    In this issue of Chemistry and Biology, a library screening approach reveals a linear octapeptide inhibitor of alpha-amylases reached by de novo design . The selected molecule shares characteristics with naturally occurring protein inhibitors -- a result that suggests general rules for the design of peptide-based amylase inhibitors may be achievable.

  17. Ligand placement based on prior structures: the guided ligand-replacement method

    SciTech Connect

    Klei, Herbert E.; Moriarty, Nigel W. Echols, Nathaniel; Terwilliger, Thomas C.; Baldwin, Eric T.; Pokross, Matt; Posy, Shana; Adams, Paul D.

    2014-01-01

    A new module, Guided Ligand Replacement (GLR), has been developed in Phenix to increase the ease and success rate of ligand placement when prior protein-ligand complexes are available. The process of iterative structure-based drug design involves the X-ray crystal structure determination of upwards of 100 ligands with the same general scaffold (i.e. chemotype) complexed with very similar, if not identical, protein targets. In conjunction with insights from computational models and assays, this collection of crystal structures is analyzed to improve potency, to achieve better selectivity and to reduce liabilities such as absorption, distribution, metabolism, excretion and toxicology. Current methods for modeling ligands into electron-density maps typically do not utilize information on how similar ligands bound in related structures. Even if the electron density is of sufficient quality and resolution to allow de novo placement, the process can take considerable time as the size, complexity and torsional degrees of freedom of the ligands increase. A new module, Guided Ligand Replacement (GLR), was developed in Phenix to increase the ease and success rate of ligand placement when prior protein–ligand complexes are available. At the heart of GLR is an algorithm based on graph theory that associates atoms in the target ligand with analogous atoms in the reference ligand. Based on this correspondence, a set of coordinates is generated for the target ligand. GLR is especially useful in two situations: (i) modeling a series of large, flexible, complicated or macrocyclic ligands in successive structures and (ii) modeling ligands as part of a refinement pipeline that can automatically select a reference structure. Even in those cases for which no reference structure is available, if there are multiple copies of the bound ligand per asymmetric unit GLR offers an efficient way to complete the model after the first ligand has been placed. In all of these applications, GLR

  18. Monofluoride bridged, binuclear metallacycles of first row transition metals supported by third generation bis(1-pyrazolyl)methane ligands: unusual magnetic properties.

    PubMed

    Reger, Daniel L; Foley, Elizabeth A; Watson, Russell P; Pellechia, Perry J; Smith, Mark D; Grandjean, Fernande; Long, Gary J

    2009-11-16

    The reaction of M(BF(4))(2).xH(2)O, where M is Fe, Co, Cu, and Zn, and the ditopic, bis(pyrazolyl)methane ligand m-[CH(pz)(2)](2)C(6)H(4), L(m), where pz is a pyrazolyl ring, yields the monofluoride bridged, binuclear [M(2)(mu-F)(mu-L(m))(2)](BF(4))(3) complexes. In contrast, a similar reaction of L(m) with Ni(BF(4))(2).6H(2)O yields dibridged [Ni(2)(mu-F)(2)(mu-L(m))(2)](BF(4))(2). The solid state structures of seven [M(2)(mu-F)(mu-L(m))(2)](BF(4))(3) complexes show that the divalent metal ion is in a five-coordinate, trigonal bipyramidal, coordination environment with either a linear or nearly linear M-F-M bridging arrangement. NMR results indicate that [Zn(2)(mu-F)(mu-L(m))(2)](BF(4))(3) retains its dimeric structure in solution. The [Ni(2)(mu-F)(2)(mu-L(m))(2)](BF(4))(2) complex has a dibridging fluoride structure that has a six-coordination environment about each nickel(II) ion. In the solid state, the [Fe(2)(mu-F)(mu-L(m))(2)](BF(4))(3) and [Co(2)(mu-F)(mu-L(m))(2)](BF(4))(3) complexes show weak intramolecular antiferromagnetic exchange coupling between the two metal(II) ions with J values of -10.4 and -0.67 cm(-1), respectively; there is no observed long-range magnetic order. Three different solvates of [Cu(2)(mu-F)(mu-L(m))(2)](BF(4))(3) are diamagnetic between 5 and 400 K, thus showing strong antiferromagnetic exchange interactions of -600 cm(-1) or more negative. Mossbauer spectra indicate that [Fe(2)(mu-F)(mu-L(m))(2)](BF(4))(3) exhibits no long-range magnetic order between 4.2 and 295 K and isomer shifts that are consistent with the presence of five-coordinate, high-spin iron(II).

  19. A universal rule for organic ligand exchange.

    PubMed

    You, Hongjun; Wang, Wenjin; Yang, Shengchun

    2014-11-12

    Most synthetic routes to high-quality nanocrystals with tunable morphologies predominantly employ long hydro-carbon molecules as ligands, which are detrimental for electronic and catalytic applications. Here, a rule is found that the adsorption energy of an organic ligand is related to its carbon-chain length. Using the density functional theory method, the adsorption energies of some commonly used ligand molecules with different carbon-chain lengths are calculated, including carboxylate, hydroxyl, and amine molecules adsorbed on metal or metal oxide crystal surface. The results indicate that the adsorption energy of the ligand molecule with a long carbon chain is weaker than that of a smaller molecule with same functional group. This rule provides a theoretical support for a new kind of ligand exchange method in which large organic ligand molecules can be exchanged by small molecules with same functional group to improve the catalytic properties.

  20. Insights into an original pocket-ligand pair classification: a promising tool for ligand profile prediction.

    PubMed

    Pérot, Stéphanie; Regad, Leslie; Reynès, Christelle; Spérandio, Olivier; Miteva, Maria A; Villoutreix, Bruno O; Camproux, Anne-Claude

    2013-01-01

    Pockets are today at the cornerstones of modern drug discovery projects and at the crossroad of several research fields, from structural biology to mathematical modeling. Being able to predict if a small molecule could bind to one or more protein targets or if a protein could bind to some given ligands is very useful for drug discovery endeavors, anticipation of binding to off- and anti-targets. To date, several studies explore such questions from chemogenomic approach to reverse docking methods. Most of these studies have been performed either from the viewpoint of ligands or targets. However it seems valuable to use information from both ligands and target binding pockets. Hence, we present a multivariate approach relating ligand properties with protein pocket properties from the analysis of known ligand-protein interactions. We explored and optimized the pocket-ligand pair space by combining pocket and ligand descriptors using Principal Component Analysis and developed a classification engine on this paired space, revealing five main clusters of pocket-ligand pairs sharing specific and similar structural or physico-chemical properties. These pocket-ligand pair clusters highlight correspondences between pocket and ligand topological and physico-chemical properties and capture relevant information with respect to protein-ligand interactions. Based on these pocket-ligand correspondences, a protocol of prediction of clusters sharing similarity in terms of recognition characteristics is developed for a given pocket-ligand complex and gives high performances. It is then extended to cluster prediction for a given pocket in order to acquire knowledge about its expected ligand profile or to cluster prediction for a given ligand in order to acquire knowledge about its expected pocket profile. This prediction approach shows promising results and could contribute to predict some ligand properties critical for binding to a given pocket, and conversely, some key pocket

  1. CB receptor ligands from plants.

    PubMed

    Woelkart, Karin; Salo-Ahen, Outi M H; Bauer, Rudolf

    2008-01-01

    Advances in understanding the physiology and pharmacology of the endogenous cannabinoid system have potentiated the interest of cannabinoid receptors as potential therapeutic targets. Cannabinoids have been shown to modulate a variety of immune cell functions and have therapeutic implications on central nervous system (CNS) inflammation, chronic inflammatory conditions such as arthritis, and may be therapeutically useful in treating autoimmune conditions such as multiple sclerosis. Many of these drug effects occur through cannabinoid receptor signalling mechanisms and the modulation of cytokines and other gene products. Further, endocannabinoids have been found to have many physiological and patho-physiological functions, including mood alteration and analgesia, control of energy balance, gut motility, motor and co-ordination activities, as well as alleviation of neurological, psychiatric and eating disorders. Plants offer a wide range of chemical diversity and have been a growing domain in the search for effective cannabinoid ligands. Cannabis sativa L. with the known plant cannabinoid, Delta(9-)tetrahydrocannabinol (THC) and Echinacea species with the cannabinoid (CB) receptor-binding lipophilic alkamides are the best known herbal cannabimimetics. This review focuses on the state of the art in CB ligands from plants, as well their possible therapeutic and immunomodulatory effects.

  2. Measurement of protein-ligand complex formation.

    PubMed

    Lowe, Peter N; Vaughan, Cara K; Daviter, Tina

    2013-01-01

    Experimental approaches to detect, measure, and quantify protein-ligand binding, along with their theoretical bases, are described. A range of methods for detection of protein-ligand interactions is summarized. Specific protocols are provided for a nonequilibrium procedure pull-down assay, for an equilibrium direct binding method and its modification into a competition-based measurement and for steady-state measurements based on the effects of ligands on enzyme catalysis.

  3. Asymmetric catalysis with chiral ferrocene ligands.

    PubMed

    Dai, Li-Xin; Tu, Tao; You, Shu-Li; Deng, Wei-Ping; Hou, Xue-Long

    2003-09-01

    Chiral ferrocene ligands have been widely used in asymmetric catalysis. The advantages of using ferrocene as a scaffold for chiral ligands are described, particularly those regarding planar chirality, rigid bulkiness, and ease of derivatization. The role of planar chirality in 1,2- and 1,1'-disubstituted ferrocene systems is discussed. By using a bulky ferrocene fragment, novel ferrocene ligands were designed, and high enantioselectivity and regioselectivity were achieved in the allylic substitution reaction of monosubstituted allyl substrates. Using the tunable electronic properties of a diphosphine-oxazoline ferrocenyl ligand, the regioselectivity of the intermolecular asymmetric Heck reaction was also examined.

  4. Integrated ligand based pharmacophore model derived from diverse FAAH covalent ligand classes.

    PubMed

    Shen, Lingling; Huang, Hongwei; Makriyannis, Alexandros; Fisher, Luke S

    2012-12-01

    3D pharmacophore modeling is an important computational methodology for ligand-enzyme binding interactions in drug discovery. More specifically, a consensus pharmacophore model derived from diverse ligands is a key determinant upon which the prediction power of computational models is based for designing novel ligands. In this work, by merging the important pharmacophore features based on four classes of covalent FAAH ligands, and then integrating the exclusion volume spheres derived from the crystal structure, we created for the first time an integrated FAAH pharmacophore model to describe the ligand-enzyme binding interactions. This new integrated FAAH pharmacophore model can correctly predict the covalent ligand binding mode, which correlates with the SAR data. The study is expected to provide insights into novel covalent ligand-FAAH binding interactions, and facilitate the design of covalent ligands against FAAH.

  5. Targeting Ligand-Dependent and Ligand-Independent Androgen Receptor Signaling in Prostate Cancer

    DTIC Science & Technology

    2013-10-01

    sub 10nM range efficacy. Our primary objective was to establish a series of compounds blocking the AR ligand-dependent and ligand-independent gene ...of AR driven genes to be more comprehensive and more in line with what is currently known about AR-driven signaling in prostate cancer. We have...developed a robust panel of genes for AR signaling that is reflective of the clinical findings in both ligand dependent and ligand-independent androgen

  6. Cis-interactions between Notch and its ligands block ligand-independent Notch activity

    PubMed Central

    Palmer, William Hunt; Jia, Dongyu; Deng, Wu-Min

    2014-01-01

    The Notch pathway is integrated into numerous developmental processes and therefore is fine-tuned on many levels, including receptor production, endocytosis, and degradation. Notch is further characterized by a twofold relationship with its Delta-Serrate (DSL) ligands, as ligands from opposing cells (trans-ligands) activate Notch, whereas ligands expressed in the same cell (cis-ligands) inhibit signaling. We show that cells without both cis- and trans-ligands can mediate Notch-dependent developmental events during Drosophila oogenesis, indicating ligand-independent Notch activity occurs when the receptor is free of cis- and trans-ligands. Furthermore, cis-ligands can reduce Notch activity in endogenous and genetically induced situations of elevated trans-ligand-independent Notch signaling. We conclude that cis-expressed ligands exert their repressive effect on Notch signaling in cases of trans-ligand-independent activation, and propose a new function of cis-inhibition which buffers cells against accidental Notch activity. DOI: http://dx.doi.org/10.7554/eLife.04415.001 PMID:25486593

  7. Oligometallic template strategy for synthesis of a macrocyclic dimer-type octaoxime ligand for its cooperative complexation.

    PubMed

    Akine, Shigehisa; Tadokoro, Toshio; Nabeshima, Tatsuya

    2012-11-05

    The new acyclic tetraoxime ligand H(4)L(1), having two allyl groups at the terminal benzene rings, was designed and synthesized. The ligand H(4)L(1) was converted to five kinds of the trinuclear complexes, [L(1)Zn(3)(OAc)(2)], [L(1)Zn(2)La(OAc)(3)], [L(1)Zn(2)Ca(OAc)(2)], [L(1)Zn(2)Sr(OAc)(2)], and [L(1)Zn(2)Ba(OAc)(2)]. The terminal allyl groups were introduced so that the olefin metathesis could convert the metal complexes into the dimeric macrocyclic ligand H(8)L(3). The X-ray crystallographic analysis of the trinuclear complexes [L(1)Zn(3)(OAc)(2)(H(2)O)], [L(1)Zn(2)La(OAc)(3)(MeOH)], [L(1)Zn(2)Ca(OAc)(2)], and [L(1)Zn(2)Sr(OAc)(2)] revealed that the distances between the two allyl groups are 11-12 Å, which should be sufficient to suppress the intramolecular reaction leading to the monomeric macrocycle H(4)L(2). Indeed, the olefin metathesis of the [L(1)Zn(2)Ca(OAc)(2)] and [L(1)Zn(2)Sr(OAc)(2)] followed by demetalation with dilute hydrochloric acid afforded the dimeric macrocycle H(8)L(3) as the major product, while the reaction of the uncomplexed ligand H(4)L(1) gave the monomeric macrocycle H(4)L(2) as the major product. The complexation behavior of H(8)L(3) at the two tetraoxime sites was investigated. Although the formation process of the hexanuclear zinc(II) complex [L(3)Zn(6)](4+) was complicated, the metal exchange of the two trinuclear zinc(II) units proceeded in a two-step fashion. The analysis of the spectral changes indicated the positive and negative cooperative effects on the double metal exchange with Ca(2+) and Ba(2+), respectively. The first metal exchange reactions with Ca(2+) made the second metal exchange more favorable. Thus, the obtained dimeric macrocycle H(8)L(3) has two tetraoxime coordination sites, whose complexation behavior is remotely affected by each other.

  8. Ligand binding by PDZ domains.

    PubMed

    Chi, Celestine N; Bach, Anders; Strømgaard, Kristian; Gianni, Stefano; Jemth, Per

    2012-01-01

    The postsynaptic density protein-95/disks large/zonula occludens-1 (PDZ) protein domain family is one of the most common protein-protein interaction modules in mammalian cells, with paralogs present in several hundred human proteins. PDZ domains are found in most cell types, but neuronal proteins, for example, are particularly rich in these domains. The general function of PDZ domains is to bring proteins together within the appropriate cellular compartment, thereby facilitating scaffolding, signaling, and trafficking events. The many functions of PDZ domains under normal physiological as well as pathological conditions have been reviewed recently. In this review, we focus on the molecular details of how PDZ domains bind their protein ligands and their potential as drug targets in this context.

  9. Ligand placement based on prior structures: the guided ligand-replacement method

    PubMed Central

    Klei, Herbert E.; Moriarty, Nigel W.; Echols, Nathaniel; Terwilliger, Thomas C.; Baldwin, Eric T.; Pokross, Matt; Posy, Shana; Adams, Paul D.

    2014-01-01

    The process of iterative structure-based drug design involves the X-ray crystal structure determination of upwards of 100 ligands with the same general scaffold (i.e. chemotype) complexed with very similar, if not identical, protein targets. In conjunction with insights from computational models and assays, this collection of crystal structures is analyzed to improve potency, to achieve better selectivity and to reduce liabilities such as absorption, distribution, metabolism, excretion and toxicology. Current methods for modeling ligands into electron-density maps typically do not utilize information on how similar ligands bound in related structures. Even if the electron density is of sufficient quality and resolution to allow de novo placement, the process can take considerable time as the size, complexity and torsional degrees of freedom of the ligands increase. A new module, Guided Ligand Replacement (GLR), was developed in Phenix to increase the ease and success rate of ligand placement when prior protein–ligand complexes are available. At the heart of GLR is an algorithm based on graph theory that associates atoms in the target ligand with analogous atoms in the reference ligand. Based on this correspondence, a set of coordinates is generated for the target ligand. GLR is especially useful in two situations: (i) modeling a series of large, flexible, complicated or macrocyclic ligands in successive structures and (ii) modeling ligands as part of a refinement pipeline that can automatically select a reference structure. Even in those cases for which no reference structure is available, if there are multiple copies of the bound ligand per asymmetric unit GLR offers an efficient way to complete the model after the first ligand has been placed. In all of these applications, GLR leverages prior knowledge from earlier structures to facilitate ligand placement in the current structure. PMID:24419386

  10. Flexible ligand docking using a genetic algorithm

    NASA Astrophysics Data System (ADS)

    Oshiro, C. M.; Kuntz, I. D.; Dixon, J. Scott

    1995-04-01

    Two computational techniques have been developed to explore the orientational and conformational space of a flexible ligand within an enzyme. Both methods use the Genetic Algorithm (GA) to generate conformationally flexible ligands in conjunction with algorithms from the DOCK suite of programs to characterize the receptor site. The methods are applied to three enzyme-ligand complexes: dihydrofolate reductase-methotrexate, thymidylate synthase-phenolpthalein and HIV protease-thioketal haloperidol. Conformations and orientations close to the crystallographically determined structures are obtained, as well as alternative structures with low energy. The potential for the GA method to screen a database of compounds is also examined. A collection of ligands is evaluated simultaneously, rather than docking the ligands individually into the enzyme.

  11. Biomimetic affinity ligands for protein purification.

    PubMed

    Sousa, Isabel T; Taipa, M Angela

    2014-01-01

    The development of sophisticated molecular modeling software and new bioinformatic tools, as well as the emergence of data banks containing detailed information about a huge number of proteins, enabled the de novo intelligent design of synthetic affinity ligands. Such synthetic compounds can be tailored to mimic natural biological recognition motifs or to interact with key surface-exposed residues on target proteins and are designated as "biomimetic ligands." A well-established methodology for generating biomimetic or synthetic affinity ligands integrates rational design with combinatorial solid-phase synthesis and screening, using the triazine scaffold and analogues of amino acids side chains to create molecular diversity.Triazine-based synthetic ligands are nontoxic, low-cost, highly stable compounds that can replace advantageously natural biological ligands in the purification of proteins by affinity-based methodologies.

  12. Evaluation of H2CHXdedpa, H2dedpa- and H2CHXdedpa-N,N'-propyl-2-NI ligands for (64)Cu(ii) radiopharmaceuticals.

    PubMed

    Ramogida, Caterina F; Boros, Eszter; Patrick, Brian O; Zeisler, Stefan K; Kumlin, Joel; Adam, Michael J; Schaffer, Paul; Orvig, Chris

    2016-08-16

    The chiral acyclic "pa" ligand (pa = picolinic acid) H2CHXdedpa (N4O2) and two NI-containing dedpa analogues (H2CHXdedpa-N,N'-propyl-2-NI, H2dedpa-N,N'-propyl-2-NI, NI = nitroimidazole) were studied as chelators for copper radiopharmaceuticals (CHX = cyclohexyl, H2dedpa = 1,2-[[carboxypyridin-2-yl]methylamino]ethane). The hexadentate ligand H2CHXdedpa was previously established as a superb system for (67/68)Ga radiochemistry. The solid state X-ray crystal structures of [Cu(CHXdedpa-N,N'-propyl-2-NI)] and [Cu(dedpa-N,N'-propyl-2-NI)] reveal the predicted hexadentate, distorted octahedral binding of the copper(ii) ion. Cyclic voltammetry of [Cu(dedpa-N,N'-propyl-2-NI)] shows that there is one reversible couple associated with the NI redox, and one irreversible but reproducible couple attributed to the Cu(ii)/Cu(i) redox cycle. Quantitative radiolabeling (>99%) of CHXdedpa(2-) and (dedpa-N,N'-propyl-2-NI)(2-) with (64)Cu was achieved under fast and efficient labeling conditions (10 min, RT, 0.5 M sodium acetate buffer, pH 5.5) at ligand concentrations as low as 10(-6) M. In vitro kinetic inertness studies of the (64)Cu labelled complexes were studied in human serum at 37 °C over 24 hours; [(64)Cu(CHXdedpa)] was found to be 98% stable compared to previously investigated [(64)Cu(dedpa)] which was only 72% intact after 24 hours.

  13. Qualification of a free ligand assay in the presence of anti-ligand antibody Fab fragments.

    PubMed

    Hansen, Ryan J; Brown, Robin M; Lu, Jirong; Wroblewski, Victor J

    2013-01-01

    The aim of this work was to develop and characterize an ELISA to measure free ligand concentrations in rat serum in the presence of a Fab to the same ligand. A variety of experiments were conducted to understand optimal assay conditions and to verify that only free ligand was detected. The parameters explored included sample incubation time on plate, the initial concentrations of Fab and ligand, and the pre-incubation time required for the Fab-ligand complex concentrations to reach equilibrium. We found the optimal experimental conditions to include a 10-minute on-plate incubation of ligand-containing samples, with a 24-hour pre-incubation time for test samples of Fab and ligand to reach equilibrium. An alternative approach, involving removal of Fab-ligand complexes from the solution prior to measuring concentrations of the ligand, was also used to verify that the assay only measured free ligand. Rats were dosed subcutaneously with Fab and the assay was used to demonstrate dose-dependent suppression of endogenous free ligand levels in vivo.

  14. Chemistry of Marine Ligands and Siderophores

    NASA Astrophysics Data System (ADS)

    Vraspir, Julia M.; Butler, Alison

    2009-01-01

    Marine microorganisms are presented with unique challenges to obtain essential metal ions required to survive and thrive in the ocean. The production of organic ligands to complex transition metal ions is one strategy to both facilitate uptake of specific metals, such as iron, and to mitigate the potential toxic effects of other metal ions, such as copper. A number of important trace metal ions are complexed by organic ligands in seawater, including iron, cobalt, nickel, copper, zinc, and cadmium, thus defining the speciation of these metal ions in the ocean. In the case of iron, siderophores have been identified and structurally characterized. Siderophores are low molecular weight iron-binding ligands produced by marine bacteria. Although progress has been made toward the identity of in situ iron-binding ligands, few compounds have been identified that coordinate the other trace metals. Deciphering the chemical structures and production stimuli of naturally produced organic ligands and the organisms they come from is fundamental to understanding metal speciation and bioavailability. The current evidence for marine ligands, with an emphasis on siderophores, and discussion of the importance and implications of metal-binding ligands in controlling metal speciation and cycling within the world's oceans are presented.

  15. ProPose: steered virtual screening by simultaneous protein-ligand docking and ligand-ligand alignment.

    PubMed

    Seifert, Markus H J

    2005-01-01

    The 'model-free' screening engine ProPose implements a general method for performing simultaneous protein-ligand docking, ligand-ligand alignment, pharmacophore queries-and combinations thereof-in order to incorporate a priori information into screening protocols. In this manuscript we describe a case study on herpes simplex virus thymidine kinase, an important antiviral drug target, where we evaluate different approaches for handling a specific type of a priori information, i.e., multiple target structures. We demonstrate that a simultaneous alignment on two target structures--in conjunction with logic operations on interactions and docking constraints derived from protein structure--is an effective means of (i) improving the enrichment of chemical substructures that are compatible with the a priori known ligands, (ii) ensuring the steric fit into the target protein, and (iii) handling target flexibility. The combination of ligand- and receptor-based methods steers the virtual screening by ranking molecules according to the similarity of their interaction pattern with known ligands, thereby--to some extent--outweighing the deficiencies of simple scoring functions often used in initial virtual screening.

  16. Ligand engineering of nanoparticle solar cells

    NASA Astrophysics Data System (ADS)

    Voros, Marton

    Semiconductor nanoparticles (NP) are promising materials to build cheap and efficient solar cells. One of the key challenges in their utilization for solar energy conversion is the control of NP surfaces and ligand-NP interfaces. Recent experiments have shown that by carefully choosing the ligands terminating the NPs, one can tailor electronic and optical absorption properties of NP assemblies, along with their transport properties. By using density functional theory based methods, we investigated how the opto-electronic properties of lead chalcogenide NPs may be tuned by using diverse organic and inorganic ligands. We interpreted experiments, and we showed that an essential prerequisite to avoid detrimental trap states is to ensure charge balance at the ligand-NP interface, possibly with the help of hydrogen treatment Work supported by the Center for Advanced Solar Photophysics, an Energy Frontier Research Center funded by the US Department of Energy, Office of Science, Office of Basic Energy Sciences.

  17. Automated design of ligands to polypharmacological profiles

    PubMed Central

    Besnard, Jérémy; Ruda, Gian Filippo; Setola, Vincent; Abecassis, Keren; Rodriguiz, Ramona M.; Huang, Xi-Ping; Norval, Suzanne; Sassano, Maria F.; Shin, Antony I.; Webster, Lauren A.; Simeons, Frederick R.C.; Stojanovski, Laste; Prat, Annik; Seidah, Nabil G.; Constam, Daniel B.; Bickerton, G. Richard; Read, Kevin D.; Wetsel, William C.; Gilbert, Ian H.; Roth, Bryan L.; Hopkins, Andrew L.

    2012-01-01

    The clinical efficacy and safety of a drug is determined by its activity profile across multiple proteins in the proteome. However, designing drugs with a specific multi-target profile is both complex and difficult. Therefore methods to rationally design drugs a priori against profiles of multiple proteins would have immense value in drug discovery. We describe a new approach for the automated design of ligands against profiles of multiple drug targets. The method is demonstrated by the evolution of an approved acetylcholinesterase inhibitor drug into brain penetrable ligands with either specific polypharmacology or exquisite selectivity profiles for G-protein coupled receptors. Overall, 800 ligand-target predictions of prospectively designed ligands were tested experimentally, of which 75% were confirmed correct. We also demonstrate target engagement in vivo. The approach can be a useful source of drug leads where multi-target profiles are required to achieve either selectivity over other drug targets or a desired polypharmacology. PMID:23235874

  18. Ligand inducible assembly of a DNA tetrahedron.

    PubMed

    Dohno, Chikara; Atsumi, Hiroshi; Nakatani, Kazuhiko

    2011-03-28

    Here we show that a small synthetic ligand can be used as a key building component for DNA nanofabrication. Using naphthyridinecarbamate dimer (NCD) as a molecular glue for DNA hybridization, we demonstrate NCD-triggered formation of a DNA tetrahedron.

  19. Advanced Organic Ligands for Protecting Metal Nanoparticles

    NASA Astrophysics Data System (ADS)

    Yu, Jonathan Ka-Wing

    Organic monolayer protected metal nanoparticles have been utilized in many different fields such as catalysis, drug delivery, and sensor chemistry. However, these nanomaterials are prone to increase in size consequently losing its function at the nanoscale. The stability these nanoparticles have been a great interest of research. This thesis focuses on the synthesis of a novel cross-linkable ligand for the protection of metal nanoparticles. Chapter 1 reviews key concepts of nanoparticles, its usefulness in applications, some of the stabilizing strategies employed, and the scope of the thesis project. Chapter 2 describes the synthetic attempts and optimization of the novel cross-linkable ligand. In addition, its characterization data is also included. Section 2.8 also highlights another fully synthesized novel hydrophobic ligand. Chapter 3 contains the summary of the work and closing remarks. Future works is also included to describe the prospects of the synthesis of the novel ligand. Chapter 4 entails the experimental data and supplementary information.

  20. GW-501516 GlaxoSmithKline/Ligand.

    PubMed

    Pelton, Patricia

    2006-04-01

    GlaxoSmithKline and Ligand are developing GW-501516, a peroxisome proliferator-activator receptor-delta agonist for the potential treatment of dyslipidemia. Phase II clinical trials of this compound are ongoing.

  1. The Retinoid X Receptors and Their Ligands

    PubMed Central

    Dawson, Marcia I.; Xia, Zebin

    2014-01-01

    This chapter presents an overview of the current status of studies on the structural and molecular biology of the retinoid X receptor subtypes α, β, and γ (RXRs, NR2B1–3), their nuclear and cytoplasmic functions, post-transcriptional processing, and recently reported ligands. Points of interest are the different changes in the ligand-binding pocket induced by variously shaped agonists, the communication of the ligand–bound pocket with the coactivator binding surface and the heterodimerization interface, and recently identified ligands that are natural products, those that function as environmental toxins or drugs that had been originally designed to interact with other targets, as well as those that were deliberately designed as RXR-selective transcriptional agonists, synergists, or antagonists. Of these synthetic ligands, the general trend in design appears to be away from fully aromatic rigid structures to those containing partial elements of the flexible tetraene side chain of 9-cis-retinoic acid. PMID:22020178

  2. Affinity Electrophoresis Using Ligands Attached To Polymers

    NASA Technical Reports Server (NTRS)

    Van Alstine, James M.; Snyder, Robert S.; Harris, J. M.; Brooks, D. E.

    1990-01-01

    In new technique, reduction of electrophoretic mobilities by addition of polyethylene glycol to ligands increases electrophoretic separabilities. In immuno-affinity electrophoresis, modification of ligands extends specificity of electrophoretic separation to particles having surface electric-charge structures otherwise making them electrophoretically inseparable. Modification of antibodies by polyethylene glycol greatly reduces ability to aggregate while enhancing ability to affect electrophoretic mobilities of cells. In hydrophobic-affinity electrophoresis, addition of polyethylene glycol reduces tendency toward aggregation of cells or macromolecules.

  3. Semiconductor Quantum Dots with Photoresponsive Ligands.

    PubMed

    Sansalone, Lorenzo; Tang, Sicheng; Zhang, Yang; Thapaliya, Ek Raj; Raymo, Françisco M; Garcia-Amorós, Jaume

    2016-10-01

    Photochromic or photocaged ligands can be anchored to the outer shell of semiconductor quantum dots in order to control the photophysical properties of these inorganic nanocrystals with optical stimulations. One of the two interconvertible states of the photoresponsive ligands can be designed to accept either an electron or energy from the excited quantum dots and quench their luminescence. Under these conditions, the reversible transformations of photochromic ligands or the irreversible cleavage of photocaged counterparts translates into the possibility to switch luminescence with external control. As an alternative to regulating the photophysics of a quantum dot via the photochemistry of its ligands, the photochemistry of the latter can be controlled by relying on the photophysics of the former. The transfer of excitation energy from a quantum dot to a photocaged ligand populates the excited state of the species adsorbed on the nanocrystal to induce a photochemical reaction. This mechanism, in conjunction with the large two-photon absorption cross section of quantum dots, can be exploited to release nitric oxide or to generate singlet oxygen under near-infrared irradiation. Thus, the combination of semiconductor quantum dots and photoresponsive ligands offers the opportunity to assemble nanostructured constructs with specific functions on the basis of electron or energy transfer processes. The photoswitchable luminescence and ability to photoinduce the release of reactive chemicals, associated with the resulting systems, can be particularly valuable in biomedical research and can, ultimately, lead to the realization of imaging probes for diagnostic applications as well as to therapeutic agents for the treatment of cancer.

  4. New bifunctional ligands for radioimmunoimaging and radioimmunotherapy

    SciTech Connect

    Brechbiel, M.W.

    1988-01-01

    The bifunctional EDTA ligand and two bifunctional DTPA ligands were synthesized by direct aminolysis of an amino acid ester followed by reduction, alkylation, and functional group modification to introduced bifunctionality. The reactive substituent chosen for protein conjugation was the isothiocyanate group. The generality of this approach was demonstrated with 9 different amino acids to produce the respective substituted diethylenetriamines. The remaining three bifunctional DTPA ligands were synthesized via classical peptide methodology producing a dipeptide amide which, after deprotection, was reduced to the triamine and alkylated to produce the ligand. Biodistribution studies of the ligands conjugated to monoclonal antibody B72.3 and labelled with In-111 revealed that superior retention of In-111 was attained and the dose to the liver was minimized when a full intact octadentate bifunctional DTPA chelate was used, e.g. DTPA > EDTA > DTTA (diethylenetritetraacetic acid from use of DTPA dianhydride (CA-DTPA)). The best scintigraphic images were obtained after 72 hours when a DTPA ligand was used to complex the In-111. Biodistribution studies using Yttrium-88 revealed that the disubstituted bifunctional DTPA was necessary to minimize the bone dose from the Yttrium while maintaining a high dose to the tumor.

  5. Interrupting autocrine ligand-receptor binding: comparison between receptor blockers and ligand decoys.

    PubMed Central

    Forsten, K E; Lauffenburger, D A

    1992-01-01

    Stimulation of cell behavioral functions by ligand/receptor binding can be accomplished in autocrine fashion, where cells secrete ligand capable of binding to receptors on their own surfaces. This proximal secretion of autocrine ligands near the surface receptors on the secreting cell suggests that control of these systems by inhibitors of receptor/ligand binding may be more difficult than for systems involving exogenous ligands. Hence, it is of interest to predict the conditions under which successful inhibition of cell receptor binding by the autocrine ligand can be expected. Previous theoretical work using a compartmentalized model for autocrine cells has elucidated the conditions under which addition of solution decoys for the autocrine ligand can interrupt cell receptor/ligand binding via competitive binding of the secreted molecules (Forsten, K. E., and D. A. Lauffenburger. 1992. Biophys. J. 61:1-12.) We now apply a similar modeling approach to examine the addition of solution blockers targeted against the cell receptor. Comparison of the two alternative inhibition strategies reveals that a significantly lower concentration of receptor blockers, compared to ligand decoys, will obtain a high degree of inhibition. The more direct interruption scheme characteristic of the receptor blockers may make them a preferred strategy when feasible. PMID:1330038

  6. Fully Flexible Docking of Medium Sized Ligand Libraries with RosettaLigand

    PubMed Central

    DeLuca, Samuel; Khar, Karen; Meiler, Jens

    2015-01-01

    RosettaLigand has been successfully used to predict binding poses in protein-small molecule complexes. However, the RosettaLigand docking protocol is comparatively slow in identifying an initial starting pose for the small molecule (ligand) making it unfeasible for use in virtual High Throughput Screening (vHTS). To overcome this limitation, we developed a new sampling approach for placing the ligand in the protein binding site during the initial ‘low-resolution’ docking step. It combines the translational and rotational adjustments to the ligand pose in a single transformation step. The new algorithm is both more accurate and more time-efficient. The docking success rate is improved by 10–15% in a benchmark set of 43 protein/ligand complexes, reducing the number of models that typically need to be generated from 1000 to 150. The average time to generate a model is reduced from 50 seconds to 10 seconds. As a result we observe an effective 30-fold speed increase, making RosettaLigand appropriate for docking medium sized ligand libraries. We demonstrate that this improved initial placement of the ligand is critical for successful prediction of an accurate binding position in the ‘high-resolution’ full atom refinement step. PMID:26207742

  7. Time, the Forgotten Dimension of Ligand Binding Teaching

    ERIC Educational Resources Information Center

    Corzo, Javier

    2006-01-01

    Ligand binding is generally explained in terms of the equilibrium constant K[subscript d] for the protein-ligand complex dissociation. However, both theoretical considerations and experimental data point to the life span of the protein-ligand complex as an important, but generally overlooked, aspect of ligand binding by macromolecules. Short-lived…

  8. Ligand clouds around protein clouds: a scenario of ligand binding with intrinsically disordered proteins.

    PubMed

    Jin, Fan; Yu, Chen; Lai, Luhua; Liu, Zhirong

    2013-01-01

    Intrinsically disordered proteins (IDPs) were found to be widely associated with human diseases and may serve as potential drug design targets. However, drug design targeting IDPs is still in the very early stages. Progress in drug design is usually achieved using experimental screening; however, the structural disorder of IDPs makes it difficult to characterize their interaction with ligands using experiments alone. To better understand the structure of IDPs and their interactions with small molecule ligands, we performed extensive simulations on the c-Myc₃₇₀₋₄₀₉ peptide and its binding to a reported small molecule inhibitor, ligand 10074-A4. We found that the conformational space of the apo c-Myc₃₇₀₋₄₀₉ peptide was rather dispersed and that the conformations of the peptide were stabilized mainly by charge interactions and hydrogen bonds. Under the binding of the ligand, c-Myc₃₇₀₋₄₀₉ remained disordered. The ligand was found to bind to c-Myc₃₇₀₋₄₀₉ at different sites along the chain and behaved like a 'ligand cloud'. In contrast to ligand binding to more rigid target proteins that usually results in a dominant bound structure, ligand binding to IDPs may better be described as ligand clouds around protein clouds. Nevertheless, the binding of the ligand and a non-ligand to the c-Myc₃₇₀₋₄₀₉ target could be clearly distinguished. The present study provides insights that will help improve rational drug design that targets IDPs.

  9. Posttranslational regulation of Fas ligand function

    PubMed Central

    Voss, Matthias; Lettau, Marcus; Paulsen, Maren; Janssen, Ottmar

    2008-01-01

    The TNF superfamily member Fas ligand acts as a prototypic death factor. Due to its ability to induce apoptosis in Fas (APO-1, CD95) expressing cells, Fas ligand participates in essential effector functions of the immune system. It is involved in natural killer cell- and T cell-mediated cytotoxicity, the establishment of immune privilege, and in termination of immune responses by induction of activation-induced cell death. In addition, Fas ligand-positive tumours may evade immune surveillance by killing Fas-positive tumour-infiltrating cells. Given these strong cytotoxic capabilities of Fas ligand, it is obvious that its function has to be strictly regulated to avoid uncontrolled damage. In hematopoietic cells, the death factor is stored in secretory lysosomes and is mobilised to the immunological synapse only upon activation. The selective sorting to and the release from this specific lysosomal compartment requires interactions of the Fas ligand cytosolic moiety, which mediates binding to various adapter proteins involved in trafficking and cytoskeletal reorganisation. In addition, Fas ligand surface expression is further regulated by posttranslational ectodomain shedding and subsequent regulated intramembrane proteolysis, releasing a soluble ectodomain cytokine into the extracellular space and an N-terminal fragment with a potential role in intracellular signalling processes. Moreover, other posttranslational modifications of the cytosolic domain, including phosphorylation and ubiquitylation, have been described to affect various aspects of Fas ligand biology. Since FasL is regarded as a potential target for immunotherapy, the further characterisation of its biological regulation and function will be of great importance for the development and evaluation of future therapeutic strategies. PMID:19114018

  10. Multiple ligand simultaneous docking: orchestrated dancing of ligands in binding sites of protein.

    PubMed

    Li, Huameng; Li, Chenglong

    2010-07-30

    Present docking methodologies simulate only one single ligand at a time during docking process. In reality, the molecular recognition process always involves multiple molecular species. Typical protein-ligand interactions are, for example, substrate and cofactor in catalytic cycle; metal ion coordination together with ligand(s); and ligand binding with water molecules. To simulate the real molecular binding processes, we propose a novel multiple ligand simultaneous docking (MLSD) strategy, which can deal with all the above processes, vastly improving docking sampling and binding free energy scoring. The work also compares two search strategies: Lamarckian genetic algorithm and particle swarm optimization, which have respective advantages depending on the specific systems. The methodology proves robust through systematic testing against several diverse model systems: E. coli purine nucleoside phosphorylase (PNP) complex with two substrates, SHP2NSH2 complex with two peptides and Bcl-xL complex with ABT-737 fragments. In all cases, the final correct docking poses and relative binding free energies were obtained. In PNP case, the simulations also capture the binding intermediates and reveal the binding dynamics during the recognition processes, which are consistent with the proposed enzymatic mechanism. In the other two cases, conventional single-ligand docking fails due to energetic and dynamic coupling among ligands, whereas MLSD results in the correct binding modes. These three cases also represent potential applications in the areas of exploring enzymatic mechanism, interpreting noisy X-ray crystallographic maps, and aiding fragment-based drug design, respectively.

  11. Design of a Hole Trapping Ligand

    DOE PAGES

    La Croix, Andrew D.; O’Hara, Andrew; Reid, Kemar R.; ...

    2017-01-18

    A new ligand that covalently attaches to the surface of colloidal CdSe/ CdS nanorods and can simultaneously chelate a molecular metal center is described. The dithiocarbamate$-$bipyridine ligand system facilitates hole transfer through energetic overlap at the inorganic$-$organic interface and conjugation through the organic ligand to a chelated metal center. Density functional theory calculations show that the coordination of the free ligand to a CdS surface causes the formation of two hybridized molecular states that lie in the band gap of CdS. The further chelation of Fe(II) to the bipyridine moiety causes the presence of seven midgap states. Hole transfer frommore » the CdS valence band to the midgap states is dipole allowed and occurs at a faster rate than what is experimentally known for the CdSe/CdS band-edge radiative recombination. In the case of the ligand bound with iron, a two-step process emerges that places the hole on the iron, again at rates much faster than band gap recombination. The system was experimentally assembled and characterized via UV$-$vis absorbance spectroscopy, fluorescence spectroscopy, time-resolved photoluminescence spectroscopy, and energy dispersive X-ray spectroscopy. Lastly, theoretically predicted red shifts in absorbance were observed experimentally, as well as the expected quench in photoluminescence and lifetimes in time-resolved photoluminescence« less

  12. Chelating ligands for nanocrystals' surface functionalization.

    PubMed

    Querner, Claudia; Reiss, Peter; Bleuse, Joël; Pron, Adam

    2004-09-22

    A new family of ligands for the surface functionalization of CdSe nanocrystals is proposed, namely alkyl or aryl derivatives of carbodithioic acids (R-C(S)SH). The main advantages of these new ligands are as follows: they nearly quantitatively exchange the initial surface ligands (TOPO) in very mild conditions; they significantly improve the resistance of nanocrystals against photooxidation because of their ability of strong chelate-type binding to metal atoms; their relatively simple preparation via Grignard intermediates facilitates the development of new bifunctional ligands containing, in addition to the anchoring carbodithioate group, a second function, which enables the grafting of molecules or macromolecules of interest on the nanocrystal surface. To give an example of this approach, we report, for the first time, the grafting of an electroactive oligomer from the polyaniline family-aniline tetramer-on CdSe nanocrystals after their functionalization with 4-formyldithiobenzoic acid. The grafting proceeds via a condensation reaction between the aldehyde group of the ligand and the terminal primary amine group of the tetramer. The resulting organic/inorganic hybrid exhibits complete extinction of the fluorescence of its constituents, indicating efficient charge or energy transfer between the organic and the inorganic semiconductors.

  13. Engineering death receptor ligands for cancer therapy.

    PubMed

    Wajant, Harald; Gerspach, Jeannette; Pfizenmaier, Klaus

    2013-05-28

    CD95, TNFR1, TRAILR1 and TRAILR2 belong to a subgroup of TNF receptors which is characterized by a conserved cell death-inducing protein domain that connects these receptors to the apoptotic machinery of the cell. Activation of death receptors in malignant cells attracts increasing attention as a principle to fight cancer. Besides agonistic antibodies the major way to stimulate death receptors is the use of their naturally occurring "death ligands" CD95L, TNF and TRAIL. However, dependent from the concept followed to develop a death ligand-based therapy various limiting aspects have to be taken into consideration on the way to a "bedside" usable drug. Problems arise in particular from the cell associated transmembrane nature of the death ligands, the poor serum half life of the soluble fragments derived from the transmembrane ligands, the ubiquitous expression of the death receptors and the existence of additional non-death receptors of the death ligands. Here, we summarize strategies how these limitations can be overcome by genetic engineering.

  14. A screening cascade to identify ERβ ligands

    PubMed Central

    Filgueira, Carly S.; Benod, Cindy; Lou, Xiaohua; Gunamalai, Prem S.; Villagomez, Rosa A.; Strom, Anders; Gustafsson, Jan-Åke; Berkenstam, Anders L.; Webb, Paul

    2014-01-01

    The establishment of effective high throughput screening cascades to identify nuclear receptor (NR) ligands that will trigger defined, therapeutically useful sets of NR activities is of considerable importance. Repositioning of existing approved drugs with known side effect profiles can provide advantages because de novo drug design suffers from high developmental failure rates and undesirable side effects which have dramatically increased costs. Ligands that target estrogen receptor β (ERβ) could be useful in a variety of diseases ranging from cancer to neurological to cardiovascular disorders. In this context, it is important to minimize cross-reactivity with ERα, which has been shown to trigger increased rates of several types of cancer. Because of high sequence similarities between the ligand binding domains of ERα and ERβ, preferentially targeting one subtype can prove challenging. Here, we describe a sequential ligand screening approach comprised of complementary in-house assays to identify small molecules that are selective for ERβ. Methods include differential scanning fluorimetry, fluorescence polarization and a GAL4 transactivation assay. We used this strategy to screen several commercially-available chemical libraries, identifying thirty ERβ binders that were examined for their selectivity for ERβ versus ERα, and tested the effects of selected ligands in a prostate cancer cell proliferation assay. We suggest that this approach could be used to rapidly identify candidates for drug repurposing. PMID:25422593

  15. Surface Ligand Mediated Plasmon Driven Photochemical Reactions.

    PubMed

    Kafle, Bijesh; Poveda, Marisa; Habteyes, Terefe G

    2017-02-07

    Contrary to the general expectation that surface ligands reduce the reactivity of surfaces by blocking the active sites, we present experimental evidence that surface ligands can in fact increase reactivity and induce important reaction pathways in plasmon-driven surface photochemistry. The remarkable effect of surface ligands is demonstrated by comparing the photochemistry of p-aminothiophenol (PATP) on resonant plasmonic gold nanorods (AuNRs) in the presence of citrate, hexadecyltrimethylammonium bromide (CTAB), and no surface ligands under visible light irradiation. The use of AuNRs with citrate and no surface ligand results in the usual azo-coupling reaction. In contrast, CTAB coated AuNRs oxidize PATP primarily to p-nitrothiophenol (PNTP). Strong correlation has been observed between the N-O and Au-Br vibration band intensities, suggesting that CTAB influences the reaction pathway through the Br- counterions that can minimize electron-hole recombination rate by reacting with hole, and hence increasing the concentration of hot electrons that drive the oxidation reaction.

  16. Controlling Gold Nanoclusters by Diphospine Ligands

    SciTech Connect

    Chen, Jing; Zhang, Qianfan; Bonaccorso, Timary A.; Williard, Paul G.; Wang, Lai S.

    2014-01-08

    We report the synthesis and structure determination of a new Au22 nanocluster coordinated by six bidentate diphosphine ligands: 1,8-bis(diphenylphosphino) octane (L8 for short). Single crystal x-ray crystallography and electrospray ionization mass spectrometry show that the cluster assembly is neutral and can be formulated as Au22(L8)6. The Au22 core consists of two Au11 units clipped together by four L8 ligands, while the additional two ligands coordinate to each Au11 unit in a bidentate fashion. Eight gold atoms at the interface of the two Au11 units are not coordinated by any ligands. Four short gold-gold distances (2.64?2.65 Å) are observed at the interface of the two Au11 clusters as a result of the clamping force of the four clipping ligands and strong electronic interactions. The eight uncoordinated surface gold atoms in the Au22(L8)6 nanocluster are unprecedented in atom-precise gold nanoparticles and can be considered as potential in-situ active sites for catalysis.

  17. Sliding tethered ligands add topological interactions to the toolbox of ligand-receptor design.

    PubMed

    Bauer, Martin; Kékicheff, Patrick; Iss, Jean; Fajolles, Christophe; Charitat, Thierry; Daillant, Jean; Marques, Carlos M

    2015-09-09

    Adhesion in the biological realm is mediated by specific lock-and-key interactions between ligand-receptor pairs. These complementary moieties are ubiquitously anchored to substrates by tethers that control the interaction range and the mobility of the ligands and receptors, thus tuning the kinetics and strength of the binding events. Here we add sliding anchoring to the toolbox of ligand-receptor design by developing a family of tethered ligands for which the spacer can slide at the anchoring point. Our results show that this additional sliding degree of freedom changes the nature of the adhesive contact by extending the spatial range over which binding may sustain a significant force. By introducing sliding tethered ligands with self-regulating length, this work paves the way for the development of versatile and reusable bio-adhesive substrates with potential applications for drug delivery and tissue engineering.

  18. A General Ligand Design for Gold Catalysis allowing Ligand-Directed Anti Nucleophilic Attack of Alkynes

    PubMed Central

    Wang, Yanzhao; Wang, Zhixun; Li, Yuxue; Wu, Gongde; Cao, Zheng; Zhang, Liming

    2014-01-01

    Most homogenous gold catalyses demand ≥0.5 mol % catalyst loading. Due to the high cost of gold, these reactions are unlikely to be applicable in medium or large scale applications. Here we disclose a novel ligand design based on the privileged biphenyl-2-phosphine framework that offers a potentially general approach to dramatically lowering catalyst loading. In this design, an amide group at the 3’ position of the ligand framework directs and promotes nucleophilic attack at the ligand gold complex-activated alkyne, which is unprecedented in homogeneous gold catalysis considering the spatial challenge of using ligand to reach antiapproaching nucleophile in a linear P-Au-alkyne centroid structure. With such a ligand, the gold(I) complex becomes highly efficient in catalyzing acid addition to alkynes, with a turnover number up to 99,000. Density functional theory calculations support the role of the amide moiety in directing the attack of carboxylic acid via hydrogen bonding. PMID:24704803

  19. Cationic ruthenium alkylidene catalysts bearing phosphine ligands.

    PubMed

    Endo, Koji; Grubbs, Robert H

    2016-02-28

    The discovery of highly active catalysts and the success of ionic liquid immobilized systems have accelerated attention to a new class of cationic metathesis catalysts. We herein report the facile syntheses of cationic ruthenium catalysts bearing bulky phosphine ligands. Simple ligand exchange using silver(i) salts of non-coordinating or weakly coordinating anions provided either PPh3 or chelating Ph2P(CH2)nPPh2 (n = 2 or 3) ligated cationic catalysts. The structures of these newly reported catalysts feature unique geometries caused by ligation of the bulky phosphine ligands. Their activities and selectivities in standard metathesis reactions were also investigated. These cationic ruthenium alkylidene catalysts reported here showed moderate activity and very similar stereoselectivity when compared to the second generation ruthenium dichloride catalyst in ring-closing metathesis, cross metathesis, and ring-opening metathesis polymerization assays.

  20. Efficient chemoenzymatic synthesis of chiral pincer ligands.

    PubMed

    Felluga, Fulvia; Baratta, Walter; Fanfoni, Lidia; Pitacco, Giuliana; Rigo, Pierluigi; Benedetti, Fabio

    2009-05-01

    Chiral, nonracemic pincer ligands based on the 6-phenyl-2-aminomethylpyridine and 2-aminomethylbenzo[h]quinoline scaffolds were obtained by a chemoenzymatic approach starting from 2-pyridyl and 2-benzoquinolyl ethanone. In the enantiodifferentiating step, secondary alcohols of opposite absolute configuration were obtained by a baker's yeast reduction of the ketones and by lipase-mediated dynamic kinetic resolution of the racemic alcohols. Their transformation into homochiral 1-methyl-1-heteroarylethanamines occurred without loss of optical purity, giving access to pincer ligands used in enantioselective catalysis.

  1. Ligand Intermediates in Metal-Catalyzed Reactions

    SciTech Connect

    Gladysz, John A.

    1999-07-31

    The longest-running goal of this project has been the synthesis, isolation, and physical chemical characterization of homogeneous transition metal complexes containing ligand types believed to be intermediates in the metal-catalyzed conversion of CO/H{sub 2}, CO{sub 2}, CH{sub 4}, and similar raw materials to organic fuels, feedstocks, etc. In the current project period, complexes that contain unusual new types of C{sub x}(carbide) and C{sub x}O{sub y} (carbon oxide) ligands have been emphasized. A new program in homogeneous fluorous phase catalysis has been launched as described in the final report.

  2. Assessment of automatic ligand building in ARP/wARP

    PubMed Central

    Evrard, Guillaume X.; Langer, Gerrit G.; Perrakis, Anastassis; Lamzin, Victor S.

    2007-01-01

    The efficiency of the ligand-building module of ARP/wARP version 6.1 has been assessed through extensive tests on a large variety of protein–ligand complexes from the PDB, as available from the Uppsala Electron Density Server. Ligand building in ARP/wARP involves two main steps: automatic identification of the location of the ligand and the actual construction of its atomic model. The first step is most successful for large ligands. The second step, ligand construction, is more powerful with X-ray data at high resolution and ligands of small to medium size. Both steps are successful for ligands with low to moderate atomic displacement parameters. The results highlight the strengths and weaknesses of both the method of ligand building and the large-scale validation procedure and help to identify means of further improvement. PMID:17164533

  3. Assessment of automatic ligand building in ARP/wARP.

    PubMed

    Evrard, Guillaume X; Langer, Gerrit G; Perrakis, Anastassis; Lamzin, Victor S

    2007-01-01

    The efficiency of the ligand-building module of ARP/wARP version 6.1 has been assessed through extensive tests on a large variety of protein-ligand complexes from the PDB, as available from the Uppsala Electron Density Server. Ligand building in ARP/wARP involves two main steps: automatic identification of the location of the ligand and the actual construction of its atomic model. The first step is most successful for large ligands. The second step, ligand construction, is more powerful with X-ray data at high resolution and ligands of small to medium size. Both steps are successful for ligands with low to moderate atomic displacement parameters. The results highlight the strengths and weaknesses of both the method of ligand building and the large-scale validation procedure and help to identify means of further improvement.

  4. Ligand expansion in ligand-based virtual screening using relevance feedback

    NASA Astrophysics Data System (ADS)

    Abdo, Ammar; Saeed, Faisal; Hamza, Hentabli; Ahmed, Ali; Salim, Naomie

    2012-03-01

    Query expansion is the process of reformulating an original query to improve retrieval performance in information retrieval systems. Relevance feedback is one of the most useful query modification techniques in information retrieval systems. In this paper, we introduce query expansion into ligand-based virtual screening (LBVS) using the relevance feedback technique. In this approach, a few high-ranking molecules of unknown activity are filtered from the outputs of a Bayesian inference network based on a single ligand molecule to form a set of ligand molecules. This set of ligand molecules is used to form a new ligand molecule. Simulated virtual screening experiments with the MDL Drug Data Report and maximum unbiased validation data sets show that the use of ligand expansion provides a very simple way of improving the LBVS, especially when the active molecules being sought have a high degree of structural heterogeneity. However, the effectiveness of the ligand expansion is slightly less when structurally-homogeneous sets of actives are being sought.

  5. CLiBE: a database of computed ligand binding energy for ligand-receptor complexes.

    PubMed

    Chen, X; Ji, Z L; Zhi, D G; Chen, Y Z

    2002-11-01

    Consideration of binding competitiveness of a drug candidate against natural ligands and other drugs that bind to the same receptor site may facilitate the rational development of a candidate into a potent drug. A strategy that can be applied to computer-aided drug design is to evaluate ligand-receptor interaction energy or other scoring functions of a designed drug with that of the relevant ligands known to bind to the same binding site. As a tool to facilitate such a strategy, a database of ligand-receptor interaction energy is developed from known ligand-receptor 3D structural entries in the Protein Databank (PDB). The Energy is computed based on a molecular mechanics force field that has been used in the prediction of therapeutic and toxicity targets of drugs. This database also contains information about ligand function and other properties and it can be accessed at http://xin.cz3.nus.edu.sg/group/CLiBE.asp. The computed energy components may facilitate the probing of the mode of action and other profiles of binding. A number of computed energies of some PDB ligand-receptor complexes in this database are studied and compared to experimental binding affinity. A certain degree of correlation between the computed energy and experimental binding affinity is found, which suggests that the computed energy may be useful in facilitating a qualitative analysis of drug binding competitiveness.

  6. Optimizing electrostatic affinity in ligand-receptor binding: Theory, computation, and ligand properties

    NASA Astrophysics Data System (ADS)

    Kangas, Erik; Tidor, Bruce

    1998-11-01

    The design of a tight-binding molecular ligand involves a tradeoff between an unfavorable electrostatic desolvation penalty incurred when the ligand binds a receptor in aqueous solution and the generally favorable intermolecular interactions made in the bound state. Using continuum electrostatic models we have developed a theoretical framework for analyzing this problem and have shown that the ligand-charge distribution can be optimized to produce the most favorable balance of these opposing free energy contributions [L.-P. Lee and B. Tidor, J. Chem. Phys. 106, 8681 (1997)]. Herein the theoretical framework is extended and calculations are performed for a wide range of model receptors. We examine methods for computing optimal ligands (including cases where there is conformational change) and the resulting properties of optimized ligands. In particular, indicators are developed to aid in the determination of the deficiencies in a specific ligand or basis. A connection is established between the optimization problem here and a generalized image problem, from which an inverse-image basis set can be defined; this basis is shown to perform very well in optimization calculations. Furthermore, the optimized ligands are shown to have favorable electrostatic binding free energies (in contrast to many natural ligands), there is a strong correlation between the receptor desolvation penalty and the optimized binding free energy for fixed geometry, and the ligand and receptor cannot generally be mutually optimal. Additionally, we introduce the display of complementary desolvation and interaction potentials and the deviation of their relationship from ideal as a useful tool for judging effective complementarity. Scripts for computing and displaying these potentials with GRASP are available at http://mit.edu/tidor.

  7. [Kinetics of ligand binding to nucleic acids at random fillings].

    PubMed

    Arakelian, V B; Babaian, S Iu; Tairian, V I; Arakelian, A V; Parsadanian, M A; Vardevanian, P O

    2006-01-01

    Ligand binding with nucleic acids is described in frames of the theory of random processes. It is shown that the probabilistic description of binding of a ligand to nucleic acid allows one to describe not only the kinetics of changes in the number of bound ligands at arbitrary fillings but also to calculate stationary values of the number of bound ligands and its dispersion. A general analysis of absorption isotherms and the kinetics of ligand binding with nucleic acids allows one to determine the rate constants of formation and decomposition of the ligand-nucleic acid complex. A comparison of the results obtained with the case of low fillings is conducted.

  8. Solar energy conversion through ligand photodissociation

    SciTech Connect

    Hoffman, B.M.; Sima, P.D.

    1983-04-06

    A new technique for photochemical conversion of solar energy based on ligand photodissociation from metal complexes is examined. The concept is illustrated with a photogalvanic cell in which voltages are generated by photodissociation of CO from carbonylferroheme and with a cell in which the illuminated electrode is coated with an iron tetraphenylporphyrin.

  9. Identification of ligands for bacterial sensor proteins.

    PubMed

    Fernández, Matilde; Morel, Bertrand; Corral-Lugo, Andrés; Rico-Jiménez, Miriam; Martín-Mora, David; López-Farfán, Diana; Reyes-Darias, José Antonio; Matilla, Miguel A; Ortega, Álvaro; Krell, Tino

    2016-02-01

    Bacteria have evolved a variety of different signal transduction mechanisms. However, the cognate signal molecule for the very large amount of corresponding sensor proteins is unknown and their functional annotation represents a major bottleneck in the field of signal transduction. The knowledge of the signal molecule is an essential prerequisite to understand the signalling mechanisms. Recently, the identification of signal molecules by the high-throughput protein screening of commercially available ligand collections using differential scanning fluorimetry has shown promise to resolve this bottleneck. Based on the analysis of a significant number of different ligand binding domains (LBDs) in our laboratory, we identified two issues that need to be taken into account in the experimental design. Since a number of LBDs require the dimeric state for ligand recognition, it has to be assured that the protein analysed is indeed in the dimeric form. A number of other examples demonstrate that purified LBDs can contain bound ligand which prevents further binding. In such cases, the apo-form can be generated by denaturation and subsequent refolding. We are convinced that this approach will accelerate the functional annotation of sensor proteins which will help to understand regulatory circuits in bacteria.

  10. [Functional selectivity of opioid receptors ligands].

    PubMed

    Audet, Nicolas; Archer-Lahlou, Elodie; Richard-Lalonde, Mélissa; Piñeyro-Filpo, Graciela

    2010-01-01

    Opiates are the most effective analgesics available for the treatment of severe pain. However, their clinical use is restricted by unwanted side effects such as tolerance, physical dependence and respiratory depression. The strategy to develop new opiates with reduced side effects has mainly focused on the study and production of ligands that specifically bind to different opiate receptors subtypes. However, this strategy has not allowed the production of novel therapeutic ligands with a better side effects profile. Thus, other research strategies need to be explored. One which is receiving increasing attention is the possibility of exploiting ligand ability to stabilize different receptor conformations with distinct signalling profiles. This newly described property, termed functional selectivity, provides a potential means of directing the stimulus generated by an activated receptor towards a specific cellular response. Here we summarize evidence supporting the existence of ligand-specific active conformations for two opioid receptors subtypes (delta and mu), and analyze how functional selectivity may contribute in the production of longer lasting, better tolerated opiate analgesics. double dagger.

  11. Cooperative Ligand Binding to Linear Chain Molecules

    ERIC Educational Resources Information Center

    Applequist, Jon

    1977-01-01

    Summarizes the Ising model of ligand binding as it applies to cooperative binding to long chain molecules. Also presents some illustrations which help to visualize the connection between the interaction parameters and the shape of the binding isotherm. (Author/MR)

  12. [Central effects of ORL1 receptor ligands].

    PubMed

    Maslov, L N; Lishmanov, Iu B; Calo, G; Ma, L

    2003-01-01

    It has been discussed literature data on molecular structure of ORL1 receptor and its interaction with intracellular signal systems and neurotransmitters. Data on chemical structure of ORL1 receptor ligands and their central effects (nociception, locomotion, feeding, cognition) are presented.

  13. CXCR3 ligands in disease and therapy.

    PubMed

    Van Raemdonck, Katrien; Van den Steen, Philippe E; Liekens, Sandra; Van Damme, Jo; Struyf, Sofie

    2015-06-01

    Chemokines, binding their various G protein-coupled receptors, lead the way for leukocytes in health and inflammation. Yet chemokine receptor expression is not limited to leukocytes. Accordingly, chemokines are remarkably pleiotropic molecules involved in a range of physiological as well as pathological processes. For example, the CXCR3 chemokine receptor is expressed on activated T lymphocytes, dendritic cells and natural killer cells, but also fibroblasts and smooth muscle, epithelial and endothelial cells. In men, these cells express either CXCR3A, its splice variant CXCR3B or a balanced combination of both. The CXCR3 ligands, activating both receptor variants, include CXCL4, CXCL4L1, CXCL9, CXCL10 and CXCL11. Upon CXCR3A activation these ELR-negative CXC chemokines mediate chemotactic and proliferative responses, for example in leukocytes. In contrast, CXCR3B induces anti-proliferative and anti-migratory effects, as exemplified by angiostatic effects on endothelial cells. Taken together, the unusual and versatile characteristics of CXCR3 and its ligands form the basis for their pertinent involvement in a myriad of diseases. In this review, we discuss the presence and function of all CXCR3 ligands in various malignant, angiogenic, infectious, inflammatory and other disorders. By extension, we have also elaborated on the potential therapeutic applicability of CXCR3 ligand administration or blockade, as well as their additional value as predictive or prognostic biomarkers. This review illustrates the multifunctional, intriguing character of the various CXCR3-binding chemokines.

  14. Ligand iron catalysts for selective hydrogenation

    DOEpatents

    Casey, Charles P.; Guan, Hairong

    2010-11-16

    Disclosed are iron ligand catalysts for selective hydrogenation of aldehydes, ketones and imines. A catalyst such as dicarbonyl iron hydride hydroxycyclopentadiene) complex uses the OH on the five member ring and hydrogen linked to the iron to facilitate hydrogenation reactions, particularly in the presence of hydrogen gas.

  15. I. Enabling Single-Chain Surfactants to Form Vesicles by Nonamphiphilic Liquid Crystals in Water II. Controlling Attachment and Ligand-Mediated Adherence of Candida albicans on Monolayers

    NASA Astrophysics Data System (ADS)

    Varghese, Nisha

    . Adhesion of C. albicans to a surface is a complex process and is governed by nonspecific attachment or multiple ligand-receptor interactions. The work demonstrates that the multiple ligand-receptor interactions used by C. albicans for adherence to a surface can be individually studied using self-assembled monolayers (SAMs) decorated with minimal motif of the ligands. The SAMs were also used to differentiate between the interactions of the two different morphological forms of C. albicans.. Chapter 5 presents a study on small molecules that were used to inhibit biofilm formed by C. albicans. The acyclic triazoles used in the study were not toxic to the C. albicans and were capable of inhibiting biofilm formed by C. albicans. The acyclic triazole can be used as promising candidates to design new antifungal agents. The chapter also reports the synthesis of squarylated homoserine lactones (SHLs) structural mimics of bacterial acyl homoserine lactones (AHLs) to study the inhibitory effects of SHLs on fungal biofilm. The bacterial AHLs are known to repress the growth of C. albicans and control fungal biofilm in native host environment. The synthesized SHLs were non-toxic to C. albicans and failed to inhibit biofilm formed by C. albicans. . Chapter 6 uses gradient nanotopography combined with controlled surface chemistry to confine bacterial biofilm formed by Escherichia coli. The E. coli biofilm were confined within micrometer sized regions of hydrophobic SAMs surrounded by polyol-terminated SAMs. The study reveals that surface with higher topography enhances the ability of the bioinert SAMs to resist bacterial adherence to surface.

  16. Ammonia formation by metal-ligand cooperative hydrogenolysis of a nitrido ligand

    NASA Astrophysics Data System (ADS)

    Askevold, Bjorn; Nieto, Jorge Torres; Tussupbayev, Samat; Diefenbach, Martin; Herdtweck, Eberhardt; Holthausen, Max C.; Schneider, Sven

    2011-07-01

    Bioinspired hydrogenation of N2 to ammonia at ambient conditions by stepwise nitrogen protonation/reduction with metal complexes in solution has experienced remarkable progress. In contrast, the highly desirable direct hydrogenation with H2 remains difficult. In analogy to the heterogeneously catalysed Haber-Bosch process, such a reaction is conceivable via metal-centred N2 splitting and unprecedented hydrogenolysis of the nitrido ligands to ammonia. We report the synthesis of a ruthenium(IV) nitrido complex. The high nucleophilicity of the nitrido ligand is demonstrated by unusual N-C coupling with π-acidic CO. Furthermore, the terminal nitrido ligand undergoes facile hydrogenolysis with H2 at ambient conditions to produce ammonia in high yield. Kinetic and quantum chemical examinations of this reaction suggest cooperative behaviour of a phosphorus-nitrogen-phosphorus pincer ligand in rate-determining heterolytic hydrogen splitting.

  17. Thermodynamic proton-ligand and metal-ligand stability constants of some drugs.

    PubMed

    Agrawal, Y K; Patel, D R

    1986-02-01

    The thermodynamic proton-ligand (pKa) and metal-ligand stability constants of clioquinol, clofibrate, nitrofurazone, and tetracycline with Cu2+, Zn2+, Mn2+, Mg2+, and Ca2+ have been determined at 35 degrees C in 50% ethanol-water media. An empirical pH correction for mixed-aqueous media has been applied. The metal-ligand stability constants were determined by following the Bjerrum Calvin titration technique as applied by Agrawal to mixed-aqueous solvents. The effect of the basicity of the ligand and the order of stability constants is discussed. The stability constants of the divalent metals follow the order: Cu2+ greater than Zn2+ greater than Mn2+ greater than Mg2+ greater than Ca2+ with all the drugs.

  18. Dissociation of Multisubunit Protein-Ligand Complexes in the Gas Phase. Evidence for Ligand Migration

    NASA Astrophysics Data System (ADS)

    Zhang, Yixuan; Deng, Lu; Kitova, Elena N.; Klassen, John S.

    2013-10-01

    The results of collision-induced dissociation (CID) experiments performed on gaseous protonated and deprotonated ions of complexes of cholera toxin B subunit homopentamer (CTB5) with the pentasaccharide (β-D-Gal p-(1→3)-β-D-Gal pNAc-(1→4)[α-D-Neu5Ac-(2→3)]-β-D-Gal p-(1→4)-β-D-Glc p (GM1)) and corresponding glycosphingolipid (β-D-Gal p-(1→3)-β-D-Gal pNAc-(1→4)[α-D-Neu5Ac-(2→3)]-β-D-Gal p-(1→4)-β-D-Glc p-Cer (GM1-Cer)) ligands, and the homotetramer streptavidin (S4) with biotin (B) and 1,2-dipalmitoyl- sn-glycero-3-phosphoethanolamine-N-(biotinyl) (Btl), are reported. The protonated (CTB5 + 5GM1)n+ ions dissociated predominantly by the loss of a single subunit, with the concomitant migration of ligand to another subunit. The simultaneous loss of ligand and subunit was observed as a minor pathway. In contrast, the deprotonated (CTB5 + 5GM1)n- ions dissociated preferentially by the loss of deprotonated ligand; the loss of ligand-bound and ligand-free subunit were minor pathways. The presence of ceramide (Cer) promoted ligand migration and the loss of subunit. The main dissociation pathway for the protonated and deprotonated (S4 + 4B)n+/- ions, as well as for deprotonated (S4 + 4Btl)n- ions, was loss of the ligand. However, subunit loss from the (S4 + 4B)n+ ions was observed as a minor pathway. The (S4 + 4Btl)n+ ions dissociated predominantly by the loss of free and ligand-bound subunit. The charge state of the complex and the collision energy were found to have little effect on the relative contribution of the different dissociation channels. Thermally-driven ligand migration between subunits was captured in the results of molecular dynamics simulations performed on protonated (CTB5 + 5GM1)15+ ions (with a range of charge configurations) at 800 K. Notably, the migration pathway was found to be highly dependent on the charge configuration of the ion. The main conclusion of this study is that the dissociation pathways of multisubunit protein-ligand

  19. Quantum.Ligand.Dock: protein–ligand docking with quantum entanglement refinement on a GPU system

    PubMed Central

    Kantardjiev, Alexander A.

    2012-01-01

    Quantum.Ligand.Dock (protein–ligand docking with graphic processing unit (GPU) quantum entanglement refinement on a GPU system) is an original modern method for in silico prediction of protein–ligand interactions via high-performance docking code. The main flavour of our approach is a combination of fast search with a special account for overlooked physical interactions. On the one hand, we take care of self-consistency and proton equilibria mutual effects of docking partners. On the other hand, Quantum.Ligand.Dock is the the only docking server offering such a subtle supplement to protein docking algorithms as quantum entanglement contributions. The motivation for development and proposition of the method to the community hinges upon two arguments—the fundamental importance of quantum entanglement contribution in molecular interaction and the realistic possibility to implement it by the availability of supercomputing power. The implementation of sophisticated quantum methods is made possible by parallelization at several bottlenecks on a GPU supercomputer. The high-performance implementation will be of use for large-scale virtual screening projects, structural bioinformatics, systems biology and fundamental research in understanding protein–ligand recognition. The design of the interface is focused on feasibility and ease of use. Protein and ligand molecule structures are supposed to be submitted as atomic coordinate files in PDB format. A customization section is offered for addition of user-specified charges, extra ionogenic groups with intrinsic pKa values or fixed ions. Final predicted complexes are ranked according to obtained scores and provided in PDB format as well as interactive visualization in a molecular viewer. Quantum.Ligand.Dock server can be accessed at http://87.116.85.141/LigandDock.html. PMID:22669908

  20. Quantum.Ligand.Dock: protein-ligand docking with quantum entanglement refinement on a GPU system.

    PubMed

    Kantardjiev, Alexander A

    2012-07-01

    Quantum.Ligand.Dock (protein-ligand docking with graphic processing unit (GPU) quantum entanglement refinement on a GPU system) is an original modern method for in silico prediction of protein-ligand interactions via high-performance docking code. The main flavour of our approach is a combination of fast search with a special account for overlooked physical interactions. On the one hand, we take care of self-consistency and proton equilibria mutual effects of docking partners. On the other hand, Quantum.Ligand.Dock is the the only docking server offering such a subtle supplement to protein docking algorithms as quantum entanglement contributions. The motivation for development and proposition of the method to the community hinges upon two arguments-the fundamental importance of quantum entanglement contribution in molecular interaction and the realistic possibility to implement it by the availability of supercomputing power. The implementation of sophisticated quantum methods is made possible by parallelization at several bottlenecks on a GPU supercomputer. The high-performance implementation will be of use for large-scale virtual screening projects, structural bioinformatics, systems biology and fundamental research in understanding protein-ligand recognition. The design of the interface is focused on feasibility and ease of use. Protein and ligand molecule structures are supposed to be submitted as atomic coordinate files in PDB format. A customization section is offered for addition of user-specified charges, extra ionogenic groups with intrinsic pK(a) values or fixed ions. Final predicted complexes are ranked according to obtained scores and provided in PDB format as well as interactive visualization in a molecular viewer. Quantum.Ligand.Dock server can be accessed at http://87.116.85.141/LigandDock.html.

  1. All-inorganic Germanium nanocrystal films by cationic ligand exchange

    DOE PAGES

    Wheeler, Lance M.; Nichols, Asa W.; Chernomordik, Boris D.; ...

    2016-01-21

    In this study, we introduce a new paradigm for group IV nanocrystal surface chemistry based on room temperature surface activation that enables ionic ligand exchange. Germanium nanocrystals synthesized in a gas-phase plasma reactor are functionalized with labile, cationic alkylammonium ligands rather than with traditional covalently bound groups. We employ Fourier transform infrared and 1H nuclear magnetic resonance spectroscopies to demonstrate the alkylammonium ligands are freely exchanged on the germanium nanocrystal surface with a variety of cationic ligands, including short inorganic ligands such as ammonium and alkali metal cations. This ionic ligand exchange chemistry is used to demonstrate enhanced transport inmore » germanium nanocrystal films following ligand exchange as well as the first photovoltaic device based on an all-inorganic germanium nanocrystal absorber layer cast from solution. This new ligand chemistry should accelerate progress in utilizing germanium and other group IV nanocrystals for optoelectronic applications.« less

  2. All-Inorganic Germanium Nanocrystal Films by Cationic Ligand Exchange.

    PubMed

    Wheeler, Lance M; Nichols, Asa W; Chernomordik, Boris D; Anderson, Nicholas C; Beard, Matthew C; Neale, Nathan R

    2016-03-09

    We introduce a new paradigm for group IV nanocrystal surface chemistry based on room temperature surface activation that enables ionic ligand exchange. Germanium nanocrystals synthesized in a gas-phase plasma reactor are functionalized with labile, cationic alkylammonium ligands rather than with traditional covalently bound groups. We employ Fourier transform infrared and (1)H nuclear magnetic resonance spectroscopies to demonstrate the alkylammonium ligands are freely exchanged on the germanium nanocrystal surface with a variety of cationic ligands, including short inorganic ligands such as ammonium and alkali metal cations. This ionic ligand exchange chemistry is used to demonstrate enhanced transport in germanium nanocrystal films following ligand exchange as well as the first photovoltaic device based on an all-inorganic germanium nanocrystal absorber layer cast from solution. This new ligand chemistry should accelerate progress in utilizing germanium and other group IV nanocrystals for optoelectronic applications.

  3. All-inorganic Germanium nanocrystal films by cationic ligand exchange

    SciTech Connect

    Wheeler, Lance M.; Nichols, Asa W.; Chernomordik, Boris D.; Anderson, Nicholas C.; Beard, Matthew C.; Neale, Nathan R.

    2016-01-21

    In this study, we introduce a new paradigm for group IV nanocrystal surface chemistry based on room temperature surface activation that enables ionic ligand exchange. Germanium nanocrystals synthesized in a gas-phase plasma reactor are functionalized with labile, cationic alkylammonium ligands rather than with traditional covalently bound groups. We employ Fourier transform infrared and 1H nuclear magnetic resonance spectroscopies to demonstrate the alkylammonium ligands are freely exchanged on the germanium nanocrystal surface with a variety of cationic ligands, including short inorganic ligands such as ammonium and alkali metal cations. This ionic ligand exchange chemistry is used to demonstrate enhanced transport in germanium nanocrystal films following ligand exchange as well as the first photovoltaic device based on an all-inorganic germanium nanocrystal absorber layer cast from solution. This new ligand chemistry should accelerate progress in utilizing germanium and other group IV nanocrystals for optoelectronic applications.

  4. Affinity Regulates Spatial Range of EGF Receptor Autocrine Ligand Binding

    SciTech Connect

    Dewitt, Ann; Iida, Tomoko; Lam, Ho-Yan; Hill, Virginia; Wiley, H S.; Lauffenburger, Douglas A.

    2002-08-08

    Proper spatial localization of EGFR signaling activated by autocrine ligands represents a critical factor in embryonic development as well as tissue organization and function, and ligand/receptor binding affinity is among the molecular and cellular properties suggested to play a role in governing this localization. The authors employ a computational model to predict how receptor-binding affinity affects local capture of autocrine ligand vis-a-vis escape to distal regions, and provide experimental test by constructing cell lines expressing EGFR along with either wild-type EGF or a low-affinity mutant, EGF{sup L47M}. The model predicts local capture of a lower affinity autocrine ligand to be less efficient when the ligand production rate is small relative to receptor appearance rate. The experimental data confirm this prediction, demonstrating that cells can use ligand/receptor binding affinity to regulate ligand spatial distribution when autocrine ligand production is limiting for receptor signaling.

  5. Fusion of ligand-coated nanoparticles with lipid bilayers: effect of ligand flexibility.

    PubMed

    Van Lehn, Reid C; Alexander-Katz, Alfredo

    2014-08-07

    Amphiphilic, monolayer-protected gold nanoparticles (AuNPs) have recently been shown to insert into and fuse with lipid bilayers, driven by the hydrophobic effect. The inserted transmembrane state is stabilized by the "snorkeling" of charged ligand end groups out of the bilayer interior. This snorkeling process is facilitated by the backbone flexibility of the alkanethiol ligands that comprise the monolayer. In this work, we show that fusion is favorable even in the absence of backbone flexibility by modeling the ligands as rigid rods. For rigid ligands, snorkeling is still accommodated by rotations of the ligand with respect to the grafting point, but the process incurs a more significant free energy penalty than if the backbone were fully flexible. We show that the rigid rod model predicts similar trends in the free energy change for insertion as the previous flexible model when the size of the AuNPs is varied. However, the rigidity of the ligand backbone reduces the overall magnitude of the free energy change compared to that of the flexible model. These results thus generalize previous findings to systems with hindered backbone flexibility due to either structural constraints or low temperature.

  6. Amino Acids in Nine Ligand-Prefer Ramachandran Regions.

    PubMed

    Cao, Chen; Wang, Lincong; Chen, Xiaoyang; Zou, Shuxue; Wang, Guishen; Xu, Shutan

    2015-01-01

    Several secondary structures, such as π-helix and left-handed helix, have been frequently identified at protein ligand-binding sites. A secondary structure is considered to be constrained to a specific region of dihedral angles. However, a comprehensive analysis of the correlation between main chain dihedral angles and ligand-binding sites has not been performed. We undertook an extensive analysis of the relationship between dihedral angles in proteins and their distance to ligand-binding sites, frequency of occurrence, molecular potential energy, amino acid composition, van der Waals contacts, and hydrogen bonds with ligands. The results showed that the values of dihedral angles have a strong preference for ligand-binding sites at certain regions in the Ramachandran plot. We discovered that amino acids preceding the ligand-prefer ϕ/ψ box residues are exposed more to solvents, whereas amino acids following ligand-prefer ϕ/ψ box residues form more hydrogen bonds and van der Waals contacts with ligands. Our method exhibited a similar performance compared with the program Ligsite-csc for both ligand-bound structures and ligand-free structures when just one ligand-binding site was predicted. These results should be useful for the prediction of protein ligand-binding sites and for analysing the relationship between structure and function.

  7. Evaluation of novel acyclic nucleoside phosphonates against human and animal gammaherpesviruses revealed an altered metabolism of cyclic prodrugs upon Epstein-Barr virus reactivation in P3HR-1 cells.

    PubMed

    Coen, Natacha; Duraffour, Sophie; Naesens, Lieve; Krecmerová, Marcela; Van den Oord, Joost; Snoeck, Robert; Andrei, Graciela

    2013-11-01

    Acyclic nucleoside phosphonates (ANPs), such as (S)-1-[(3-hydroxy-2-phosphonomethoxy)propyl)]cytosine (HPMPC), are an important group of broad-spectrum antiviral agents with activity against DNA viruses. In this report, we present the in vitro potencies of novel ANPs against gammaherpesviruses, including Kaposi's sarcoma-associated herpesvirus, Epstein-Barr virus (EBV), and three animal gammaherpesviruses. 1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine (HPMP-5-azaC), (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]-3-deazaadenine (3-deaza-HPMPA), and their cyclic derivatives have emerged as highly potent antigammaherpesvirus agents. Interestingly, cyclic prodrugs of ANPs exhibited reduced activities against EBV strain P3HR-1, but not against EBV strain Akata. Cell culture metabolism studies with HPMPC and cyclic HPMPC revealed that these differences were attributable to an altered drug metabolism in P3HR-1 cells after EBV reactivation and, more specifically, to a reduced hydrolysis of cyclic HPMPC by cyclic CMP phosphodiesterase. We did not correlate this effect with phosphodiesterase downregulation, or to functional mutations. Instead, altered cyclic AMP levels in P3HR-1 cells indicated a competitive inhibition of the phosphodiesterase by this cyclic nucleotide. Finally, both HPMPC and HPMP-5-azaC emerged as highly effective inhibitors in vivo through significant inhibition of murine gammaherpesvirus replication and dissemination. With the current need for potent antigammaherpesvirus agents, our findings underline the requirement of appropriate surrogate viruses for antiviral susceptibility testing and highlight HPMP-5-azaC as a promising compound for future clinical development.

  8. Enhanced Ligand Sampling for Relative Protein–Ligand Binding Free Energy Calculations

    PubMed Central

    2016-01-01

    Free energy calculations are used to study how strongly potential drug molecules interact with their target receptors. The accuracy of these calculations depends on the accuracy of the molecular dynamics (MD) force field as well as proper sampling of the major conformations of each molecule. However, proper sampling of ligand conformations can be difficult when there are large barriers separating the major ligand conformations. An example of this is for ligands with an asymmetrically substituted phenyl ring, where the presence of protein loops hinders the proper sampling of the different ring conformations. These ring conformations become more difficult to sample when the size of the functional groups attached to the ring increases. The Adaptive Integration Method (AIM) has been developed, which adaptively changes the alchemical coupling parameter λ during the MD simulation so that conformations sampled at one λ can aid sampling at the other λ values. The Accelerated Adaptive Integration Method (AcclAIM) builds on AIM by lowering potential barriers for specific degrees of freedom at intermediate λ values. However, these methods may not work when there are very large barriers separating the major ligand conformations. In this work, we describe a modification to AIM that improves sampling of the different ring conformations, even when there is a very large barrier between them. This method combines AIM with conformational Monte Carlo sampling, giving improved convergence of ring populations and the resulting free energy. This method, called AIM/MC, is applied to study the relative binding free energy for a pair of ligands that bind to thrombin and a different pair of ligands that bind to aspartyl protease β-APP cleaving enzyme 1 (BACE1). These protein–ligand binding free energy calculations illustrate the improvements in conformational sampling and the convergence of the free energy compared to both AIM and AcclAIM. PMID:25906170

  9. Protein-ligand binding affinity determination by the waterLOGSY method: An optimised approach considering ligand rebinding

    PubMed Central

    Huang, Renjie; Bonnichon, Arnaud; Claridge, Timothy D. W.; Leung, Ivanhoe K. H.

    2017-01-01

    WaterLOGSY is a popular ligand-observed NMR technique to screen for protein-ligand interactions, yet when applied to measure dissociation constants (KD) through ligand titration, the results were found to be strongly dependent on sample conditions. Herein, we show that accurate KDs can be obtained by waterLOGSY with optimised experimental setup. PMID:28256624

  10. Protein-ligand binding affinity determination by the waterLOGSY method: An optimised approach considering ligand rebinding

    NASA Astrophysics Data System (ADS)

    Huang, Renjie; Bonnichon, Arnaud; Claridge, Timothy D. W.; Leung, Ivanhoe K. H.

    2017-03-01

    WaterLOGSY is a popular ligand-observed NMR technique to screen for protein-ligand interactions, yet when applied to measure dissociation constants (KD) through ligand titration, the results were found to be strongly dependent on sample conditions. Herein, we show that accurate KDs can be obtained by waterLOGSY with optimised experimental setup.

  11. Diamine Ligands in Copper-Catalyzed Reactions

    PubMed Central

    Surry, David S.

    2012-01-01

    The utility of copper-mediated cross-coupling reactions has been significantly increased by the development of mild reaction conditions and the ability to employ catalytic amounts of copper. The use of diamine-based ligands has been important in these advances and in this review we discuss these systems, including the choice of reaction conditions and applications in the synthesis of pharmaceuticals, natural products and designed materials. PMID:22384310

  12. Container molecules based on imine type ligands.

    PubMed

    Schulze, A Carina; Oppel, Iris M

    2012-01-01

    This chapter will give a short overview about container molecules, their synthesis and possible applications. The main focus is on those which are based on imine type ligands. These containers can be used for example for guest exchange, gas separation, as chemical sensors or for the stabilisation of white phosphorus under water. The described cages have wide openings or tightly closed ones. For one cage the reversible opening and closing is also described.

  13. galectin-3 ligand — EDRN Public Portal

    Cancer.gov

    Galectin-3 is an endogenous lectin that binds glycan epitopes of cell membrane and some extracellular glycoproteins such as integrins and laminin. Galectin-3 is involved in several biological activities including regulation of cellular cycle, modulation of adhesion and tumor progression and metastasis. Serum galectin-3 ligands have been shown to modulate the immune reaction against tumors and viruses and their level increases in sera of several neoplastic diseases.

  14. Selective oxoanion separation using a tripodal ligand

    DOEpatents

    Custelcean, Radu; Moyer, Bruce A.; Rajbanshi, Arbin

    2016-02-16

    The present invention relates to urea-functionalized crystalline capsules self-assembled by sodium or potassium cation coordination and by hydrogen-bonding water bridges to selectively encapsulate tetrahedral divalent oxoanions from highly competitive aqueous alkaline solutions and methods using this system for selective anion separations from industrial solutions. The method involves competitive crystallizations using a tripodal tris(urea) functionalized ligand and, in particular, provides a viable approach to sulfate separation from nuclear wastes.

  15. Gated escaping of ligand out of protein

    NASA Astrophysics Data System (ADS)

    Sheu, Sheh-Yi; Yang, Dah-Yen

    2000-01-01

    We construct a new gating model and develop a new theory to study the escaping process of a ligand out of a spherical cavity with a puncture (or gate) on the surface. The gate undulation can be regulated by any time-dependent function and the motion of the ligand inside the spherical cavity is mapped into a two-dimensional entropy potential surface. Hence the driving force of our model is entropy only. For a static gate, the escaping process corresponds to climbing a two-dimensional entropy barrier. When the gate open angle is small, the escaping rate is proportional to the square of the opening angle. The prefactor of the escaping rate constant depends on the curvature of the entropy potential surface. For coherent gating, the survival time depends not only on the gate undulation frequency but also on how the initial state is defined. On the escaping from protein, our escaping rate shows it is qualitatively consistent with the experimental result of ligand recombination in myoglobin.

  16. RAGE and its ligands in retinal disease.

    PubMed

    Barile, Gaetano R; Schmidt, Ann M

    2007-12-01

    RAGE, the receptor for advanced glycation endproducts (AGEs), is a multiligand signal transduction receptor of the immunoglobulin superfamily of cell surface molecules that has been implicated in the pathogenesis of diabetic complications, neurodegenerative diseases, inflammatory disorders, and cancer. These diverse biologic disorders reflect the multiplicity of ligands capable of cellular interaction via RAGE that include, in addition to AGEs, amyloid-beta (Abeta) peptide, the S100/calgranulin family of proinflammatory cytokines, and amphoterin, a member of the High Mobility Group Box (HMGB) DNA-binding proteins. In the retina, RAGE expression is present in neural cells, the vasculature, and RPE cells, and it has also been detected in pathologic cellular retinal responses including epiretinal and neovascular membrane formation. Ligands for RAGE, in particular AGEs, have emerged as relevant to the pathogenesis of diabetic retinopathy and age-related macular disease. While the understanding of RAGE and its role in retinal dysfunction with aging, diabetes mellitus, and/or activation of pro-inflammatory pathways is less complete compared to other organ systems, increasing evidence indicates that RAGE can initiate and sustain significant cellular perturbations in the inner and outer retina. For these reasons, antagonism of RAGE interactions with its ligands may be a worthwhile therapeutic target in such seemingly disparate, visually threatening retinal diseases as diabetic retinopathy, age-related macular degeneration, and proliferative vitreoretinopathy.

  17. Modeling of the Aryl Hydrocarbon Receptor (AhR) ligand binding domain and its utility in virtual ligand screening to predict new AhR ligands

    PubMed Central

    Bisson, William; Koch, Daniel; O’Donnell, Edmond; Khalil, Sammy M.; Kerkvliet, Nancy; Tanguay, Robert; Abagyan, Ruben; Kolluri, Siva Kumar

    2012-01-01

    The Aryl Hydrocarbon Receptor (AhR) is a ligand-activated transcription factor; the AhR Per-AhR/Arnt-Sim (PAS) domain binds ligands. We developed homology models of the AhR PAS domain to characterize previously observed intra- and inter-species differences in ligand binding using Molecular Docking. In silico structure-based virtual ligand screening using our model resulted in the identification of pinocembrin and 5-hydroxy-7-methoxyflavone, which promoted nuclear translocation and transcriptional activation of AhR and AhR-dependent induction of endogenous target genes. PMID:19719119

  18. Assessment of automatic ligand building in ARP/wARP

    SciTech Connect

    Evrard, Guillaume X. Langer, Gerrit G.; Lamzin, Victor S.

    2007-01-01

    The performance of the ligand-building module of the ARP/wARP software suite is assessed through a large-scale test on known protein–ligand complexes. The results provide a detailed benchmark and guidelines for future improvements. The efficiency of the ligand-building module of ARP/wARP version 6.1 has been assessed through extensive tests on a large variety of protein–ligand complexes from the PDB, as available from the Uppsala Electron Density Server. Ligand building in ARP/wARP involves two main steps: automatic identification of the location of the ligand and the actual construction of its atomic model. The first step is most successful for large ligands. The second step, ligand construction, is more powerful with X-ray data at high resolution and ligands of small to medium size. Both steps are successful for ligands with low to moderate atomic displacement parameters. The results highlight the strengths and weaknesses of both the method of ligand building and the large-scale validation procedure and help to identify means of further improvement.

  19. The Recognition of Identical Ligands by Unrelated Proteins

    PubMed Central

    Barelier, Sarah; Sterling, Teague; O'Meara, Matthew J.; Shoichet, Brian K.

    2015-01-01

    The binding of drugs and reagents to off-targets is well-known. Whereas many off-targets are related to the primary target by sequence and fold, many ligands bind to unrelated pairs of proteins, and these are harder to anticipate. If the binding site in the off-target can be related to that of the primary target, this challenge resolves into aligning the two pockets. However, other cases are possible: the ligand might interact with entirely different residues and environments in the off-target, or wholly different ligand atoms may be implicated in the two complexes. To investigate these scenarios at atomic resolution, the structures of 59 ligands in 116 complexes (62 pairs in total), where the protein pairs were unrelated by fold but bound an identical ligand, were examined. In almost half of the pairs, the ligand interacted with unrelated residues in the two proteins (29 pairs), and in 14 of the pairs wholly different ligand moieties were implicated in each complex. Even in those 19 pairs of complexes that presented similar environments to the ligand, ligand superposition rarely resulted in the overlap of related residues. There appears to be no single pattern-matching “code” for identifying binding sites in unrelated proteins that bind identical ligands, though modeling suggests that there might be a limited number of different patterns that suffice to recognize different ligand functional groups. PMID:26421501

  20. Identification of Ligand-Receptor Interactions: Ligand Molecular Arrays, SPR and NMR Methodologies.

    PubMed

    Day, Christopher J; Hartley-Tassell, Lauren E; Korolik, Victoria

    2017-01-01

    Despite many years of research into bacterial chemotaxis, the only well characterized system to date is that of E. coli. Even for E. coli, the direct ligand binding had been fully characterized only for aspartate and serene receptors Tar and Tsr. In 30 years since, no other direct receptor-ligand interaction had been described for bacteria, until the characterization of the C. jejuni aspartate and multiligand receptors (Hartley-Tassell et al. Mol Microbiol 75:710-730, 2010). While signal transduction components of many sensory pathways have now been characterized, ligand-receptor interactions remain elusive due to paucity of high-throughput screening methods. Here, we describe the use of microarray screening we developed to identify ligands, surface plasmon resonance, and saturation transfer difference nuclear magnetic resonance (STD-NMR) we used to verify the hits and to determine the affinity constants of the interactions, allowing for more targeted verification of ligands with traditional chemotaxis and in vivo assays described in Chapter 13 .

  1. Nanoparticle multivalency counterbalances the ligand affinity loss upon PEGylation.

    PubMed

    Hennig, Robert; Pollinger, Klaus; Veser, Anika; Breunig, Miriam; Goepferich, Achim

    2014-11-28

    The conjugation of receptor ligands to shielded nanoparticles is a widely used strategy to precisely control nanoparticle-cell interactions. However, it is often overlooked that a ligand's affinity can be severely impaired by its attachment to the polyethylene glycol (PEG) chains that are frequently used to protect colloids from serum protein adsorption. Using the model ligand EXP3174, a small-molecule antagonist for the angiotensin II receptor type 1 (AT1R), we investigated the ligand's affinity before and after its PEGylation and when attached to PEGylated nanoparticles. The PEGylated ligand displayed a 580-fold decreased receptor affinity compared to the native ligand. Due to their multivalency, the nanoparticles regained a low nanomolar receptor affinity, which is in the range of the affinity of the native ligand. Moreover, a four orders of magnitude higher concentration of free ligand was required to displace PEGylated nanoparticles carrying EXP3174 from the receptor. On average, one nanoparticle was decorated with 11.2 ligand molecules, which led to a multivalent enhancement factor of 22.5 compared to the monovalent PEGylated ligand. The targeted nanoparticles specifically bound the AT1R and showed no interaction to receptor negative cells. Our study shows that the attachment of a small-molecule ligand to a PEG chain can severely affect its receptor affinity. Concomitantly, when the ligand is tethered to nanoparticles, the immense avidity greatly increases the ligand-receptor interaction. Based on our results, we highly recommend the affinity testing of receptor ligands before and after PEGylation to identify potent molecules for active nanoparticle targeting.

  2. A chemogenomics view on protein-ligand spaces

    PubMed Central

    Strömbergsson, Helena; Kleywegt, Gerard J

    2009-01-01

    Background Chemogenomics is an emerging inter-disciplinary approach to drug discovery that combines traditional ligand-based approaches with biological information on drug targets and lies at the interface of chemistry, biology and informatics. The ultimate goal in chemogenomics is to understand molecular recognition between all possible ligands and all possible drug targets. Protein and ligand space have previously been studied as separate entities, but chemogenomics studies deal with large datasets that cover parts of the joint protein-ligand space. Since drug discovery has traditionally focused on ligand optimization, the chemical space has been studied extensively. The protein space has been studied to some extent, typically for the purpose of classification of proteins into functional and structural classes. Since chemogenomics deals not only with ligands but also with the macromolecules the ligands interact with, it is of interest to find means to explore, compare and visualize protein-ligand subspaces. Results Two chemogenomics protein-ligand interaction datasets were prepared for this study. The first dataset covers the known structural protein-ligand space, and includes all non-redundant protein-ligand interactions found in the worldwide Protein Data Bank (PDB). The second dataset contains all approved drugs and drug targets stored in the DrugBank database, and represents the approved drug-drug target space. To capture biological and physicochemical features of the chemogenomics datasets, sequence-based descriptors were computed for the proteins, and 0, 1 and 2 dimensional descriptors for the ligands. Principal component analysis (PCA) was used to analyze the multidimensional data and to create global models of protein-ligand space. The nearest neighbour method, computed using the principal components, was used to obtain a measure of overlap between the datasets. Conclusion In this study, we present an approach to visualize protein-ligand spaces from a

  3. Evaluation of small ligand-protein interaction by ligation reaction with DNA-modified ligand.

    PubMed

    Sugita, Rie; Mie, Masayasu; Funabashi, Hisakage; Kobatake, Eiry

    2010-01-01

    A method for the evaluation of interactions between protein and ligand using DNA-modified ligands, including signal enhancement of the DNA ligation reactions, is described. For proof of principle, a DNA probe modified by biotin was used. Two DNA probes were prepared with complementary sticky-ends. While one DNA probe was modified at the 5'-end of the sticky-end, the other was not modified. The probes could be ligated together by T4 DNA ligase along the strand without biotin modification. However, in the presence of streptavidin or anti-biotin Fab, the ligation reaction joining the two probes could not occur on either strand.

  4. Landscape of protein–small ligand binding modes

    PubMed Central

    Kinoshita, Kengo

    2016-01-01

    Abstract Elucidating the mechanisms of specific small‐molecule (ligand) recognition by proteins is a long‐standing conundrum. While the structures of these molecules, proteins and ligands, have been extensively studied, protein–ligand interactions, or binding modes, have not been comprehensively analyzed. Although methods for assessing similarities of binding site structures have been extensively developed, the methods for the computational treatment of binding modes have not been well established. Here, we developed a computational method for encoding the information about binding modes as graphs, and assessing their similarities. An all‐against‐all comparison of 20,040 protein–ligand complexes provided the landscape of the protein–ligand binding modes and its relationships with protein‐ and chemical spaces. While similar proteins in the same SCOP Family tend to bind relatively similar ligands with similar binding modes, the correlation between ligand and binding similarities was not very high (R 2 = 0.443). We found many pairs with novel relationships, in which two evolutionally distant proteins recognize dissimilar ligands by similar binding modes (757,474 pairs out of 200,790,780 pairs were categorized into this relationship, in our dataset). In addition, there were an abundance of pairs of homologous proteins binding to similar ligands with different binding modes (68,217 pairs). Our results showed that many interesting relationships between protein–ligand complexes are still hidden in the structure database, and our new method for assessing binding mode similarities is effective to find them. PMID:27327045

  5. Ligand-targeted particulate nanomedicines undergoing clinical evaluation: current status.

    PubMed

    van der Meel, Roy; Vehmeijer, Laurens J C; Kok, Robbert J; Storm, Gert; van Gaal, Ethlinn V B

    2013-10-01

    Since the introduction of Doxil® on the market nearly 20years ago, a number of nanomedicines have become part of treatment regimens in the clinic. With the exception of antibody-drug conjugates, these nanomedicines are all devoid of targeting ligands and rely solely on their physicochemical properties and the (patho)physiological processes in the body for their biodistribution and targeting capability. At the same time, many preclinical studies have reported on nanomedicines exposing targeting ligands, or ligand-targeted nanomedicines, yet none of these have been approved at this moment. In the present review, we provide a concise overview of 13 ligand-targeted particulate nanomedicines (ligand-targeted PNMs) that have progressed into clinical trials. The progress of each ligand-targeted PNM is discussed based on available (pre)clinical data. Main conclusions of these analyses are that (a) ligand-targeted PNMs have proven to be safe and efficacious in preclinical models; (b) the vast majority of ligand-targeted PNMs is generated for the treatment of cancer; (c) contribution of targeting ligands to the PNM efficacy is not unambiguously proven; and (d) targeting ligands do not cause localization of the PNM within the target tissue, but rather provide benefits in terms of target cell internalization and target tissue retention once the PNM has arrived at the target site. Increased understanding of the in vivo fate and interactions of the ligand-targeted PNMs with proteins and cells in the human body is mandatory to rationally advance the clinical translation of ligand-targeted PNMs. Future perspectives for ligand-targeted PNM approaches include the delivery of drugs that are unable or inefficient in passing cellular membranes, treatment of drug resistant tumors, targeting of the tumor blood supply, the generation of targeted vaccines and nanomedicines that are able to cross the blood-brain barrier.

  6. (Ligand intermediates in metal-catalyzed reactions)

    SciTech Connect

    Not Available

    1992-01-01

    This report consists of sections on sigma bond complexes of alkenes, a new carbon-hydrogen bond activation reaction of alkene complexes, carbon-hydrogen bond migrations in alkylidene complexes, carbon- hydrogen bond migrations in alkyne complexes, synthesis, structure and reactivity of C{sub x} complexes, synthesis and reactivity of alcohol and ether complexes, new catalysts for the epimerization of secondary alcohols; carbon-hydrogen bond activation in alkoxide complexes, pi/sigma equilibria in metal/O=CXX' complexes, and other hydrocarbon ligands; miscellaneous.(WET)

  7. Transmutable nanoparticles with reconfigurable surface ligands

    NASA Astrophysics Data System (ADS)

    Kim, Youngeun; Macfarlane, Robert J.; Jones, Matthew R.; Mirkin, Chad A.

    2016-02-01

    Unlike conventional inorganic materials, biological systems are exquisitely adapted to respond to their surroundings. Proteins and other biological molecules can process a complex set of chemical binding events as informational inputs and respond accordingly via a change in structure and function. We applied this principle to the design and synthesis of inorganic materials by preparing nanoparticles with reconfigurable surface ligands, where interparticle bonding can be programmed in response to specific chemical cues in a dynamic manner. As a result, a nascent set of “transmutable nanoparticles” can be driven to crystallize along multiple thermodynamic trajectories, resulting in rational control over the phase and time evolution of nanoparticle-based matter.

  8. Differential Effects of TR Ligands on Hormone Dissociation Rates: Evidence for Multiple Ligand Entry/Exit Pathways

    PubMed Central

    Lima, Suzana T. Cunha; Nguyen, Ngoc-Ha; Togashi, Marie; Apriletti, James W.; Nguyen, Phuong; Polikarpov, Igor; Scanlan, Thomas S.; Baxter, John D.; Webb, Paul

    2009-01-01

    Some nuclear receptor (NR) ligands promote dissociation of radiolabeled bound hormone from the buried ligand binding cavity (LBC) more rapidly than excess unlabeled hormone itself. This result was interpreted to mean that challenger ligands bind allosteric sites on the LBD to induce hormone dissociation, and recent findings indicate that ligands bind weakly to multiple sites on the LBD surface. Here, we show that a large fraction of thyroid hormone receptor (TR) ligands promote rapid dissociation (T1/2 <2 hours) of radiolabeled T3 versus T3 (T1/2 ≈5–7 hours). We cannot discern relationships between this effect and ligand size, activity or affinity for TRβ. One ligand, GC-24, binds the TR LBC and (weakly) to the TRβ-LBD surface that mediates dimer/heterodimer interaction, but we cannot link this interaction to rapid T3 dissociation. Instead, several lines of evidence suggest that the challenger ligand must interact with the buried LBC to promote rapid T3 release. Since previous molecular dynamics simulations suggest that TR ligands leave the LBC by several routes, we propose that a subset of challenger ligands binds and stabilizes a partially unfolded intermediate state of TR that arises during T3 release and that this effect enhances hormone dissociation. PMID:19729063

  9. Does the ligand-biopolymer equilibrium binding constant depend on the number of bound ligands?

    PubMed

    Beshnova, Daria A; Lantushenko, Anastasia O; Evstigneev, Maxim P

    2010-11-01

    Conventional methods, such as Scatchard or McGhee-von Hippel analyses, used to treat ligand-biopolymer interactions, indirectly make the assumption that the microscopic binding constant is independent of the number of ligands, i, already bound to the biopolymer. Recent results on the aggregation of aromatic molecules (Beshnova et al., J Chem Phys 2009, 130, 165105) indicated that the equilibrium constant of self-association depends intrinsically on the number of molecules in an aggregate due to loss of translational and rotational degrees of freedom on formation of the complex. The influence of these factors on the equilibrium binding constant for ligand-biopolymer complexation was analyzed in this work. It was shown that under the conditions of binding of "small" molecules, these factors can effectively be ignored and, hence, do not provide any hidden systematic error in such widely-used approaches, such as the Scatchard or McGhee-von Hippel methods for analyzing ligand-biopolymer complexation. © 2010 Wiley Periodicals, Inc. Biopolymers 93: 932-935, 2010.

  10. SuperLigands – a database of ligand structures derived from the Protein Data Bank

    PubMed Central

    Michalsky, Elke; Dunkel, Mathias; Goede, Andrean; Preissner, Robert

    2005-01-01

    Background Currently, the PDB contains approximately 29,000 protein structures comprising over 70,000 experimentally determined three-dimensional structures of over 5,000 different low molecular weight compounds. Information about these PDB ligands can be very helpful in the field of molecular modelling and prediction, particularly for the prediction of protein binding sites and function. Description Here we present an Internet accessible database delivering PDB ligands in the MDL Mol file format which, in contrast to the PDB format, includes information about bond types. Structural similarity of the compounds can be detected by calculation of Tanimoto coefficients and by three-dimensional superposition. Topological similarity of PDB ligands to known drugs can be assessed via Tanimoto coefficients. Conclusion SuperLigands supplements the set of existing resources of information about small molecules bound to PDB structures. Allowing for three-dimensional comparison of the compounds as a novel feature, this database represents a valuable means of analysis and prediction in the field of biological and medical research. PMID:15943884

  11. DNA-ligand interactions gained and lost: light-induced ligand redistribution in a supramolecular cascade.

    PubMed

    Berdnikova, Daria V; Aliyeu, Tseimur M; Paululat, Thomas; Fedorov, Yuri V; Fedorova, Olga A; Ihmels, Heiko

    2015-03-21

    A supramolecular five-component cascade is presented that enables light-controlled transport of an in situ modified ligand between three host systems based on the different complexation preferences of cyclodextrin, cucurbituril, and double-stranded DNA. The results point out novel approaches for the control of drug-DNA interactions in DNA-targeting therapy.

  12. Phenotypic spandrel: absolute discrimination and ligand antagonism

    NASA Astrophysics Data System (ADS)

    François, Paul; Hemery, Mathieu; Johnson, Kyle A.; Saunders, Laura N.

    2016-12-01

    We consider the general problem of sensitive and specific discrimination between biochemical species. An important instance is immune discrimination between self and not-self, where it is also observed experimentally that ligands just below the discrimination threshold negatively impact response, a phenomenon called antagonism. We characterize mathematically the generic properties of such discrimination, first relating it to biochemical adaptation. Then, based on basic biochemical rules, we establish that, surprisingly, antagonism is a generic consequence of any strictly specific discrimination made independently from ligand concentration. Thus antagonism constitutes a ‘phenotypic spandrel’: a phenotype existing as a necessary by-product of another phenotype. We exhibit a simple analytic model of discrimination displaying antagonism, where antagonism strength is linear in distance from the detection threshold. This contrasts with traditional proofreading based models where antagonism vanishes far from threshold and thus displays an inverted hierarchy of antagonism compared to simpler models. The phenotypic spandrel studied here is expected to structure many decision pathways such as immune detection mediated by TCRs and FCɛRIs, as well as endocrine signalling/disruption.

  13. Molecular modulators of benzodiazepine receptor ligand binding

    SciTech Connect

    Villar, H.O.; Loew, G.H. )

    1989-01-01

    Ten derivatives of {beta}-carbolines with known affinities to the GABA{sub A}/BDZ (benzodiazepine) receptor were studied using the Am 1 and MNDO/H Semiempirical techniques to identify and characterize molecular modulators of receptor recognition. Steric, lipophilic, and electrostatic properties of these compounds were calculated and examined for their possible role in recognition. Particular attention was paid to the regions around the two most favorable proton-accepting sites, the ON and the substituent at the C{sub 3} position, already implicated in recognition, as well as to the acidic N9H group that could be a proton donating center. To probe further the role of these three ligand sites in receptor interactions, a model of the receptor using three methanol molecules was made and optimum interactions of these three sites with them characterized. The results indicate some similarity in the shape of these ligands, which could reflect a steric requirement. The receptor affinity appears to be modulated to some extent by the ratio of lipophilic to hydrophilic surface, the negative potential at the {beta}N, provided there is also one at the C{sub 3} substituent confirming the importance of two accepting sites in recognition. The acidic N9H does not appear to be a modulator of affinity or does it form a stable H-bond with methanol as acceptor. The two proton donating molecules do form such a stable complex, and both are needed for high affinity.

  14. Continuous microfluidic assortment of interactive ligands (CMAIL)

    NASA Astrophysics Data System (ADS)

    Hsiao, Yi-Hsing; Huang, Chao-Yang; Hu, Chih-Yung; Wu, Yen-Yu; Wu, Chung-Hsiun; Hsu, Chia-Hsien; Chen, Chihchen

    2016-08-01

    Finding an interactive ligand-receptor pair is crucial to many applications, including the development of monoclonal antibodies. Biopanning, a commonly used technique for affinity screening, involves a series of washing steps and is lengthy and tedious. Here we present an approach termed continuous microfluidic assortment of interactive ligands, or CMAIL, for the screening and sorting of antigen-binding single-chain variable antibody fragments (scFv) displayed on bacteriophages (phages). Phages carrying native negative charges on their coat proteins were electrophoresed through a hydrogel matrix functionalized with target antigens under two alternating orthogonal electric fields. During the weak horizontal electric field phase, phages were differentially swept laterally depending on their affinity for the antigen, and all phages were electrophoresed down to be collected during the strong vertical electric field phase. Phages of different affinity were spatially separated, allowing the continuous operation. More than 105 CFU (colony forming unit) antigen-interacting phages were isolated with ~100% specificity from a phage library containing 3 × 109 individual members within 40 minutes of sorting using CMAIL. CMAIL is rapid, sensitive, specific, and does not employ washing, elution or magnetic beads. In conclusion, we have developed an efficient and cost-effective method for isolating and sorting affinity reagents involving phage display.

  15. Continuous microfluidic assortment of interactive ligands (CMAIL)

    PubMed Central

    Hsiao, Yi-Hsing; Huang, Chao-Yang; Hu, Chih-Yung; Wu, Yen-Yu; Wu, Chung-Hsiun; Hsu, Chia-Hsien; Chen, Chihchen

    2016-01-01

    Finding an interactive ligand-receptor pair is crucial to many applications, including the development of monoclonal antibodies. Biopanning, a commonly used technique for affinity screening, involves a series of washing steps and is lengthy and tedious. Here we present an approach termed continuous microfluidic assortment of interactive ligands, or CMAIL, for the screening and sorting of antigen-binding single-chain variable antibody fragments (scFv) displayed on bacteriophages (phages). Phages carrying native negative charges on their coat proteins were electrophoresed through a hydrogel matrix functionalized with target antigens under two alternating orthogonal electric fields. During the weak horizontal electric field phase, phages were differentially swept laterally depending on their affinity for the antigen, and all phages were electrophoresed down to be collected during the strong vertical electric field phase. Phages of different affinity were spatially separated, allowing the continuous operation. More than 105 CFU (colony forming unit) antigen-interacting phages were isolated with ~100% specificity from a phage library containing 3 × 109 individual members within 40 minutes of sorting using CMAIL. CMAIL is rapid, sensitive, specific, and does not employ washing, elution or magnetic beads. In conclusion, we have developed an efficient and cost-effective method for isolating and sorting affinity reagents involving phage display. PMID:27578501

  16. Activating Cell Death Ligand Signaling Through Proteasome Inhibition

    DTIC Science & Technology

    2009-05-01

    Activating Cell Death Ligand Signaling Through Proteasome Inhibition PRINCIPAL INVESTIGATOR: Steven R Schwarze...SUBTITLE Activating Cell Death Ligand Signaling Through 5a. CONTRACT NUMBER Proteasome Inhibition 5b. GRANT NUMBER W81XWH-08-1-0392 5c...proteasome inhibition can act as an anti-neoplastic agent in vivo by sensitizing cancer cells to cell death ligands in the tumor microenvironment

  17. Selective high affinity polydentate ligands and methods of making such

    DOEpatents

    DeNardo, Sally; DeNardo, Gerald; Balhorn, Rodney

    2010-02-16

    This invention provides novel polydentate selective high affinity ligands (SHALs) that can be used in a variety of applications in a manner analogous to the use of antibodies. SHALs typically comprise a multiplicity of ligands that each bind different region son the target molecule. The ligands are joined directly or through a linker thereby forming a polydentate moiety that typically binds the target molecule with high selectivity and avidity.

  18. Quasielastic neutron scattering study of POSS ligand dynamics

    SciTech Connect

    Jalarvo, Niina H; Tyagi, Madhusudan; Crawford, Michael

    2015-01-01

    Polyoligosilsesquioxanes are molecules having cage-like structures composed of silicon and oxygen. These molecules can have a wide variety of functional ligands attached to them. Depending on the nature of the ligand, interesting properties and applications are found. In this work we present results from quasielastic neutron scattering measurements of four different POSS molecules that illustrate the presence of strong coupling between the ligand dynamics and the POSS crystal structures.

  19. Cobalt(II), nickel(II) and copper(II) complexes of a hexadentate pyridine amide ligand. Effect of donor atom (ether vs. thioether) on coordination geometry, spin-state of cobalt and M(III)-M(II) redox potential.

    PubMed

    Pandey, Sharmila; Das, Partha Pratim; Singh, Akhilesh Kumar; Mukherjee, Rabindranath

    2011-10-28

    Using an acyclic hexadentate pyridine amide ligand, containing a -OCH(2)CH(2)O- spacer between two pyridine-2-carboxamide units (1,4-bis[o-(pyrydine-2-carboxamidophenyl)]-1,4-dioxabutane (H(2)L(9)), in its deprotonated form), four new complexes, [Co(II)(L(9))] (1) and its one-electron oxidized counterpart [Co(III)(L(9))][NO(3)]·2H(2)O (2), [Ni(II)(L(9))] (3) and [Cu(II)(L(9))] (4), have been synthesized. Structural analyses revealed that the Co(II) centre in 1 and the Ni(II) centre in 3 are six-coordinate, utilizing all the available donor sites and the Cu(II) centre in 4 is effectively five-coordinated (one of the ether O atoms does not participate in coordination). The structural parameters associated with the change in the metal coordination environment have been compared with corresponding complexes of thioether-containing hexadentate ligands. The μ(eff) values at 298 K of 1-4 correspond to S = 3/2, S = 0, S = 1 and S = 1/2, respectively. Absorption spectra for all the complexes have been investigated. EPR spectral properties of the copper(II) complex 4 have been investigated, simulated and analyzed. Cyclic voltammetric experiments in CH(2)Cl(2) reveal quasireversible Co(III)-Co(II), Ni(III)-Ni(II) and Cu(II)-Cu(I) redox processes. In going from ether O to thioether S coordination, the effect of the metal coordination environment on the redox potential values of Co(III)-Co(II) (here the effect of spin-state as well), Ni(III)-Ni(II) and Cu(II)-Cu(I) processes have been systematically analyzed.

  20. Mixed Extracellular Matrix Ligands Synergistically Modulate Integrin Adhesion and Signaling

    PubMed Central

    Reyes, Catherine D.; Petrie, Timothy A.; García, Andrés J

    2008-01-01

    Cell adhesion to extracellular matrix (ECM) components through cell-surface integrin receptors is essential to the formation, maintenance and repair of numerous tissues, and therefore represents a central theme in the design of bioactive materials that successfully interface with the body. While the adhesive responses associated with a single ligand have been extensively analyzed, the effects of multiple integrin subtypes binding to multivalent ECM signals remain poorly understood. In the present study, we generated a high throughput platform of non-adhesive surfaces presenting well-defined, independent densities of two integrin-specific engineered ligands for the type I collagen (COL-I) receptor α2β1 and the fibronectin (FN) receptor α5β1 to evaluate the effects of integrin cross-talk on adhesive responses. Engineered surfaces displayed ligand density-dependent adhesive effects, and mixed ligand surfaces significantly enhanced cell adhesion strength and focal adhesion assembly compared to single FN and COL-I ligand surfaces. Moreover, surfaces presenting mixed COL-I/FN ligands synergistically enhanced FAK activation compared to the single ligand substrates. The enhanced adhesive activities of the mixed ligand surfaces also promoted elevated proliferation rates. Our results demonstrate interplay between multivalent ECM ligands in adhesive responses and downstream cellular signaling. PMID:18613064

  1. Superior serum half life of albumin tagged TNF ligands

    SciTech Connect

    Mueller, Nicole; Schneider, Britta; Pfizenmaier, Klaus; Wajant, Harald

    2010-06-11

    Due to their immune stimulating and apoptosis inducing properties, ligands of the TNF family attract increasing interest as therapeutic proteins. A general limitation of in vivo applications of recombinant soluble TNF ligands is their notoriously rapid clearance from circulation. To improve the serum half life of the TNF family members TNF, TWEAK and TRAIL, we genetically fused soluble variants of these molecules to human serum albumin (HSA). The serum albumin-TNF ligand fusion proteins were found to be of similar bioactivity as the corresponding HSA-less counterparts. Upon intravenous injection (i.v.), serum half life of HSA-TNF ligand fusion proteins, as determined by ELISA, was around 15 h as compared to approximately 1 h for all of the recombinant control TNF ligands without HSA domain. Moreover, serum samples collected 6 or 24 h after i.v. injection still contained high TNF ligand bioactivity, demonstrating that there is only limited degradation/inactivation of circulating HSA-TNF ligand fusion proteins in vivo. In a xenotransplantation model, significantly less of the HSA-TRAIL fusion protein compared to the respective control TRAIL protein was required to achieve inhibition of tumor growth indicating that the increased half life of HSA-TNF ligand fusion proteins translates into better therapeutic action in vivo. In conclusion, our data suggest that genetic fusion to serum albumin is a powerful and generally applicable mean to improve bioavailability and in vivo activity of TNF ligands.

  2. Biased ligands: pathway validation for novel GPCR therapeutics.

    PubMed

    Rominger, David H; Cowan, Conrad L; Gowen-MacDonald, William; Violin, Jonathan D

    2014-06-01

    G protein-coupled receptors (GPCRs), in recent years, have been shown to signal via multiple distinct pathways. Furthermore, biased ligands for some receptors can differentially stimulate or inhibit these pathways versus unbiased endogenous ligands or drugs. Biased ligands can be used to gain a deeper understanding of the molecular targets and cellular responses associated with a GPCR, and may be developed into therapeutics with improved efficacy, safety and/or tolerability. Here we review examples and approaches to pathway validation that establish the relevance and therapeutic potential of distinct pathways that can be selectively activated or blocked by biased ligands.

  3. ADAM Proteases: Ligand Processing and Modulation of the Notch Pathway

    PubMed Central

    Zolkiewska, Anna

    2009-01-01

    ADAM metalloproteases play important roles in development and disease. One of the key functions of ADAMs is the proteolytic processing of Notch receptors and their ligands. ADAM-mediated cleavage of Notch represents the first step of the regulated intramembrane proteolysis of the receptor, leading to activation of the Notch pathway. Recent reports indicate that the transmembrane Notch ligands also undergo ADAM-mediated processing in cultured cells and in vivo. The proteolytic processing of Notch ligands modulates the strength and duration of Notch signals, leads to generation of soluble intracellular domains of the ligands, and may support a bi-directional signaling between cells. PMID:18344021

  4. Hysteresis of ligand binding in CNGA2 ion channels

    PubMed Central

    Nache, Vasilica; Eick, Thomas; Schulz, Eckhard; Schmauder, Ralf; Benndorf, Klaus

    2013-01-01

    Tetrameric cyclic nucleotide-gated (CNG) channels mediate receptor potentials in olfaction and vision. The channels are activated by the binding of cyclic nucleotides to a binding domain embedded in the C terminus of each subunit. Here using a fluorescent cGMP derivative (fcGMP), we show for homotetrameric CNGA2 channels that ligand unbinding is ~50 times faster at saturating than at subsaturating fcGMP. Analysis with complex Markovian models reveals two pathways for ligand unbinding; the partially liganded open channel unbinds its ligands from closed states only, whereas the fully liganded channel reaches a different open state from which it unbinds all four ligands rapidly. Consequently, the transition pathways for ligand binding and activation of a fully liganded CNGA2 channel differ from that of ligand unbinding and deactivation, resulting in pronounced hysteresis of the gating mechanism. This concentration-dependent gating mechanism allows the channels to respond to changes in the cyclic nucleotide concentration with different kinetics. PMID:24287615

  5. Riboswitch Structure: an Internal Residue Mimicking the Purine Ligand

    SciTech Connect

    Delfosse, V.; Bouchard, P; Bonneau, E; Dagenais, P; Lemay, J; Lafontaine, D; Legault, P

    2009-01-01

    The adenine and guanine riboswitches regulate gene expression in response to their purine ligand. X-ray structures of the aptamer moiety of these riboswitches are characterized by a compact fold in which the ligand forms a Watson-Crick base pair with residue 65. Phylogenetic analyses revealed a strict restriction at position 39 of the aptamer that prevents the G39-C65 and A39-U65 combinations, and mutational studies indicate that aptamers with these sequence combinations are impaired for ligand binding. In order to investigate the rationale for sequence conservation at residue 39, structural characterization of the U65C mutant from Bacillus subtilis pbuE adenine riboswitch aptamer was undertaken. NMR spectroscopy and X-ray crystallography studies demonstrate that the U65C mutant adopts a compact ligand-free structure, in which G39 occupies the ligand-binding site of purine riboswitch aptamers. These studies present a remarkable example of a mutant RNA aptamer that adopts a native-like fold by means of ligand mimicking and explain why this mutant is impaired for ligand binding. Furthermore, this work provides a specific insight into how the natural sequence has evolved through selection of nucleotide identities that contribute to formation of the ligand-bound state, but ensures that the ligand-free state remains in an active conformation.

  6. Dewetting-Controlled Binding of Ligands to Hydrophobic Pockets

    PubMed Central

    Setny, P.; Wang, Z.; Cheng, L.-T.; Li, B.; McCammon, J. A.; Dzubiella, J.

    2010-01-01

    We report on a combined atomistic molecular dynamics simulation and implicit solvent analysis of a generic hydrophobic pocket-ligand (host-guest) system. The approaching ligand induces complex wetting-dewetting transitions in the weakly solvated pocket. The transitions lead to bimodal solvent fluctuations which govern magnitude and range of the pocket-ligand attraction. A recently developed implicit water model, based on the minimization of a geometric functional, captures the sensitive aqueous interface response to the concave-convex pocket-ligand configuration semiquantitatively. PMID:19905832

  7. Design of targeting ligands in medicinal inorganic chemistry.

    PubMed

    Storr, Tim; Thompson, Katherine H; Orvig, Chris

    2006-06-01

    This tutorial review will highlight recent advances in medicinal inorganic chemistry pertaining to the use of multifunctional ligands for enhanced effect. Ligands that adequately bind metal ions and also include specific targeting features are gaining in popularity due to their ability to enhance the efficacy of less complicated metal-based agents. Moving beyond the traditional view of ligands modifying reactivity, stabilizing specific oxidation states, and contributing to substitution inertness, we will discuss recent work involving metal complexes with multifunctional ligands that target specific tissues, membrane receptors, or endogenous molecules, including enzymes.

  8. Ultrafast heme-ligand recombination in truncated hemoglobin HbO from Mycobacterium tuberculosis: A ligand cage

    NASA Astrophysics Data System (ADS)

    Jasaitis, Audrius; Ouellet, Hugues; Lambry, Jean-Christophe; Martin, Jean-Louis; Friedman, Joel M.; Guertin, Michel; Vos, Marten H.

    2012-03-01

    Truncated hemoglobin HbO from Mycobacterium tuberculosis displays very slow exchange of diatomic ligands with its environment. Using femtosecond spectroscopy, we show that upon photoexcitation, ligands rebind with unusual speed and efficiency. Only ˜1% O2 can escape from the heme pocket and less than 1% NO. Most remarkably, CO rebinding occurs for 95%, predominantly in 1.2 ns. The general CO rebinding properties are unexpectedly robust against changes in the interactions with close by aromatic residues Trp88 (G8) and Tyr36 (CD1). Molecular dynamics simulations of the CO complex suggest that interactions of the ligand with structural water molecules as well as its rotational freedom play a role in the high reactivity of the ligand and the heme. The slow exchange of ligands between heme and environment may result from a combination of hindered ligand access to the heme pocket by the network of distal aromatic residues, and low escape probability from the pocket.

  9. LibME-automatic extraction of 3D ligand-binding motifs for mechanistic analysis of protein-ligand recognition.

    PubMed

    He, Wei; Liang, Zhi; Teng, MaiKun; Niu, LiWen

    2016-12-01

    Identifying conserved binding motifs is an efficient way to study protein-ligand recognition. Most 3D binding motifs only contain information from the protein side, and so motifs that combine information from both protein and ligand sides are desired. Here, we propose an algorithm called LibME (Ligand-binding Motif Extractor), which automatically extracts 3D binding motifs composed of the target ligand and surrounding conserved residues. We show that the motifs extracted by LibME for ATP and its analogs are highly similar to well-known motifs reported by previous studies. The superiority of our method to handle flexible ligands was also demonstrated using isocitric acid as an example. Finally, we show that these motifs, together with their visual exhibition, permit better investigating and understanding of protein-ligand recognition process.

  10. Ligand "Brackets" for Ga-Ga Bond.

    PubMed

    Fedushkin, Igor L; Skatova, Alexandra A; Dodonov, Vladimir A; Yang, Xiao-Juan; Chudakova, Valentina A; Piskunov, Alexander V; Demeshko, Serhiy; Baranov, Evgeny V

    2016-09-06

    The reactivity of digallane (dpp-Bian)Ga-Ga(dpp-Bian) (1) (dpp-Bian = 1,2-bis[(2,6-diisopropylphenyl)imino]acenaphthene) toward acenaphthenequinone (AcQ), sulfur dioxide, and azobenzene was investigated. The reaction of 1 with AcQ in 1:1 molar ratio proceeds via two-electron reduction of AcQ to give (dpp-Bian)Ga(μ2-AcQ)Ga(dpp-Bian) (2), in which diolate [AcQ](2-) acts as "bracket" for the Ga-Ga bond. The interaction of 1 with AcQ in 1:2 molar ratio proceeds with an oxidation of the both dpp-Bian ligands as well as of the Ga-Ga bond to give (dpp-Bian)Ga(μ2-AcQ)2Ga(dpp-Bian) (3). At 330 K in toluene complex 2 decomposes to give compounds 3 and 1. The reaction of complex 2 with atmospheric oxygen results in oxidation of a Ga-Ga bond and affords (dpp-Bian)Ga(μ2-AcQ)(μ2-O)Ga(dpp-Bian) (4). The reaction of digallane 1 with SO2 produces, depending on the ratio (1:2 or 1:4), dithionites (dpp-Bian)Ga(μ2-O2S-SO2)Ga(dpp-Bian) (5) and (dpp-Bian)Ga(μ2-O2S-SO2)2Ga(dpp-Bian) (6). In compound 5 the Ga-Ga bond is preserved and supported by dithionite dianionic bracket. In compound 6 the gallium centers are bridged by two dithionite ligands. Both 5 and 6 consist of dpp-Bian radical anionic ligands. Four-electron reduction of azobenzene with 1 mol equiv of digallane 1 leads to complex (dpp-Bian)Ga(μ2-NPh)2Ga(dpp-Bian) (7). Paramagnetic compounds 2-7 were characterized by electron spin resonance spectroscopy, and their molecular structures were established by single-crystal X-ray analysis. Magnetic behavior of compounds 2, 5, and 6 was investigated by superconducting quantum interference device technique in the range of 2-295 K.

  11. [Effect of ligand concentration on the precision of determining the parameters of ligand-receptor interaction by serial dilution methods].

    PubMed

    Bobrovnik, S A

    2004-01-01

    Earlier we suggested the method of serial dilution, which allows one to determine the parameters of ligand-receptor interaction even if the reactants are in a mixture and their concentrations are unknown. The method is especially useful if the liability of studied receptor does not allow its separation from corresponding ligand. The important prerequisite of the method's precision is that the concentration of the ligand should be sufficiently high comparing to the concentration of the receptor. In the present paper it was demonstrated that the method allows one to obtain sufficiently good precision even in the case when the concentration of the ligand is only one tenth of the receptor concentration.

  12. Characterizing mixed phosphonic acid ligand capping on CdSe/ZnS quantum dots using ligand exchange and NMR spectroscopy.

    PubMed

    Davidowski, Stephen K; Lisowski, Carmen E; Yarger, Jeffery L

    2016-03-01

    The ligand capping of phosphonic acid functionalized CdSe/ZnS core-shell quantum dots (QDs) was investigated with a combination of solution and solid-state (31) P nuclear magnetic resonance (NMR) spectroscopy. Two phosphonic acid ligands were used in the synthesis of the QDs, tetradecylphosphonic acid and ethylphosphonic acid. Both alkyl phosphonic acids showed broad liquid and solid-state (31) P NMR resonances for the bound ligands, indicative of heterogeneous binding to the QD surface. In order to quantify the two ligand populations on the surface, ligand exchange facilitated by phenylphosphonic acid resulted in the displacement of the ethylphosphonic acid and tetradecylphosphonic acid and allowed for quantification of the free ligands using (31) P liquid-state NMR. After washing away the free ligand, two broad resonances were observed in the liquids' (31) P NMR corresponding to the alkyl and aromatic phosphonic acids. The washed samples were analyzed via solid-state (31) P NMR, which confirmed the ligand populations on the surface following the ligand exchange process. Copyright © 2015 John Wiley & Sons, Ltd.

  13. Calculating the mean time to capture for tethered ligands and its effect on the chemical equilibrium of bound ligand pairs.

    PubMed

    Shen, Lu; Decker, Caitlin G; Maynard, Heather D; Levine, Alex J

    2016-09-01

    We present here the calculation of the mean time to capture of a tethered ligand to the receptor. This calculation is then used to determine the shift in the partitioning between (1) free, (2) singly bound, and (3) doubly bound ligands in chemical equilibrium as a function of the length of the tether. These calculations are used in the research article Fibroblast Growth Factor 2 Dimer with Superagonist in vitro Activity Improves Granulation Tissue Formation During Wound Healing (Decker et al., in press [1]) to explain quantitatively how changes in polymeric linker length in the ligand dimers modifies the efficacy of these molecules relative to that of free ligands.

  14. Interaction between alkaline earth cations and oxo ligands: a DFT study of the affinity of Mg2+ for carbonyl ligands.

    PubMed

    Moreira da Costa, Leonardo; Stoyanov, Stanislav R; Walkimar de M Carneiro, José

    2012-09-01

    The affinities of Mg(2+) for various substituted carbonyl ligands were determined at the DFT (B3LYP/6-31+G(d)) and semi-empirical (PM6) levels of theory. Two sets of carbonyl ligands were studied: monosubstituted [aldehydes R-CHO and RPh-CHO] and homodisubstituted [ketones R(2)C=O and (RPh)(2)C=O], where R = NH(2), OCH(3), OH, CH(3), H, F, Cl, Br, CN, or NO(2)). In the (RPh)(2)CO case, the R group was bonded to the para position of a phenyl ring. The enthalpies of interaction between the ligands and a pentaaquomagnesium(II) complex were calculated to determine the affinity of each ligand for the Mg(2+) cation and to correlate with geometrical and electronic parameters. These parameters exhibited the same trends for all of the ligands studied, showing that the affinity of Mg(2+) for electron-donating ligands is higher than its affinity for electron-withdrawing ligands. In the complexes, electron-donating groups increase both the electrostatic and the covalent components of the Mg-ligand interaction. This behavior correlates with the Mg-O(carbonyl) distance and the ligand electron-donor strength.

  15. Early development of sigma-receptor ligands.

    PubMed

    Narayanan, Sanju; Bhat, Rohit; Mesangeau, Christophe; Poupaert, Jacques H; McCurdy, Christopher R

    2011-01-01

    Sigma receptors (σ-1 and σ-2) are non-opioid proteins implicated in the pathophysiology of various neurological disorders and cancer. The σ-1 subtype is a chaperon protein widely distributed in the CNS and peripheral tissues. These receptors are involved in the modulation of K(+)- and Ca(2+)-dependent signaling cascades at the endoplasmic reticulum and modulation of neurotransmitter release. σ-1 receptors are emerging targets for the treatment of neurophychiatric diseases (schizophrenia and depression) and cocaine addiction. σ-2 receptors are lipid raft proteins. They are highly expressed on many tumor cells and hence considered potential targets for anticancer drugs. σ receptors bind to a diverse class of pharmacological compounds like cocaine, methamphetamine, benzomorphans like (±)-pentazocine, (±)-SKF-10,047 and endogenous neurosteroids and sphingolipids. In this review we focus on the early development of σ receptor-specific ligands and radiolabeling agents.

  16. Phosphinothiolates as ligands for polyhydrido copper nanoclusters.

    PubMed

    Huertos, Miguel A; Cano, Israel; Bandeira, Nuno A G; Benet-Buchholz, Jordi; Bo, Carles; van Leeuwen, Piet W N M

    2014-12-01

    The reaction of [CuI(HSC6 H4 PPh2 )]2 with NaBH4 in CH2 Cl2 /EtOH led to air- and moisture-stable copper hydride nanoparticles (CuNPs) containing phosphinothiolates as new ligands, one of which was isolated by crystallization. The X-ray crystal structure of [Cu18 H7 L10 I] (L=(-) S(C6 H4 )PPh2 ) shows unprecedented features in its 28-atom framework (18 Cu and 10 S atoms). Seven hydrogen atoms, in hydride form, are needed for charge balance and were located by density functional theory methods. H2 was released from the copper hydride nanoparticles by thermolysis and visible light irradiation.

  17. Rational design of class I MHC ligands

    NASA Astrophysics Data System (ADS)

    Rognan, D.; Scapozza, L.; Folkers, G.; Daser, Angelika

    1995-04-01

    From the knowledge of the three-dimensional structure of a class I MHC protein, several non natural peptides were designed in order to either optimize the interactions of one secondary anchor amino acid with its HLA binding pocket or to substitute the non interacting part with spacer residues. All peptides were synthesized and tested for binding to the class I MHC protein in an in vitro reconstitution assay. As predicted, the non natural peptides present an enhanced binding to the HLA-B27 molecule with respect to their natural parent peptides. This study constitutes the first step towards the rational design of non peptidic MHC ligands that should be very promising tools for the selective immunotherapy of autoimmune diseases.

  18. Ligand interactions with galactose oxidase: mechanistic insights.

    PubMed Central

    Whittaker, M M; Whittaker, J W

    1993-01-01

    Interactions between galactose oxidase and small molecules have been explored using a combination of optical absorption, circular dichroism, and electron paramagnetic resonance (EPR) spectroscopies to detect complex formation and characterize the products. Anions bind directly to the cupric center in both active and inactive galactose oxidase, converting to complexes with optical and EPR spectra that are distinctly different from those of the starting aquo enzyme. Azide binding is coupled to stoichiometric proton uptake by the enzyme, reflecting the generation of a strong base (pKa > 9) in the active site anion adduct. At low temperature, the aquo enzyme converts to a form that exhibits the characteristic optical and EPR spectra of an anion complex, apparently reflecting deprotonation of the coordinated water. Anion binding results in a loss of the optical transition arising from coordinated tyrosine, implying displacement of the axial tyrosine ligand on forming the adduct. Nitric oxide binds to galactose oxidase, forming a specific complex exhibiting an unusual EPR spectrum with all g values below 2. The absence of Cu splitting in this spectrum and the observation that the cupric EPR signal from the active site metal ion is not significantly decreased in the complex suggest a nonmetal interaction site for NO in galactose oxidase. These results have been interpreted in terms of a mechanistic scheme where substrate binding displaces a tyrosinate ligand from the active site cupric ion, generating a base that may serve to deprotonate the coordinated hydroxyl group of the substrate, activating it for oxidation. The protein-NO interactions may probe a nonmetal O2 binding site in this enzyme. PMID:8386015

  19. Do organic ligands affect calcite dissolution rates?

    NASA Astrophysics Data System (ADS)

    Oelkers, Eric H.; Golubev, Sergey V.; Pokrovsky, Oleg S.; Bénézeth, Pascale

    2011-04-01

    Steady state Iceland-spar calcite dissolution rates were measured at 25 °C in aqueous solutions containing 0.1 M NaCl and up to 0.05 M dissolved bicarbonate at pH from 7.9 to 9.1 in the presence of 13 distinct dissolved organic ligands in mixed-flow reactors. The organic ligands considered in this study include those most likely to be present in either (1) aquifers at the conditions pertinent to CO 2 sequestration or (2) soil/early diagenetic environments: acetate, phthalate, citrate, EDTA 4-, succinate, D-glucosaminate, L-glutamate, D-gluconate, 2,4-dihydroxybenzoate, 3,4-dihydroxybenzoate, fumarate, malonate, and gallate. Results show that the presence of <0.05 mol/kg of these organic anions changes calcite dissolution rates by less than a factor of 2.5 with the exception of citrate and EDTA 4-. The presence of 0.05 mol/kg citrate and EDTA 4- increases calcite dissolution rates by as much as a factor of 35 and 500, respectively, compared to rates in organic anion-free solutions. Further calcite dissolution experiments were performed in the presence of organic polymers similar to bacterial exudates, cell exopolysaccharides, and analogs of microbial cell envelopes: alginate, lichen extract, humic acid, pectin, and gum xanthan. In no case did the presence of <100 ppm of these organics change calcite dissolution rates by more than a factor of 2.5. Results obtained in this study suggest that the presence of aqueous organic anions negligibly affects calcite forward dissolution rates in most natural environments. Some effect on calcite reactivity may be observed, however, by the presence of organic anions if they change substantially the chemical affinity of the fluid with respect to calcite.

  20. How to Compute Labile Metal-Ligand Equilibria

    ERIC Educational Resources Information Center

    de Levie, Robert

    2007-01-01

    The different methods used for computing labile metal-ligand complexes, which are suitable for an iterative computer solution, are illustrated. The ligand function has allowed students to relegate otherwise tedious iterations to a computer, while retaining complete control over what is calculated.

  1. Improved ligand geometries in crystallographic refinement using AFITT in PHENIX

    PubMed Central

    Janowski, Pawel A.; Moriarty, Nigel W.; Kelley, Brian P.; Case, David A.; York, Darrin M.; Adams, Paul D.; Warren, Gregory L.

    2016-01-01

    Modern crystal structure refinement programs rely on geometry restraints to overcome the challenge of a low data-to-parameter ratio. While the classical Engh and Huber restraints work well for standard amino-acid residues, the chemical complexity of small-molecule ligands presents a particular challenge. Most current approaches either limit ligand restraints to those that can be readily described in the Crystallographic Information File (CIF) format, thus sacrificing chemical flexibility and energetic accuracy, or they employ protocols that substantially lengthen the refinement time, potentially hindering rapid automated refinement workflows. PHENIX–AFITT refinement uses a full molecular-mechanics force field for user-selected small-molecule ligands during refinement, eliminating the potentially difficult problem of finding or generating high-quality geometry restraints. It is fully integrated with a standard refinement protocol and requires practically no additional steps from the user, making it ideal for high-throughput workflows. PHENIX–AFITT refinements also handle multiple ligands in a single model, alternate conformations and covalently bound ligands. Here, the results of combining AFITT and the PHENIX software suite on a data set of 189 protein–ligand PDB structures are presented. Refinements using PHENIX–AFITT significantly reduce ligand conformational energy and lead to improved geometries without detriment to the fit to the experimental data. For the data presented, PHENIX–AFITT refinements result in more chemically accurate models for small-molecule ligands. PMID:27599738

  2. Regulation of ligands for the activating receptor NKG2D

    PubMed Central

    Mistry, Anita R; O'Callaghan, Chris A

    2007-01-01

    The outcome of an encounter between a cytotoxic cell and a potential target cell depends on the balance of signals from inhibitory and activating receptors. Natural Killer group 2D (NKG2D) has recently emerged as a major activating receptor on T lymphocytes and natural killer cells. In both humans and mice, multiple different genes encode ligands for NKG2D, and these ligands are non-classical major histocompatibility complex class I molecules. The NKG2D–ligand interaction triggers an activating signal in the cell expressing NKG2D and this promotes cytotoxic lysis of the cell expressing the ligand. Most normal tissues do not express ligands for NKG2D, but ligand expression has been documented in tumour and virus-infected cells, leading to lysis of these cells. Tight regulation of ligand expression is important. If there is inappropriate expression in normal tissues, this will favour autoimmune processes, whilst failure to up-regulate the ligands in pathological conditions would favour cancer development or dissemination of intracellular infection. PMID:17614877

  3. Technetium radiodiagnostic fatty acids derived from bisamide bisthiol ligands

    DOEpatents

    Jones, Alun G.; Lister-James, John; Davison, Alan

    1988-05-24

    A bisamide-bisthiol ligand containing fatty acid substituted thiol useful for producing Tc-labelled radiodiagnostic imaging agents is described. The ligand forms a complex with the radionuclide .sup.99m Tc suitable for administration as a radiopharmaceutical to obtain images of the heart for diagnosis of myocardial disfunction.

  4. Proteome-wide covalent ligand discovery in native biological systems

    PubMed Central

    Backus, Keriann M.; Correia, Bruno E.; Lum, Kenneth M.; Forli, Stefano; Horning, Benjamin D.; González-Páez, Gonzalo E.; Chatterjee, Sandip; Lanning, Bryan R.; Teijaro, John R.; Olson, Arthur J.; Wolan, Dennis W.; Cravatt, Benjamin F.

    2016-01-01

    Small molecules are powerful tools for investigating protein function and can serve as leads for new therapeutics. Most human proteins, however, lack small-molecule ligands, and entire protein classes are considered “undruggable” 1,2. Fragment-based ligand discovery (FBLD) can identify small-molecule probes for proteins that have proven difficult to target using high-throughput screening of complex compound libraries 1,3. Although reversibly binding ligands are commonly pursued, covalent fragments provide an alternative route to small-molecule probes 4–10, including those that can access regions of proteins that are difficult to access through binding affinity alone 5,10,11. In this manuscript, we report a quantitative analysis of cysteine-reactive small-molecule fragments screened against thousands of proteins. Covalent ligands were identified for >700 cysteines found in both druggable proteins and proteins deficient in chemical probes, including transcription factors, adaptor/scaffolding proteins, and uncharacterized proteins. Among the atypical ligand-protein interactions discovered were compounds that react preferentially with pro- (inactive) caspases. We used these ligands to distinguish extrinsic apoptosis pathways in human cell lines versus primary human T-cells, showing that the former is largely mediated by caspase-8 while the latter depends on both caspase-8 and −10. Fragment-based covalent ligand discovery provides a greatly expanded portrait of the ligandable proteome and furnishes compounds that can illuminate protein functions in native biological systems. PMID:27309814

  5. [Peripheral effects of ligands of ORL1 receptors].

    PubMed

    Maslov, L N; Lishmanov, Iu B; Calo, G; Ma, L; Lambert, D G

    2003-01-01

    It has been discussed literature data on the role for ORL1 (NOR) receptors in the regulation of function of gastrointestinal, respiratory, cardiovascular, immune, endocrine systems. In addition, it has been discussed a possibility of penetration of blood brain barrier for ORL1 receptor ligands and species dependence of NOR-ligands' effects.

  6. Multifunctional ligand for use as a diagnostic or therapeutic pharmaceutical

    DOEpatents

    Katti, K.V.; Volkert, W.A.; Ketring, A.R.; Singh, P.R.

    1996-05-14

    A compound and method of making a compound for use as a diagnostic or therapeutic pharmaceutical are revealed. The ligand comprises either a phosphorous or germanium core and at least two hydrazine groups forming a ligand for bonding to a metal extending from the phosphorous or germanium core.

  7. Digestive Ripening of Au Nanoparticles Using Multidentate Ligands.

    PubMed

    Sahu, Puspanjali; Shimpi, Jayesh; Lee, Han Ju; Lee, T Randall; Prasad, Bhagavatula L V

    2017-02-16

    The efficiency of multidentate ligands as digestive ripening (DR) agents for the preparation of monodisperse Au nanoparticles (NPs) was investigated. This systematic investigation was performed using ligands possessing one, two, or three thiol moieties as ligands/DR agents. Our results clearly establish that among the different ligands, monodentate ligands and the use of temperature in the range of 60-120 °C offer the best conditions for DR. In addition, when DR was carried out at lower temperatures (e.g., 60 °C), the NP size increased as the number of thiol groups per ligand increased. However, in the case of ligands possessing two and three thiol moieties, when they were heated with polydispersed particles at higher temperatures (120 or 180 °C), the etching process dominated, which affected the quality of the NPs in terms of their monodispersity. We conclude that the temperature-dependent strength of the interaction between the ligand headgroup and the NP surface plays a vital role in controlling the final particle sizes.

  8. Ligand-modified metal clusters for gas separation and purification

    DOEpatents

    Okrut, Alexander; Ouyang, Xiaoying; Runnebaum, Ron; Gates, Bruce C.; Katz, Alexander

    2017-02-21

    Provided is an organic ligand-bound metal surface that selects one gaseous species over another. The species can be closely sized molecular species having less than 1 Angstrom difference in kinetic diameter. In one embodiment, the species comprise carbon monoxide and ethylene. Such organic ligand-bound metal surfaces can be successfully used in gas phase separations or purifications, sensing, and in catalysis.

  9. Models of protein-ligand crystal structures: trust, but verify

    NASA Astrophysics Data System (ADS)

    Deller, Marc C.; Rupp, Bernhard

    2015-09-01

    X-ray crystallography provides the most accurate models of protein-ligand structures. These models serve as the foundation of many computational methods including structure prediction, molecular modelling, and structure-based drug design. The success of these computational methods ultimately depends on the quality of the underlying protein-ligand models. X-ray crystallography offers the unparalleled advantage of a clear mathematical formalism relating the experimental data to the protein-ligand model. In the case of X-ray crystallography, the primary experimental evidence is the electron density of the molecules forming the crystal. The first step in the generation of an accurate and precise crystallographic model is the interpretation of the electron density of the crystal, typically carried out by construction of an atomic model. The atomic model must then be validated for fit to the experimental electron density and also for agreement with prior expectations of stereochemistry. Stringent validation of protein-ligand models has become possible as a result of the mandatory deposition of primary diffraction data, and many computational tools are now available to aid in the validation process. Validation of protein-ligand complexes has revealed some instances of overenthusiastic interpretation of ligand density. Fundamental concepts and metrics of protein-ligand quality validation are discussed and we highlight software tools to assist in this process. It is essential that end users select high quality protein-ligand models for their computational and biological studies, and we provide an overview of how this can be achieved.

  10. Polymerization catalysts containing electron-withdrawing amide ligands

    DOEpatents

    Watkin, John G.; Click, Damon R.

    2002-01-01

    The present invention describes methods of making a series of amine-containing organic compounds which are used as ligands for group 3-10 and lanthanide metal compounds. The ligands have electron-withdrawing groups bonded to them. The metal compounds, when combined with a cocatalyst, are catalysts for the polymerization of olefins.

  11. An agent based model of integrin clustering: Exploring the role of ligand clustering, integrin homo-oligomerization, integrin-ligand affinity, membrane crowdedness and ligand mobility

    NASA Astrophysics Data System (ADS)

    Jamali, Yousef; Jamali, Tahereh; Mofrad, Mohammad R. K.

    2013-07-01

    Integrins are cell-surface protein heterodimers that coordinate cellular responses to mechanochemical cues from the extracellular matrix (ECM) and stimulate the assembly of small adhesion complexes, which are the initial sites of cell-ECM adhesion. Clustering of integrins is known to mediate signaling through a variety of signal transduction pathways. Yet, the molecular mechanisms of integrin clustering are poorly understood. In this paper, we develop computational models, using agent based modeling (ABM) techniques, to explore two key underlying mechanisms of integrin clustering, namely ligand organization and integrin homo-oligomerization. Our models help to shed light on the potential roles ligand clustering and integrin homo-oligomerization may play in controlling integrin clustering. A potential mechanism for the clustering of integrin is discussed and the effects of other parameters such as integrin-ligand affinity, membrane crowdedness and ligand mobility on integrin clustering are examined.

  12. Enthalpy of ligand substitution in cis organopalladium complexes with monodentate ligands.

    PubMed

    Salas, Gorka; Casares, Juan A; Espinet, Pablo

    2009-10-21

    The enthalpy for the substitution reaction cis-[PdRf(2)(THF)(2)] + 2 L -->cis-[PdRf(2)L(2)] + 2THF (THF = tetrahydrofuran) has been measured in THF by calorimetric methods for Rf = 3,5-dichloro-2,4,6-trifluorophenyl, L = PPh(3), AsPh(3), SbPh(3), PMePh(2), PCyPh(2), PMe(3), AsMePh(2), or L(2) = dppe (1,2-bis(diphenylphosphino)ethane), dppf (1,1'-bis(diphenylphosphino)ferrocene). The values determined show that the substitution enthalpy has a strong dependence on the electronic and steric properties of the ligand. The study of the consecutive substitution reactions cis-[PdRf(2)(THF)(2)] + L -->cis-[PdRf(2)L(THF)] + THF, and cis-[PdRf(2)L(THF)] + L -->cis-[PdRf(2)L(2)] + THF has been carried our for L = PPh(3) and L = PCyPh(2). The first substitution is clearly more favorable for the bulkier leaving ligand, but the second gives practically the same DeltaH value for both cases, indicating that the differences in steric hindrance happen to compensate the electronic differences for both ligands. The X-ray structures of cis-[PdRf(2)(PMePh(2))(2)], cis-[PdRf(2)(dppe)] and cis-[PdRf(2)(dppf)] are reported.

  13. Regulation of ligands for the NKG2D activating receptor

    PubMed Central

    Raulet, David H.; Gasser, Stephan; Gowen, Benjamin G.; Deng, Weiwen; Jung, Heiyoun

    2014-01-01

    NKG2D is an activating receptor expressed by all NK cells and subsets of T cells. It serves as a major recognition receptor for detection and elimination of transformed and infected cells and participates in the genesis of several inflammatory diseases. The ligands for NKG2D are self-proteins that are induced by pathways that are active in certain pathophysiological states. NKG2D ligands are regulated transcriptionally, at the level of mRNA and protein stability, and by cleavage from the cell surface. In some cases, ligand induction can be attributed to pathways that are activated specifically in cancer cells or infected cells. We review the numerous pathways that have been implicated in the regulation of NKG2D ligands, discuss the pathologic states in which those pathways are likely to act, and attempt to synthesize the findings into general schemes of NKG2D ligand regulation in NK cell responses to cancer and infection. PMID:23298206

  14. Predicting protein-ligand affinity with a random matrix framework.

    PubMed

    Lee, Alpha A; Brenner, Michael P; Colwell, Lucy J

    2016-11-29

    Rapid determination of whether a candidate compound will bind to a particular target receptor remains a stumbling block in drug discovery. We use an approach inspired by random matrix theory to decompose the known ligand set of a target in terms of orthogonal "signals" of salient chemical features, and distinguish these from the much larger set of ligand chemical features that are not relevant for binding to that particular target receptor. After removing the noise caused by finite sampling, we show that the similarity of an unknown ligand to the remaining, cleaned chemical features is a robust predictor of ligand-target affinity, performing as well or better than any algorithm in the published literature. We interpret our algorithm as deriving a model for the binding energy between a target receptor and the set of known ligands, where the underlying binding energy model is related to the classic Ising model in statistical physics.

  15. Exploiting Ultra Tight-Binding Ligands for Separations Technologies

    SciTech Connect

    Busch, Daryle; Givens, Richard S.; Zuo, Xiaobin; Zhang, Chi; Mosha, Donnati; Lee, Jong0Ill; Bushan, K. Mani; Hassan, Mansour M.; Loving, Galen

    2003-09-10

    The classic slowness that has kept the most powerful ligands from being used in separations applications is under attack in two ways: (1) replacing metal ion - ligand equilibration with switch binding and release as the mode of complexation. By exploiting the tight-binding capabilities of cryptands, the capture of selected metal ions isolates them from their environment. These cryptands are constructed with photoactivatable functions that sever the cryptand, releasing encapsulated metal ions. The precursors have been modified to capture the metal ion concomitant with crytate formation. (2) developing a methodology (the soil poultice) so slow that powerful ligands can be used. A solution containing the specially designed ligand is mixed with a solid macroporous imprinted polymer (MIPs) and applied to the contaminated area. The ligand captures the metal ion and the MIPs captures the resulting complex. Current studies focus on combinations of MIPs-complex interactions to optimize strength of binding and selectivity.

  16. Development of chiral sulfoxide ligands for asymmetric catalysis.

    PubMed

    Trost, Barry M; Rao, Meera

    2015-04-20

    Nitrogen-, phosphorus-, and oxygen-based ligands with chiral backbones have been the historic workhorses of asymmetric transition-metal-catalyzed reactions. On the contrary, sulfoxides containing chirality at the sulfur atom have mainly been used as chiral auxiliaries for diastereoselective reactions. Despite several distinct advantages over traditional ligand scaffolds, such as the proximity of the chiral information to the metal center and the ability to switch between S and O coordination, these compounds have only recently emerged as a versatile class of chiral ligands. In this Review, we detail the history of the development of chiral sulfoxide ligands for asymmetric catalysis. We also provide brief descriptions of metal-sulfoxide bonding and strategies for the synthesis of enantiopure sulfoxides. Finally, insights into the future development of this underutilized ligand class are discussed.

  17. Ligand binding was acquired during evolution of nuclear receptors

    PubMed Central

    Escriva, Hector; Safi, Rachid; Hänni, Catherine; Langlois, Marie-Claire; Saumitou-Laprade, Pierre; Stehelin, Dominique; Capron, André; Pierce, Raymond; Laudet, Vincent

    1997-01-01

    The nuclear receptor (NR) superfamily comprises, in addition to ligand-activated transcription factors, members for which no ligand has been identified to date. We demonstrate that orphan receptors are randomly distributed in the evolutionary tree and that there is no relationship between the position of a given liganded receptor in the tree and the chemical nature of its ligand. NRs are specific to metazoans, as revealed by a screen of NR-related sequences in early- and non-metazoan organisms. The analysis of the NR gene duplication pattern during the evolution of metazoans shows that the present NR diversity arose from two waves of gene duplications. Strikingly, our results suggest that the ancestral NR was an orphan receptor that acquired ligand-binding ability during subsequent evolution. PMID:9192646

  18. Non-aqueous chemistry of uranyl complexes with tripodal ligands

    NASA Astrophysics Data System (ADS)

    Burns, Carol J.; Clark, David L.; Duval, Paul B.; Scott, Brian L.

    2000-07-01

    The trans dioxo uranyl(VI) ion (UO22+) is remarkably stable with respect to the U=O bond, which dominates the stereochemistry of its coordination compounds in both aqueous and non-aqueous solutions. The linear O=U=O unit directs all other ligands to coordinate in an equatorial plane perpendicular to the O=U=O axis. In aqueous solution, uranyl coordination chemistry has been developed with a wide array of weak-field ligands that coordinate in the equatorial plane. In contrast, non-aqueous uranyl chemistry incorporating stronger donor ligands at equatorial sites has been less well developed. In this paper, the use of tripodal ligands with strong amide and alkoxide donors is employed, with an aim towards probing the electronic and steric effects of these cis-directing ligands on the structure and bonding of the trans dioxo unit.

  19. CD22 regulates B lymphocyte function in vivo through both ligand-dependent and ligand-independent mechanisms.

    PubMed

    Poe, Jonathan C; Fujimoto, Yoko; Hasegawa, Minoru; Haas, Karen M; Miller, Ann S; Sanford, Isaac G; Bock, Cheryl B; Fujimoto, Manabu; Tedder, Thomas F

    2004-10-01

    The interaction of CD22 with alpha2,6-linked sialic acid ligands has been widely proposed to regulate B lymphocyte function and migration. Here, we generated gene-targeted mice that express mutant CD22 molecules that do not interact with these ligands. CD22 ligand binding regulated the expression of cell surface CD22, immunoglobulin M and major histocompatibility complex class II on mature B cells, maintenance of the marginal zone B cell population, optimal B cell antigen receptor-induced proliferation, and B cell turnover rates. However, CD22 negative regulation of calcium mobilization after B cell antigen receptor ligation, CD22 phosphorylation, recruitment of SHP-1 to CD22 and B cell migration did not require CD22 ligand engagement. These observations resolve longstanding questions regarding the physiological importance of CD22 ligand binding in the regulation of B cell function in vivo.

  20. Gas adsorption and gas mixture separations using mixed-ligand MOF material

    DOEpatents

    Hupp, Joseph T.; Mulfort, Karen L.; Snurr, Randall Q.; Bae, Youn-Sang

    2011-01-04

    A method of separating a mixture of carbon dioxiode and hydrocarbon gas using a mixed-ligand, metal-organic framework (MOF) material having metal ions coordinated to carboxylate ligands and pyridyl ligands.

  1. Receptor Specific Ligands for Spect Imaging

    SciTech Connect

    Kung, H. F.

    2003-02-25

    In the past funding period we have concentrated in developing new 99mTc labeled MIBG analogs. Basic chemistry of ligand synthesis, radiochemistry of Re and 99mTc complex formation, separation of stereoisomers and in vitro stability were investigated. We have prepared a number of new MIBG derivatives containing chelating moiety N2S2 and additional groups to increase lipophilicity. Unfortunately none of the new 99mTc labeled MIBG analogs showed promise as an imaging agent for myocardial neuronal function. Radioactive-iodine-labeled meta-iodobenzylguanidine (MIBG) is currently being used as an in vivo imaging agent to evaluate neuroendocrine tumors as well as the myocardial sympathetic nervous system in patients with myocardial infarct and cardiomyopathy. It is generally accepted that MIBG is an analog of norepinephrine and its uptake in the heart corresponds to the distribution of norepinephrine and the density of sympathetic neurons. A series of MIBG derivatives containing suitable chelating functional groups N2S2 for the formation of [Tcv0]+3N2S2 complex was successfully synthesized and the 99mTc-labeled complexes were prepared and tested in rats. One of the compounds, [99mTc]M2, tested showed significant, albeit lower, heart uptakes post iv injection in rats (0.18% dose/organ at 4 hours) as compared to [l25l]MIBG (1.4% dose/organ at 4 hours). The heart uptake of the 99mTc-labeled complex, [99mTc]M2, appears to be specific and can be reduced by coinjection with nonradioactive MIBG or by pretreatment with desipramine. a selective norepinephrine transporter inhibitor. Further evaluation of the in vitro uptake of [99mTc]M2 in cultured neuroblastoma cells displayed consistently lower, but measurable uptake (app. 10% of that for [125l]MlBG). These preliminary results suggested that the mechanisms of heart uptake of [99mTc]M2 may be related to those for [125l]MIBG uptake. To improve the heart uptake of the MIBG derivatives we have developed chemistry related to the

  2. Electronic spectra and photophysics of platinum(II) complexes with alpha-diimine ligands - Solid-state effects. I - Monomers and ligand pi dimers

    NASA Technical Reports Server (NTRS)

    Miskowski, Vincent M.; Houlding, Virginia H.

    1989-01-01

    Two types of emission behavior for Pt(II) complexes containing alpha-diimine ligands have been observed in dilute solution. If the complex also has weak field ligands such as chloride, ligand field (d-d) excited states become the lowest energy excited states. If only strong field ligands are present, a diimine 3(pi-pi/asterisk/) state becomes the lowest. In none of the cases studied did metal-to-ligand charge transfer excited state lie lowest.

  3. Brain endogenous liver X receptor ligands selectively promote midbrain neurogenesis.

    PubMed

    Theofilopoulos, Spyridon; Wang, Yuqin; Kitambi, Satish Srinivas; Sacchetti, Paola; Sousa, Kyle M; Bodin, Karl; Kirk, Jayne; Saltó, Carmen; Gustafsson, Magnus; Toledo, Enrique M; Karu, Kersti; Gustafsson, Jan-Åke; Steffensen, Knut R; Ernfors, Patrik; Sjövall, Jan; Griffiths, William J; Arenas, Ernest

    2013-02-01

    Liver X receptors (Lxrα and Lxrβ) are ligand-dependent nuclear receptors critical for ventral midbrain neurogenesis in vivo. However, no endogenous midbrain Lxr ligand has so far been identified. Here we used LC/MS and functional assays to identify cholic acid as a new Lxr ligand. Moreover, 24(S),25-epoxycholesterol (24,25-EC) was found to be the most potent and abundant Lxr ligand in the developing mouse midbrain. Both Lxr ligands promoted neural development in an Lxr-dependent manner in zebrafish in vivo. Notably, each ligand selectively regulated the development of distinct midbrain neuronal populations. Whereas cholic acid increased survival and neurogenesis of Brn3a-positive red nucleus neurons, 24,25-EC promoted dopaminergic neurogenesis. These results identify an entirely new class of highly selective and cell type-specific regulators of neurogenesis and neuronal survival. Moreover, 24,25-EC promoted dopaminergic differentiation of embryonic stem cells, suggesting that Lxr ligands may thus contribute to the development of cell replacement and regenerative therapies for Parkinson's disease.

  4. Mass spectrometric analysis of protein–ligand interactions

    PubMed Central

    Ishii, Kentaro; Noda, Masanori; Uchiyama, Susumu

    2016-01-01

    The interactions of small molecules with proteins (protein–ligand interactions) mediate various biological phenomena including signal transduction and protein transcription and translation. Synthetic compounds such as drugs can also bind to target proteins, leading to the inhibition of protein–ligand interactions. These interactions typically accompany association–dissociation equilibrium according to the free energy difference between free and bound states; therefore, the quantitative biophysical analysis of the interactions, which uncovers the stoichiometry and dissociation constant, is important for understanding biological reactions as well as for rational drug development. Mass spectrometry (MS) has been used to determine the precise molecular masses of molecules. Recent advancements in MS enable us to determine the molecular masses of protein–ligand complexes without disrupting the non-covalent interactions through the gentle desolvation of the complexes by increasing the vacuum pressure of a chamber in a mass spectrometer. This method is called MS under non-denaturing conditions or native MS and allows the unambiguous determination of protein–ligand interactions. Under a few assumptions, MS has also been applied to determine the dissociation constants for protein–ligand interactions. The structural information of a protein–ligand interaction, such as the location of the interaction and conformational change in a protein, can also be analyzed using hydrogen/deuterium exchange MS. In this paper, we briefly describe the history, principle, and recent applications of MS for the study of protein–ligand interactions. PMID:27924262

  5. BINANA: A Novel Algorithm for Ligand-Binding Characterization

    PubMed Central

    Durrant, Jacob D.; McCammon, J. Andrew

    2011-01-01

    Computational chemists and structural biologists are often interested in characterizing ligand-receptor complexes for hydrogen-bond, hydrophobic, salt-bridge, van der Waals, and other interactions in order to assess ligand binding. When done by hand, this characterization can become tedious, especially when many complexes need be analyzed. In order to facilitate the characterization of ligand binding, we here present a novel Python-implemented computer algorithm called BINANA (BINding ANAlyzer), which is freely available for download at http://www.nbcr.net/binana/. To demonstrate the utility of the new algorithm, we use BINANA to confirm that the number of hydrophobic contacts between a ligand and its protein receptor is positively correlated with ligand potency. Additionally, we show how BINANA can be used to search through a large ligand-receptor database to identify those complexes that are remarkable for selected binding features, and to identify lead candidates from a virtual screen with specific, desirable binding characteristics. We are hopeful that BINANA will be useful to computational chemists and structural biologists who wish to automatically characterize many ligand-receptor complexes for key binding characteristics. PMID:21310640

  6. Novel biosensors for the detection of estrogen receptor ligands.

    PubMed

    De, Siddhartha; Macara, Ian G; Lannigan, Deborah A

    2005-08-01

    There exists a significant need for the detection of novel estrogen receptor (ER) ligands for pharmaceutical uses, especially for treating complications associated with menopause. We have developed fluorescence resonance energy transfer (FRET)-based biosensors that permit the direct in vitro detection of ER ligands. These biosensors contain an ER ligand-binding domain (LBD) flanked by the FRET donor fluorophore, cyan fluorescent protein (CFP), and the acceptor fluorophore, yellow fluorescent protein (YFP). The ER-LBD has been modified so that Ala 430 has been changed to Asp, which increases the magnitude of the FRET signal in response to ligand-binding by more than four-fold compared to the wild-type LBD. The binding of agonists can be distinguished from that of antagonists on the basis of the distinct ligand-induced conformations in the ER-LBD. The approach to binding equilibrium occurs within 30min, and the FRET signal is stable over 24h. The biosensor demonstrates a high signal-to-noise, with a Z' value (a statistical determinant of assay quality) of 0.72. The affinity of the ER for different ligands can be determined using a modified version of the biosensor in which a truncated YFP and an enhanced CFP are used. Thus, we have developed platforms for high-throughput screens for the identification of novel estrogen receptor ligands. Moreover, we have demonstrated that this FRET technology can be applied to other nuclear receptors, such as the androgen receptor.

  7. Structural Analysis of Chemokine Receptor-Ligand Interactions.

    PubMed

    Arimont, Marta; Sun, Shan-Liang; Leurs, Rob; Smit, Martine; de Esch, Iwan J P; de Graaf, Chris

    2017-03-10

    This review focuses on the construction and application of structural chemokine receptor models for the elucidation of molecular determinants of chemokine receptor modulation and the structure-based discovery and design of chemokine receptor ligands. A comparative analysis of ligand binding pockets in chemokine receptors is presented, including a detailed description of the CXCR4, CCR2, CCR5, CCR9, and US28 X-ray structures, and their implication for modeling molecular interactions of chemokine receptors with small-molecule ligands, peptide ligands, and large antibodies and chemokines. These studies demonstrate how the integration of new structural information on chemokine receptors with extensive structure-activity relationship and site-directed mutagenesis data facilitates the prediction of the structure of chemokine receptor-ligand complexes that have not been crystallized. Finally, a review of structure-based ligand discovery and design studies based on chemokine receptor crystal structures and homology models illustrates the possibilities and challenges to find novel ligands for chemokine receptors.

  8. NMR-based analysis of protein-ligand interactions.

    PubMed

    Cala, Olivier; Guillière, Florence; Krimm, Isabelle

    2014-02-01

    Physiological processes are mainly controlled by intermolecular recognition mechanisms involving protein-protein and protein-ligand (low molecular weight molecules) interactions. One of the most important tools for probing these interactions is high-field solution nuclear magnetic resonance (NMR) through protein-observed and ligand-observed experiments, where the protein receptor or the organic compounds are selectively detected. NMR binding experiments rely on comparison of NMR parameters of the free and bound states of the molecules. Ligand-observed methods are not limited by the protein molecular size and therefore have great applicability for analysing protein-ligand interactions. The use of these NMR techniques has considerably expanded in recent years, both in chemical biology and in drug discovery. We review here three major ligand-observed NMR methods that depend on the nuclear Overhauser effect-transferred nuclear Overhauser effect spectroscopy, saturation transfer difference spectroscopy and water-ligand interactions observed via gradient spectroscopy experiments-with the aim of reporting recent developments and applications for the characterization of protein-ligand complexes, including affinity measurements and structural determination.

  9. ZINC 15 – Ligand Discovery for Everyone

    PubMed Central

    2015-01-01

    Many questions about the biological activity and availability of small molecules remain inaccessible to investigators who could most benefit from their answers. To narrow the gap between chemoinformatics and biology, we have developed a suite of ligand annotation, purchasability, target, and biology association tools, incorporated into ZINC and meant for investigators who are not computer specialists. The new version contains over 120 million purchasable “drug-like” compounds – effectively all organic molecules that are for sale – a quarter of which are available for immediate delivery. ZINC connects purchasable compounds to high-value ones such as metabolites, drugs, natural products, and annotated compounds from the literature. Compounds may be accessed by the genes for which they are annotated as well as the major and minor target classes to which those genes belong. It offers new analysis tools that are easy for nonspecialists yet with few limitations for experts. ZINC retains its original 3D roots – all molecules are available in biologically relevant, ready-to-dock formats. ZINC is freely available at http://zinc15.docking.org. PMID:26479676

  10. Xylamine, a ligand for the catecholamine transporter

    SciTech Connect

    Waggaman, L.A.

    1985-01-01

    Previous studies have established xylamine (N-2'-chloro-ethyl-N-ethyl-2-methylbenzylamine) irreversibly inhibits neuronal norepinephrine uptake with no concomitant effect on other neurotransmitter systems. Since xylamine is thought to alkylate transport-associated sites in the plasma membrane of noradrenergic neurons, so the loss of endogenous norepinephrine may be a consequence of neuronal membrane damage resulting from the alkylation of membrane components. In these studies, xylamine, under in vitro conditions, irreversibly inhibited both neuronal norepinephrine and dopamine uptake in the rat cortex and striatum, respectively. The efficacy of xylamine as a neuronal dopamine uptake inhibitor appeared to depend on its ability to access dopaminergic neurons during tissue exposure to the drug. In sympathetically innervated peripheral tissues, (/sup 3/H)xylamine was accumulated in noradrenergic neurons in a carrier-dependent manner. Although the data suggested that xylamine was interacting with the norepinephrine uptake carrier, (/sup 3/H)xylamine exposure to isolated synaptic membranes from superior cervical ganglia revealed a large proportion of (/sup 3/H)xylamine binding that was not associated with the noradrenergic transporter. For a closer characterization of xylamine binding in synaptic membranes, brain tissue was chosen as a more practical source of these membranes. While these experiments did not meet with great success, xylamine remains potentially useful as a ligand for identifying the catecholamine transporter, particularly in conjunction with procedures for protein purification and reconstitution.

  11. Cationic aluminum alkyl complexes incorporating aminotroponiminate ligands.

    PubMed

    Korolev, A V; Ihara, E; Guzei, I A; Young, V G; Jordan, R F

    2001-08-29

    The synthesis, structures, and reactivity of cationic aluminum complexes containing the N,N'-diisopropylaminotroponiminate ligand ((i)Pr(2)-ATI(-)) are described. The reaction of ((i)Pr(2)-ATI)AlR(2) (1a-e,g,h; R = H (a), Me (b), Et (c), Pr (d), (i)Bu (e), Cy (g), CH(2)Ph (h)) with [Ph(3)C][B(C(6)F(5))(4)] yields ((i)()Pr(2)-ATI)AlR(+) species whose fate depends on the properties of the R ligand. 1a and 1b react with 0.5 equiv of [Ph(3)C][B(C(6)F(5))(4)] to produce dinuclear monocationic complexes [([(i)Pr(2)-ATI] AlR)(2)(mu-R)][(C(6)F(5))(4)] (2a,b). The cation of 2b contains two ((i)()Pr(2)-ATI)AlMe(+) units linked by an almost linear Al-Me-Al bridge; 2a is presumed to have an analogous structure. 2b does not react further with [Ph(3)C][B(C(6)F(5))(4)]. However, 1a reacts with 1 equiv of [Ph(3)C][B(C(6)F(5))(4)] to afford ((i Pr(2)-ATI)Al(C(6)F(5))(mu-H)(2)B(C(6)F(5))(2) (3) and other products, presumably via C(6)F(5)(-) transfer and ligand redistribution of a [((i)()Pr(2)-ATI)AlH][(C(6)F(5))(4)] intermediate. 1c-e react with 1 equiv of [Ph(3)C][B(C(6)F(5))(4)] to yield stable base-free [((i)Pr(2)-ATI)AlR][B(C(6)F(5))(4)] complexes (4c-e). 4c crystallizes from chlorobenzene as 4c(ClPh).0.5PhCl, which has been characterized by X-ray crystallography. In the solid state the PhCl ligand of 4c(ClPh) is coordinated by a dative PhCl-Al bond and an ATI/Ph pi-stacking interaction. 1g,h react with [Ph(3)C][B(C(6)F(5))(4)] to yield ((i)Pr(2)-ATI)Al(R)(C(6)F(5)) (5g,h) via C(6)F(5)(-) transfer of [((i)Pr(2)-ATI)AlR][(BC(6)F(5))(4)] intermediates. 1c,h react with B(C(6)F(5))(3) to yield ((i)Pr(2)-ATI)Al(R)(C(6)F(5)) (5c,h) via C(6)F(5)(-) transfer of [((i)Pr(2)-ATI)AlR][RB(C(6)F(5))(3)] intermediates. The reaction of 4c-e with MeCN or acetone yields [((i)Pr(2)-ATI)Al(R)(L)][B(C(6)F(5))(4)] adducts (L = MeCN (8c-e), acetone (9c-e)), which undergo associative intermolecular L exchange. 9c-e undergo slow beta-H transfer to afford the dinuclear dicationic alkoxide complex [(((i

  12. Validated ligand mapping of ACE active site

    NASA Astrophysics Data System (ADS)

    Kuster, Daniel J.; Marshall, Garland R.

    2005-08-01

    Crystal structures of angiotensin-converting enzyme (ACE) complexed with three inhibitors (lisinopril, captopril, enalapril) provided experimental data for testing the validity of a prior active site model predicting the bound conformation of the inhibitors. The ACE active site model - predicted over 18 years ago using a series of potent ACE inhibitors of diverse chemical structure - was recreated using published data and commercial software. Comparison between the predicted structures of the three inhibitors bound to the active site of ACE and those determined experimentally yielded root mean square deviation (RMSD) values of 0.43-0.81 Å, among the distances defining the active site map. The bound conformations of the chemically relevant atoms were accurately deduced from the geometry of ligands, applying the assumption that the geometry of the active site groups responsible for binding and catalysis of amide hydrolysis was constrained. The mapping of bound inhibitors at the ACE active site was validated for known experimental compounds, so that the constrained conformational search methodology may be applied with confidence when no experimentally determined structure of the enzyme yet exists, but potent, diverse inhibitors are available.

  13. The Death Ligand TRAIL in Diabetic Nephropathy

    PubMed Central

    Lorz, Corina; Benito-Martín, Alberto; Boucherot, Anissa; Ucero, Alvaro C.; Rastaldi, Maria Pia; Henger, Anna; Armelloni, Silvia; Santamaría, Beatriz; Berthier, Celine C.; Kretzler, Matthias; Egido, Jesus; Ortiz, Alberto

    2008-01-01

    Apoptotic cell death contributes to diabetic nephropathy (DN), but its role is not well understood. The tubulointerstitium from DN biopsy specimens was microdissected, and expression profiles of genes related to apoptosis were analyzed. A total of 112 (25%) of 455 cell death–related genes were found to be significantly differentially regulated. Among those that showed the greatest changes in regulation were two death receptors, OPG (the gene encoding osteoprotegerin) and Fas, and the death ligand TRAIL. Glomerular and proximal tubular TRAIL expression, assessed by immunohistochemistry, was higher in DN kidneys than controls and was associated with clinical and histologic severity of disease. In vitro, proinflammatory cytokines but not glucose alone regulated TRAIL expression in the human proximal tubular cell line HK-2. TRAIL induced tubular cell apoptosis in a dosage-dependant manner, an effect that was more marked in the presence of high levels of glucose and proinflammatory cytokines. TRAIL also activated NF-κB, and inhibition of NF-κB sensitized cells to TRAIL-induced apoptosis. It is proposed that TRAIL-induced cell death could play an important role in the progression of human DN. PMID:18287563

  14. Charge Optimization Theory for Induced-Fit Ligands

    PubMed Central

    2012-01-01

    The design of ligands with high affinity and specificity remains a fundamental challenge in understanding molecular recognition and developing therapeutic interventions. Charge optimization theory addresses this problem by determining ligand charge distributions that produce the most favorable electrostatic contribution to the binding free energy. The theory has been applied to the design of binding specificity as well. However, the formulations described only treat a rigid ligand—one that does not change conformation upon binding. Here, we extend the theory to treat induced-fit ligands for which the unbound ligand conformation may differ from the bound conformation. We develop a thermodynamic pathway analysis for binding contributions relevant to the theory, and we illustrate application of the theory using HIV-1 protease with our previously designed and validated subnanomolar inhibitor. Direct application of rigid charge optimization approaches to nonrigid cases leads to very favorable intramolecular electrostatic interactions that are physically unreasonable, and analysis shows the ligand charge distribution massively stabilizes the preconformed (bound) conformation over the unbound. After analyzing this case, we provide a treatment for the induced-fit ligand charge optimization problem that produces physically realistic results. The key factor is introducing the constraint that the free energy of the unbound ligand conformation be lower or equal to that of the preconformed ligand structure, which corresponds to the notion that the unbound structure is the ground unbound state. Results not only demonstrate the applicability of this methodology to discovering optimized charge distributions in an induced-fit model, but also provide some insights into the energetic consequences of ligand conformational change on binding. Specifically, the results show that, from an electrostatic perspective, induced-fit binding is not an adaptation designed to enhance binding

  15. Encoding protein-ligand interaction patterns in fingerprints and graphs.

    PubMed

    Desaphy, Jérémy; Raimbaud, Eric; Ducrot, Pierre; Rognan, Didier

    2013-03-25

    We herewith present a novel and universal method to convert protein-ligand coordinates into a simple fingerprint of 210 integers registering the corresponding molecular interaction pattern. Each interaction (hydrophobic, aromatic, hydrogen bond, ionic bond, metal complexation) is detected on the fly and physically described by a pseudoatom centered either on the interacting ligand atom, the interacting protein atom, or the geometric center of both interacting atoms. Counting all possible triplets of interaction pseudoatoms within six distance ranges, and pruning the full integer vector to keep the most frequent triplets enables the definition of a simple (210 integers) and coordinate frame-invariant interaction pattern descriptor (TIFP) that can be applied to compare any pair of protein-ligand complexes. TIFP fingerprints have been calculated for ca. 10,000 druggable protein-ligand complexes therefore enabling a wide comparison of relationships between interaction pattern similarity and ligand or binding site pairwise similarity. We notably show that interaction pattern similarity strongly depends on binding site similarity. In addition to the TIFP fingerprint which registers intermolecular interactions between a ligand and its target protein, we developed two tools (Ishape, Grim) to align protein-ligand complexes from their interaction patterns. Ishape is based on the overlap of interaction pseudoatoms using a smooth Gaussian function, whereas Grim utilizes a standard clique detection algorithm to match interaction pattern graphs. Both tools are complementary and enable protein-ligand complex alignments capitalizing on both global and local pattern similarities. The new fingerprint and companion alignment tools have been successfully used in three scenarios: (i) interaction-biased alignment of protein-ligand complexes, (ii) postprocessing docking poses according to known interaction patterns for a particular target, and (iii) virtual screening for bioisosteric

  16. Binding of flexible and constrained ligands to the Grb2 SH2 domain: structural effects of ligand preorganization

    PubMed Central

    Clements, John H.; DeLorbe, John E.; Benfield, Aaron P.; Martin, Stephen F.

    2010-01-01

    Structures of the Grb2 SH2 domain complexed with a series of pseudopeptides containing flexible (benzyl succinate) and constrained (aryl cyclopropanedicarboxylate) replacements of the phosphotyrosine (pY) residue in tripeptides derived from Ac-pYXN-NH2 (where X = V, I, E and Q) were elucidated by X-ray crystallography. Complexes of flexible/constrained pairs having the same pY + 1 amino acid were analyzed in order to ascertain what structural differences might be attributed to constraining the phosphotyrosine replacement. In this context, a given structural dissimilarity between complexes was considered to be significant if it was greater than the corresponding difference in complexes coexisting within the same asymmetric unit. The backbone atoms of the domain generally adopt a similar conformation and orientation relative to the ligands in the complexes of each flexible/constrained pair, although there are some significant differences in the relative orientations of several loop regions, most notably in the BC loop that forms part of the binding pocket for the phosphate group in the tyrosine replacements. These variations are greater in the set of complexes of constrained ligands than in the set of complexes of flexible ligands. The constrained ligands make more direct polar contacts to the domain than their flexible counterparts, whereas the more flexible ligand of each pair makes more single-water-mediated contacts to the domain; there was no correlation between the total number of protein–ligand contacts and whether the phosphotyrosine replacement of the ligand was preorganized. The observed differences in hydrophobic interactions between the complexes of each flexible/constrained ligand pair were generally similar to those observed upon comparing such contacts in coexisting complexes. The average adjusted B factors of the backbone atoms of the domain and loop regions are significantly greater in the complexes of constrained ligands than in the complexes of

  17. Facile dimer synthesis for DNA-binding polyamide ligands.

    PubMed

    Wetzler, Modi; Wemmer, David E

    2010-08-06

    Pyrrole-imidazole polyamide ligands are highly sequence specific synthetic DNA-binding ligands that bind with high affinity. To counter the synthetic difficulties associated with coupling the electron-rich heterocyclic acids to the electron-deficient nucleophilic imidazole amine, a novel approach is described for synthesis of Fmoc-protected dimers for solid-phase peptide synthesis (SPPS). This method produces the dimers in high yields, is broadly applicable to other heterocyclic-containing polyamides, and results in improved ligand yields and synthesis times.

  18. A divergent strategy for attaching polypyridyl ligands to peptides.

    PubMed

    Jabre, Nitinkumar D; Respondek, Tomasz; Ulku, Selma A; Korostelova, Nadiya; Kodanko, Jeremy J

    2010-02-05

    A divergent method for incorporating polypyridyl ligands into peptides is reported. Three N-Fmoc unnatural amino acids (1-3) that contain varying linkers between the alpha-carbon and a 2-(hydroxymethyl)pyridyl group were synthesized in enantioenriched form. These amino acids were used as anchors for incorporating multidentate ligands onto a peptide chain in a site-specific fashion. Multiple peptide-ligand conjugates were synthesized from single precursors by solution- or solid-phase methods. Peptides containing more than one metal-binding unit can be produced by this method.

  19. Plasmon resonance enhanced mechanical detection of ligand binding

    SciTech Connect

    Ariyaratne, Amila; Zocchi, Giovanni

    2015-01-05

    Small molecule binding to the active site of enzymes typically modifies the mechanical stiffness of the enzyme. We exploit this effect, in a setup which combines nano-mechanics and surface plasmon resonance (SPR) enhanced optics, for the label free detection of ligand binding to an enzyme. The large dynamic range of the signal allows to easily obtain binding curves for small ligands, in contrast to traditional SPR methods which rely on small changes in index of refraction. Enzyme mechanics, assessed by nano-rheology, thus emerges as an alternative to electronic and spin resonances, assessed by traditional spectroscopies, for detecting ligand binding.

  20. Ligands targeting the excitatory amino acid transporters (EAATs).

    PubMed

    Dunlop, John; Butera, John A

    2006-01-01

    This review provides an overview of ligands for the excitatory amino acid transporters (EAATs), a family of high-affinity glutamate transporters localized to the plasma membrane of neurons and astroglial cells. Ligand development from the perspective of identifying novel and more selective tools for elucidating transporter subtype function, and the potential of transporter ligands in a therapeutic setting are discussed. Acute pharmacological modulation of EAAT activity in the form of linear and conformationally restricted glutamate and aspartate analogs is presented, in addition to recent strategies aimed more toward modulating transporter expression levels, the latter of particular significance to the development of transporter based therapeutics.

  1. Polyethylene glycol-based homologated ligands for nicotinic acetylcholine receptors☆

    PubMed Central

    Scates, Bradley A.; Lashbrook, Bethany L.; Chastain, Benjamin C.; Tominaga, Kaoru; Elliott, Brandon T.; Theising, Nicholas J.; Baker, Thomas A.; Fitch, Richard W.

    2010-01-01

    A homologous series of polyethylene glycol (PEG) monomethyl ethers were conjugated with three ligand series for nicotinic acetylcholine receptors. Conjugates of acetylaminocholine, the cyclic analog 1-acetyl-4,4-dimethylpiperazinium, and pyridyl ether A-84543 were prepared. Each series was found to retain significant affinity at nicotinic receptors in rat cerebral cortex with tethers of up to six PEG units. Such compounds are hydrophilic ligands which may serve as models for fluorescent/affinity probes and multivalent ligands for nAChR. PMID:19006672

  2. Advances and Challenges in Protein-Ligand Docking

    PubMed Central

    Huang, Sheng-You; Zou, Xiaoqin

    2010-01-01

    Molecular docking is a widely-used computational tool for the study of molecular recognition, which aims to predict the binding mode and binding affinity of a complex formed by two or more constituent molecules with known structures. An important type of molecular docking is protein-ligand docking because of its therapeutic applications in modern structure-based drug design. Here, we review the recent advances of protein flexibility, ligand sampling, and scoring functions—the three important aspects in protein-ligand docking. Challenges and possible future directions are discussed in the Conclusion. PMID:21152288

  3. Ligand and Structure-based Methodologies for the Prediction of the Activity of G Protein-Coupled Receptor Ligands

    PubMed Central

    Costanzi, Stefano; Tikhonova, Irina G.; Harden, T. Kendall; Jacobson, Kenneth A.

    2008-01-01

    Summary Accurate in silico models for the quantitative prediction of the activity of G protein-coupled receptor (GPCR) ligands would greatly facilitate the process of drug discovery and development. Several methodologies have been developed based on the properties of the ligands, the direct study of the receptor-ligand interactions, or a combination of both approaches. Ligand-based three-dimensional quantitative structure-activity relationships (3D-QSAR) techniques, not requiring knowledge of the receptor structure, have been historically the first to be applied to the prediction of the activity of GPCR ligands. They are generally endowed with robustness and good ranking ability; however they are highly dependent on training sets. Structure-based techniques generally do not provide the level of accuracy necessary to yield meaningful rankings when applied to GPCR homology models. However, they are essentially independent from training sets and have a sufficient level of accuracy to allow an effective discrimination between binders and nonbinders, thus qualifying as viable lead discovery tools. The combination of ligand and structure-based methodologies in the form of receptor-based 3D-QSAR and ligand and structure-based consensus models results in robust and accurate quantitative predictions. The contribution of the structure-based component to these combined approaches is expected to become more substantial and effective in the future, as more sophisticated scoring functions are developed and more detailed structural information on GPCRs is gathered. PMID:18483766

  4. Ligand and structure-based methodologies for the prediction of the activity of G protein-coupled receptor ligands

    NASA Astrophysics Data System (ADS)

    Costanzi, Stefano; Tikhonova, Irina G.; Harden, T. Kendall; Jacobson, Kenneth A.

    2009-11-01

    Accurate in silico models for the quantitative prediction of the activity of G protein-coupled receptor (GPCR) ligands would greatly facilitate the process of drug discovery and development. Several methodologies have been developed based on the properties of the ligands, the direct study of the receptor-ligand interactions, or a combination of both approaches. Ligand-based three-dimensional quantitative structure-activity relationships (3D-QSAR) techniques, not requiring knowledge of the receptor structure, have been historically the first to be applied to the prediction of the activity of GPCR ligands. They are generally endowed with robustness and good ranking ability; however they are highly dependent on training sets. Structure-based techniques generally do not provide the level of accuracy necessary to yield meaningful rankings when applied to GPCR homology models. However, they are essentially independent from training sets and have a sufficient level of accuracy to allow an effective discrimination between binders and nonbinders, thus qualifying as viable lead discovery tools. The combination of ligand and structure-based methodologies in the form of receptor-based 3D-QSAR and ligand and structure-based consensus models results in robust and accurate quantitative predictions. The contribution of the structure-based component to these combined approaches is expected to become more substantial and effective in the future, as more sophisticated scoring functions are developed and more detailed structural information on GPCRs is gathered.

  5. Role of ligand-dependent GR phosphorylation and half-life in determination of ligand-specific transcriptional activity.

    PubMed

    Avenant, Chanel; Ronacher, Katharina; Stubsrud, Elisabeth; Louw, Ann; Hapgood, Janet P

    2010-10-07

    A central question in glucocorticoid mechanism of action via the glucocorticoid receptor (GR) is what determines ligand-selective transcriptional responses. Using a panel of 12 GR ligands, we show that the extent of GR phosphorylation at S226 and S211, GR half-life and transcriptional response, occur in a ligand-selective manner. While GR phosphorylation at S226 was shown to inhibit maximal transcription efficacy, phosphorylation at S211 is required for maximal transactivation, but not for transrepression efficacy. Both ligand-selective GR phosphorylation and half-life correlated with efficacy for transactivation and transrepression. For both expressed and endogenous GR, in two different cell lines, agonists resulted in the greatest extent of phosphorylation and the greatest extent of GR downregulation, suggesting a link between these functions. However, using phosphorylation-deficient GR mutants we established that phosphorylation of the GR at S226 or S211 does not determine the rank order of ligand-selective GR transactivation. These results are consistent with a model whereby ligand-selective GR phosphorylation and half-life are a consequence of upstream events, such as ligand-specific GR conformations, which are maintained in the phosphorylation mutants.

  6. A Natural Mutation in Helix 5 of the Ligand Binding Domain of Glucocorticoid Receptor Enhances Receptor-Ligand Interaction

    PubMed Central

    Reyer, Henry; Ponsuksili, Siriluck; Kanitz, Ellen; Pöhland, Ralf; Wimmers, Klaus; Murani, Eduard

    2016-01-01

    The glucocorticoid receptor (GR) is a central player in the neuroendocrine stress response; it mediates feedback regulation of the hypothalamus-pituitary-adrenal (HPA) axis and physiological actions of glucocorticoids in the periphery. Despite intensive investigations of GR in the context of receptor-ligand interaction, only recently the first naturally occurring gain-of-function substitution, Ala610Val, of the ligand binding domain was identified in mammals. We showed that this mutation underlies a major quantitative trait locus for HPA axis activity in pigs, reducing cortisol production by about 40–50 percent. To unravel the molecular mechanisms behind this gain of function, receptor-ligand interactions were evaluated in silico, in vitro and in vivo. In accordance with previously observed phenotypic effects, the mutant Val610 GR showed significantly increased activation in response to glucocorticoid and non-glucocorticoid steroids, and, as revealed by GR-binding studies in vitro and in pituitary glands, enhanced ligand binding. Concordantly, the protein structure prediction depicted reduced binding distances between the receptor and ligand, and altered interactions in the ligand binding pocket. Consequently, the Ala610Val substitution opens up new structural information for the design of potent GR ligands and to examine effects of the enhanced GR responsiveness to glucocorticoids on the entire organism. PMID:27736993

  7. End-to-end azido-pinned interlocking lanthanide squares.

    PubMed

    Li, Xiao-Lei; Wu, Jianfeng; Zhao, Lang; Shi, Wei; Cheng, Peng; Tang, Jinkui

    2017-03-09

    A rare end-to-end azido-pinned interlocking lanthanide square was self-assembled using a ditopic Schiff-base (H2L) and NaN3 as ligands. Obvious ferromagnetic interaction and a record anisotropy barrier of 152(4) K among lanthanide azido-bridged SMMs in a zero dc field were observed.

  8. Bench-top to clinical therapies: A review of melanocortin ligands from 1954 to 2016.

    PubMed

    Ericson, Mark D; Lensing, Cody J; Fleming, Katlyn A; Schlasner, Katherine N; Doering, Skye R; Haskell-Luevano, Carrie

    2017-03-29

    The discovery of the endogenous melanocortin agonists in the 1950s have resulted in sixty years of melanocortin ligand research. Early efforts involved truncations or select modifications of the naturally occurring agonists leading to the development of many potent and selective ligands. With the identification and cloning of the five known melanocortin receptors, many ligands were improved upon through bench-top in vitro assays. Optimization of select properties resulted in ligands adopted as clinical candidates. A summary of every melanocortin ligand is outside the scope of this review. Instead, this review will focus on the following topics: classic melanocortin ligands, selective ligands, small molecule (non-peptide) ligands, ligands with sex-specific effects, bivalent and multivalent ligands, and ligands advanced to clinical trials. Each topic area will be summarized with current references to update the melanocortin field on recent progress. This article is part of a Special Issue entitled: Melanocortin Receptors - edited by Ya-Xiong Tao.

  9. Chemistry and pharmacology of GABAB receptor ligands.

    PubMed

    Froestl, Wolfgang

    2010-01-01

    This chapter presents new clinical applications of the prototypic GABA(B) receptor agonist baclofen for the treatment of addiction by drugs of abuse, such as alcohol, cocaine, nicotine, morphine, and heroin, a novel baclofen prodrug Arbaclofen placarbil, the GABA(B) receptor agonist AZD3355 (Lesogabaran) currently in Phase 2 clinical trials for the treatment of gastroesophageal reflux disease, and four positive allosteric modulators of GABA(B) receptors (CGP7930, GS39783, NVP-BHF177, and BHFF), which have less propensity for the development of tolerance due to receptor desensitization than classical GABA(B) receptor agonists. All four compounds showed anxiolytic affects. In the presence of positive allosteric modulators the "classical" GABA(B) receptor antagonists CGP35348 and 2-hydroxy-saclofen showed properties of partial GABA(B) receptor agonists. Seven micromolar affinity GABA(B) receptor antagonists, phaclofen; 2-hydroxy-saclofen; CGP's 35348, 36742, 46381, 51176; and SCH50911, are discussed. CGP36742 (SGS742) showed statistically significant improvements of working memory and attention in a Phase 2 clinical trial in mild, but not in moderate Alzheimer patients. Eight nanomolar affinity GABA(B) receptor antagonists are presented (CGP's 52432, 54626, 55845, 56433, 56999, 61334, 62349, and 63360) that were used by pharmacologists for numerous in vitro and in vivo investigations. CGP's 36742, 51176, 55845, and 56433 showed antidepressant effects. Several compounds are also available as radioligands, such as [(3)H]CGP27492, [(3)H]CGP54626, [(3)H]CGP5699, and [(3)H]CGP62349. Three novel fluorescent and three GABA(B) receptor antagonists with very high specific radioactivity (>2,000 Ci/mmol) are presented. [(125)I]CGP64213 and the photoaffinity ligand [(125)I]CGP71872 allowed the identification of GABA(B1a) and GABA(B1b) receptors in the expression cloning work.

  10. Disulfide Bond Requirements for Active Wnt Ligands*

    PubMed Central

    MacDonald, Bryan T.; Hien, Annie; Zhang, Xinjun; Iranloye, Oladoyin; Virshup, David M.; Waterman, Marian L.; He, Xi

    2014-01-01

    Secreted Wnt lipoproteins are cysteine-rich and lipid-modified morphogens that bind to the Frizzled (FZD) receptor and LDL receptor-related protein 6 (LRP6). Wnt engages FZD through protruding thumb and index finger domains, which are each assembled from paired β strands secured by disulfide bonds and grasp two sides of the FZD ectodomain. The importance of Wnt disulfide bonds has been assumed but uncharacterized. We systematically analyzed cysteines and associated disulfide bonds in the prototypic Wnt3a. Our data show that mutation of any individual cysteine of Wnt3a results in covalent Wnt oligomers through ectopic intermolecular disulfide bond formation and diminishes/abolishes Wnt signaling. Although individual cysteine mutations in the amino part of the saposin-like domain and in the base of the index finger are better tolerated and permit residual Wnt3a secretion/activity, those in the amino terminus, the thumb, and at the tip of the index finger are incompatible with secretion and/or activity. A few select double cysteine mutants based on the disulfide bond pattern restore Wnt secretion/activity. Further, a double cysteine mutation at the index finger tip results in a Wnt3a with normal secretion but minimal FZD binding and dominant negative properties. Our results experimentally validate predictions from the Wnt crystal structure and highlight critical but different roles of the saposin-like and cytokine-like domains, including the thumb and the index finger in Wnt folding/secretion and FZD binding. Finally, we modified existing expression vectors for 19 epitope-tagged human WNT proteins by removal of a tag-supplied ectopic cysteine, thereby generating tagged WNT ligands active in canonical and non-canonical signaling. PMID:24841207

  11. The Foundations of Protein-Ligand Interaction

    NASA Astrophysics Data System (ADS)

    Klebe, Gerhard

    For the specific design of a drug we must first answer the question: How does a drug achieve its activity? An active ingredient must, in order to develop its action, bind to a particular target molecule in the body. Usually this is a protein, but also nucleic acids in the form of RNA and DNA can be target structures for active agents. The most important condition for binding is at first that the active agent exhibits the correct size and shape in order to optimally fit into a cavity exposed to the surface of the protein, the "bindingpocket". It is further necessary for the surface properties of the ligand and protein to be mutually compatible to form specific interactions. In 1894 Emil Fischer compared the exact fit of a substrate for the catalytic centre of an enzyme with the picture of a "lock-and-key". Paul Ehrlich coined in 1913 "Corpora non agunt nisi fixata", literally "bodies do not work when they are not bound". He wanted to imply that active agents that are meant to kill bacteria or parasites must be "fixed" by them, i.e. linked to their structures. Both concepts form the starting point for any rational concept in the development of active pharmaceutical ingredients. In many respects they still apply today. A drug must, after being administered, reach its target and interact with a biological macromolecule. Specific agents have a large affinity and sufficient selectivity to bind to the macromolecule's active site. This is the only way they can develop the desired biological activity without side-effects.

  12. Ligand engineering of lead chalcogenide nanoparticle solar cells

    NASA Astrophysics Data System (ADS)

    Voros, Marton; Brawand, Nicholas; Galli, Giulia

    Semiconductor nanoparticles (NP) are promising materials to build cheap and efficient solar cells. One of the key challenges in their utilization for solar energy conversion is the control of ligand-NP interfaces. Recent experiments have shown that by carefully choosing the ligands terminating the NPs, one can tailor electronic and optical absorption properties of NP assemblies, along with their transport properties. By using density functional theory based methods, we investigated how the opto-electronic properties of lead chalcogenide NPs may be tuned by using diverse organic and inorganic ligands. We interpreted experiments, and we showed that an essential prerequisite to avoid detrimental trap states is to ensure charge balance at the ligand-NP interface, possibly with the help of hydrogen treatment. Work supported by the Center for Advanced Solar Photophysics, an Energy Frontier Research Center funded by the US Department of Energy, Office of Science, Office of Basic Energy Sciences.

  13. Bivalent Ligands for the Serotonin 5-HT3 Receptor

    PubMed Central

    2011-01-01

    The serotonin 5-HT3 receptor is a ligand-gated ion channel, which by virtue of its pentameric architecture, can be considered to be an intriguing example of intrinsically multivalent biological receptors. This paper describes a general design approach to the study of multivalency in this multimeric ion channel. Bivalent ligands for 5-HT3 receptor have been designed by linking an arylpiperazine moiety to probes showing different functional features. Both homobivalent and heterobivalent ligands have shown 5-HT3 receptor affinity in the nanomolar range, providing evidence for the viability of our design approach. Moreover, the high affinity shown by homobivalent ligands suggests that bivalency is a promising approach in 5-HT3 receptor modulation and provides the rational basis for applying the concepts of multivalency to the study of 5-HT3 receptor function. PMID:24900351

  14. Ligand development in the Ni-catalyzed hydrocyanation of alkenes.

    PubMed

    Bini, Laura; Müller, Christian; Vogt, Dieter

    2010-11-28

    The addition of HCN to alkenes is a very useful reaction for the synthesis of functional organic substrates. Industrially the nickel-catalyzed hydrocyanation has gained considerable importance mainly because of the production of adiponitrile in the DuPont process. In this process the hydrocyanation of butadiene is carried out using aryl phosphite-modified nickel catalyst. Since the performance of organo-transition metal complexes is largely determined by the ligand environment of the metal, fundamental understanding and ligand development is of pivotal importance for any progress. This feature article gives an account of the development and application of different mono- and bidentate phosphorus-based ligands in the Ni-catalyzed hydrocyanation reaction of alkenes. Special attention will be paid to the development of insight and understanding of the ligand structural and electronic properties towards the improvement of the catalyst performance in terms of stability, activity, and selectivity.

  15. Pharmacophore-based discovery of ligands for drug transporters

    PubMed Central

    Chang, Cheng; Ekins, Sean; Bahadduri, Praveen; Swaan, Peter W.

    2006-01-01

    The ability to identify ligands for drug transporters is an important step in drug discovery and development. It can both improve accurate profiling of lead pharmacokinetic properties and assist in the discovery of new chemical entities targeting transporters. In silico approaches, especially pharmacophore-based database screening methods have great potential in improving the throughput of current transporter ligand identification assays, leading to a higher hit rate by focusing in vitro testing to the most promising hits. In this review, the potential of different in silico methods in transporter ligand identification studies are compared and summarized with an emphasis on pharmacophore modeling. Various implementations of pharmacophore model generation, database compilation and flexible screening algorithms are also introduced. Recent successful utilization of database searching with pharmacophores to identify novel ligands for the pharmaceutically significant transporters hPepT1, P-gp, BCRP, MRP1 and DAT are reviewed and challenges encountered with current approaches are discussed. PMID:17097188

  16. "Clickable" affinity ligands for effective separation of glycoproteins.

    PubMed

    Suksrichavalit, Thummaruk; Yoshimatsu, Keiichi; Prachayasittikul, Virapong; Bülow, Leif; Ye, Lei

    2010-06-04

    In this paper, we present a new modular approach to immobilize boronic acid ligands that can offer effective separation of glycoproteins. A new "clickable" boronic acid ligand was synthesized by introducing a terminal acetylene group into commercially available 3-aminophenyl boronic acid. The clickable ligand, 3-(prop-2-ynyloxycarbonylamino)phenylboronic acid (2) could be easily coupled to azide-functionalized hydrophilic Sepharose using Cu(I)-catalyzed 1,3-dipolar cycloaddition reaction under mild condition. Compared to other boronic acid affinity gels, the new affinity gel displayed superior effectiveness in separating model glycoproteins (ovalbumin and RNase B) from closely related bovine serum albumin and RNase A in the presence of crude Escherichia coli proteins. Because of the simplicity of the immobilization through "click chemistry", the new ligand 2 is expected to not only offer improved glycoprotein separation in other formats, but also act as a useful building block to develop new chemical sensors for analysis of other glycan compounds.

  17. Paramagnetic Ligand Tagging To Identify Protein Binding Sites

    PubMed Central

    2015-01-01

    Transient biomolecular interactions are the cornerstones of the cellular machinery. The identification of the binding sites for low affinity molecular encounters is essential for the development of high affinity pharmaceuticals from weakly binding leads but is hindered by the lack of robust methodologies for characterization of weakly binding complexes. We introduce a paramagnetic ligand tagging approach that enables localization of low affinity protein–ligand binding clefts by detection and analysis of intermolecular protein NMR pseudocontact shifts, which are invoked by the covalent attachment of a paramagnetic lanthanoid chelating tag to the ligand of interest. The methodology is corroborated by identification of the low millimolar volatile anesthetic interaction site of the calcium sensor protein calmodulin. It presents an efficient route to binding site localization for low affinity complexes and is applicable to rapid screening of protein–ligand systems with varying binding affinity. PMID:26289584

  18. Unique advantages of organometallic supporting ligands for uranium complexes

    SciTech Connect

    Diaconescu, Paula L.; Garcia, Evan

    2014-05-31

    The objective of our research project was to study the reactivity of uranium complexes supported by ferrocene-based ligands. In addition, this research provides training of graduate students as the next generation of actinide scientists.

  19. Ligand Binding to Macromolecules: Allosteric and Sequential Models of Cooperativity.

    ERIC Educational Resources Information Center

    Hess, V. L.; Szabo, Attila

    1979-01-01

    A simple model is described for the binding of ligands to macromolecules. The model is applied to the cooperative binding by hemoglobin and aspartate transcarbamylase. The sequential and allosteric models of cooperative binding are considered. (BB)

  20. Searching for Practically Useful P-Chirogenic Phosphine Ligands.

    PubMed

    Imamoto, Tsuneo

    2016-12-01

    In this account, the design, synthesis, and application of P-chirogenic phosphine ligands that have been mainly carried out in our laboratory over the last three decades are described. Various enantiopure P-chirogenic phosphine ligands have been efficiently prepared by using phosphine boranes as intermediates. Conformationally rigid and electron-rich P-chirogenic phosphine ligands possessing C2 symmetry as well as a bulky alkyl group and a small group at the phosphorus atoms exhibit excellent enantioselectivities and catalytic efficiency in a variety of transition-metal-catalyzed asymmetric reactions. Enantiopure 2,3-bis(tert-butylmethylphosphino)quinoxaline (QuinoxP*) is an air-stable crystalline solid that shows superior enantioinduction ability in catalytic asymmetric syntheses. Mechanistic studies of Rh-catalyzed asymmetric hydrogenation using structurally simple P-chirogenic phosphine ligands, such as tBu-BisP*, are briefly described.

  1. CD40 ligand immunotherapy in cancer: an efficient approach.

    PubMed

    Kuwashima, N; Kageyama, S; Eto, Y; Urashima, M

    2001-01-01

    Cancer cells do not elicit a clinically sufficient anti-tumor immune response that results in tumor rejection. Recently, many investigators have been trying to enhance anti-tumor immunity and encouraging results have been reported. This review will discuss current anti-cancer immunotherapy; interleukin-2 therapy, tumor vaccine secreting Granulocyte macrophage-colony stimulating factor, dendritic cells fused with tumor cells, and CD40 ligand immunotherapy. Moreover, we introduce our two kinds of CD40 ligand immuno-genetherapy; (1) oral CD40 ligand gene therapy against lymphoma using attenuated Salmonella typhimurium (published in BLOOD 2000), (2) cancer vaccine transfected with CD40 ligand ex vivo for neuroblastoma (unpublished). Both approaches resulted in a high degree of protection against the tumor progression and they are simple and safe in the murine system.

  2. Tetrapyrroles as Endogenous TSPO Ligands in Eukaryotes and Prokaryotes: Comparisons with Synthetic Ligands

    PubMed Central

    Veenman, Leo; Vainshtein, Alex; Yasin, Nasra; Azrad, Maya; Gavish, Moshe

    2016-01-01

    The 18 kDa translocator protein (TSPO) is highly 0conserved in eukaryotes and prokaryotes. Since its discovery in 1977, numerous studies established the TSPO’s importance for life essential functions. For these studies, synthetic TSPO ligands typically are applied. Tetrapyrroles present endogenous ligands for the TSPO. Tetrapyrroles are also evolutionarily conserved and regulate multiple functions. TSPO and tetrapyrroles regulate each other. In animals TSPO-tetrapyrrole interactions range from effects on embryonic development to metabolism, programmed cell death, response to stress, injury and disease, and even to life span extension. In animals TSPOs are primarily located in mitochondria. In plants TSPOs are also present in plastids, the nuclear fraction, the endoplasmic reticulum, and Golgi stacks. This may contribute to translocation of tetrapyrrole intermediates across organelles’ membranes. As in animals, plant TSPO binds heme and protoporphyrin IX. TSPO-tetrapyrrole interactions in plants appear to relate to development as well as stress conditions, including salt tolerance, abscisic acid-induced stress, reactive oxygen species homeostasis, and finally cell death regulation. In bacteria, TSPO is important for switching from aerobic to anaerobic metabolism, including the regulation of photosynthesis. As in mitochondria, in bacteria TSPO is located in the outer membrane. TSPO-tetrapyrrole interactions may be part of the establishment of the bacterial-eukaryote relationships, i.e., mitochondrial-eukaryote and plastid-plant endosymbiotic relationships. PMID:27271616

  3. Tetrapyrroles as Endogenous TSPO Ligands in Eukaryotes and Prokaryotes: Comparisons with Synthetic Ligands.

    PubMed

    Veenman, Leo; Vainshtein, Alex; Yasin, Nasra; Azrad, Maya; Gavish, Moshe

    2016-06-04

    The 18 kDa translocator protein (TSPO) is highly 0conserved in eukaryotes and prokaryotes. Since its discovery in 1977, numerous studies established the TSPO's importance for life essential functions. For these studies, synthetic TSPO ligands typically are applied. Tetrapyrroles present endogenous ligands for the TSPO. Tetrapyrroles are also evolutionarily conserved and regulate multiple functions. TSPO and tetrapyrroles regulate each other. In animals TSPO-tetrapyrrole interactions range from effects on embryonic development to metabolism, programmed cell death, response to stress, injury and disease, and even to life span extension. In animals TSPOs are primarily located in mitochondria. In plants TSPOs are also present in plastids, the nuclear fraction, the endoplasmic reticulum, and Golgi stacks. This may contribute to translocation of tetrapyrrole intermediates across organelles' membranes. As in animals, plant TSPO binds heme and protoporphyrin IX. TSPO-tetrapyrrole interactions in plants appear to relate to development as well as stress conditions, including salt tolerance, abscisic acid-induced stress, reactive oxygen species homeostasis, and finally cell death regulation. In bacteria, TSPO is important for switching from aerobic to anaerobic metabolism, including the regulation of photosynthesis. As in mitochondria, in bacteria TSPO is located in the outer membrane. TSPO-tetrapyrrole interactions may be part of the establishment of the bacterial-eukaryote relationships, i.e., mitochondrial-eukaryote and plastid-plant endosymbiotic relationships.

  4. Fluorescent and Lanthanide Labeling for Ligand Screens, Assays, and Imaging

    PubMed Central

    Josan, Jatinder S.; De Silva, Channa R.; Yoo, Byunghee; Lynch, Ronald M.; Pagel, Mark D.; Vagner, Josef; Hruby, Victor J.

    2012-01-01

    The use of fluorescent (or luminescent) and metal contrast agents in high-throughput screens, in vitro assays, and molecular imaging procedures has rapidly expanded in recent years. Here we describe the development and utility of high-affinity ligands for cancer theranostics and other in vitro screening studies. In this context, we also illustrate the syntheses and use of heteromultivalent ligands as targeted imaging agents. PMID:21318902

  5. Square planar Cu(I) stabilized by a pyridinediimine ligand.

    PubMed

    Cheung, Pui Man; Berger, Robert F; Zakharov, Lev N; Gilbertson, John D

    2016-03-18

    A set of distorted square planar Cu(I) complexes were synthesized and characterized utilizing the sterically encumbering pyridinediimine ligand, (iPr)PDI (where (iPr)PDI = 2,6-(2,6-(i)Pr2C6H3N=CMe)2C5H3N). The oxidation state of the Cu center(s) were elucidated to be Cu(I) with a neutral PDI ligand system based on structural, spectroscopic, and computational data.

  6. Self-assembled molecular films incorporating a ligand

    DOEpatents

    Bednarski, M.D.; Wilson, T.E.; Mastandra, M.S.

    1996-04-23

    Functionalized monomers are presented which can be used in the fabrication of molecular films for controlling adhesion, detection of receptor-ligand binding and enzymatic reactions; new coatings for lithography; and for semiconductor materials. The monomers are a combination of a ligand, a linker, optionally including a polymerizable group, and a surface attachment group. The processes and an apparatus for making films from these monomers, as well as methods of using the films are also provided. 7 figs.

  7. Drawing Mononuclear Octahedral Coordination Compounds Containing Tridentate Chelating Ligands

    ERIC Educational Resources Information Center

    Mohamadou, Aminou; Ple, Karen; Haudrechy, Arnaud

    2011-01-01

    Complexes with tridentate ligands of the type [M(A-B-C)2], where A [not equal to] B [not equal to] C and with an imposed bonding sequence A-B-C, require special attention to draw all possible stereoisomers. Depending on the nature of the central donor atom B of the tridentate ligand, an easy drawing method is presented that shows seven chiral…

  8. Self-assembled molecular films incorporating a ligand

    DOEpatents

    Bednarski, Mark D.; Wilson, Troy E.; Mastandra, Mark S.

    1996-01-01

    Functionalized monomers are presented which can be used in the fabrication of molecular films for controlling adhesion, detection of receptor-ligand binding and enzymatic reactions; new coatings for lithography; and for semiconductor materials. The monomers are a combination of a ligand, a linker, optionally including a polymerizable group, and a surface attachment group. The processes and an apparatus for making films from these monomers, as well as methods of using the films are also provided.

  9. Reaction chemistry and ligand exchange at cadmium selenide nanocrystal surfaces

    SciTech Connect

    Owen, Jonathan; Park, Jungwon; Trudeau, Paul-Emile; Alivisatos, A. Paul

    2008-12-02

    Chemical modification of nanocrystal surfaces is fundamentally important to their assembly, their implementation in biology and medicine, and greatly impacts their electrical and optical properties. However, it remains a major challenge owing to a lack of analytical tools to directly determine nanoparticle surface structure. Early nuclear magnetic resonance (NMR) and X-ray photoelectron spectroscopy (XPS) studies of CdSe nanocrystals prepared in tri-n-octylphosphine oxide (1) and tri-n-octylphosphine (2), suggested these coordinating solvents are datively bound to the particle surface. However, assigning the broad NMR resonances of surface-bound ligands is complicated by significant concentrations of phosphorus-containing impurities in commercial sources of 1, and XPS provides only limited information about the nature of the phosphorus containing molecules in the sample. More recent reports have shown the surface ligands of CdSe nanocrystals prepared in technical grade 1, and in the presence of alkylphosphonic acids, include phosphonic and phosphinic acids. These studies do not, however, distinguish whether these ligands are bound datively, as neutral, L-type ligands, or by X-type interaction of an anionic phosphonate/phosphinate moiety with a surface Cd{sup 2+} ion. Answering this question would help clarify why ligand exchange with such particles does not proceed generally as expected based on a L-type ligand model. By using reagents with reactive silicon-chalcogen and silicon-chlorine bonds to cleave the ligands from the nanocrystal surface, we show that our CdSe and CdSe/ZnS core-shell nanocrystal surfaces are likely terminated by X-type binding of alkylphosphonate ligands to a layer of Cd{sup 2+}/Zn{sup 2+} ions, rather than by dative interactions. Further, we provide spectroscopic evidence that 1 and 2 are not coordinated to our purified nanocrystals.

  10. CD6-ligand interactions: a paradigm for SRCR domain function?

    PubMed

    Aruffo, A; Bowen, M A; Patel, D D; Haynes, B F; Starling, G C; Gebe, J A; Bajorath, J

    1997-10-01

    The scavenger receptor cysteine-rich (SRCR) superfamily, which includes proteins expressed by leukocytes, can be subdivided into groups A and B. Group B contains the lymphocyte cell-surface receptor CD6. This article reviews recent progress in understanding the interaction between CD6 and its ligand, activated leukocyte cell adhesion molecule (ALCAM). Analysis of the CD6-ALCAM interaction may help to understand how other SRCR domains bind to their ligands.

  11. Models of protein–ligand crystal structures: trust, but verify

    PubMed Central

    Deller, Marc C.

    2015-01-01

    X-ray crystallography provides the most accurate models of protein–ligand structures. These models serve as the foundation of many computational methods including structure prediction, molecular modelling, and structure-based drug design. The success of these computational methods ultimately depends on the quality of the underlying protein–ligand models. X-ray crystallography offers the unparalleled advantage of a clear mathematical formalism relating the experimental data to the protein–ligand model. In the case of X-ray crystallography, the primary experimental evidence is the electron density of the molecules forming the crystal. The first step in the generation of an accurate and precise crystallographic model is the interpretation of the electron density of the crystal, typically carried out by construction of an atomic model. The atomic model must then be validated for fit to the experimental electron density and also for agreement with prior expectations of stereochemistry. Stringent validation of protein–ligand models has become possible as a result of the mandatory deposition of primary diffraction data, and many computational tools are now available to aid in the validation process. Validation of protein–ligand complexes has revealed some instances of overenthusiastic interpretation of ligand density. Fundamental concepts and metrics of protein–ligand quality validation are discussed and we highlight software tools to assist in this process. It is essential that end users select high quality protein–ligand models for their computational and biological studies, and we provide an overview of how this can be achieved. PMID:25665575

  12. Supramolecular polymers based on the quadruplex formation of ditopic guanosine macromonomers in nonaqueous media.

    PubMed

    Pintér, Gabor; Batta, Gyula; Horvath, Pal; Löki, Istvan; Kurtan, Tibor; Antus, Sandor; Kéki, Sandor; Zsuga, Miklós; Nagy, Gabor; Aradi, Janos; Gunda, Tamas; Herczegh, Pal

    2007-05-08

    The formation of supramolecular polymeric aggregates with a molecular mass of 100 kDa in a nonaqueous solution from a telechelic dimer of isopropylidene guanosine in the presence of K(+) ions is reported. The possible structure of macromonomers resulting from the development of G4 quartets was deduced from DOSY NMR, circular dichroism spectra, and dynamic light scattering measurements.

  13. Regulation of NKG2D ligand gene expression.

    PubMed

    Eagle, Robert A; Traherne, James A; Ashiru, Omodele; Wills, Mark R; Trowsdale, John

    2006-03-01

    The activating immunoreceptor NKG2D has seven known host ligands encoded by the MHC class I chain-related MIC and ULBP/RAET genes. Why there is such diversity of NKG2D ligands is not known but one hypothesis is that they are differentially expressed in different tissues in response to different stresses. To explore this, we compared expression patterns and promoters of NKG2D ligand genes. ULBP/RAET genes were transcribed independent of each other in a panel of cell lines. ULBP/RAET gene expression was upregulated on infection with human cytomegalovirus; however, a clinical strain, Toledo, induced expression more slowly than did a laboratory strain, AD169. ULBP4/RAET1E was not induced by infection with either strain. To investigate the mechanisms behind the similarities and differences in NKG2D ligand gene expression a comparative sequence analysis of NKG2D ligand gene putative promoter regions was conducted. Sequence alignments demonstrated that there was significant sequence diversity; however, one region of high similarity between most of the genes is evident. This region contains a number of potential transcription factor binding sites, including those involved in shock responses and sites for retinoic acid-induced factors. Promoters of some NKG2D ligand genes are polymorphic and several sequence alterations in these alleles abolished putative transcription factor binding.

  14. Riboswitch structure in the ligand-free state.

    PubMed

    Liberman, Joseph A; Wedekind, Joseph E

    2012-01-01

    Molecular investigations of riboswitches bound to small-molecule effectors have produced a wealth of information on how these molecules achieve high affinity and specificity for a target ligand. X-ray crystal structures have been determined for the ligand-free state for representatives of the preQ₁-I, S-adenosylmethionine I, lysine, and glycine aptamer classes. These structures in conjunction with complimentary techniques, such as in-line probing, NMR spectroscopy, Förster resonance energy transfer, small-angle scattering, and computational simulations, have demonstrated that riboswitches adopt multiple conformations in the absence of ligand. Despite a number of investigations that support ligand-dependent folding, mounting evidence suggests that free-state riboswitches interact with their effectors in the sub-populations of largely prefolded states as embodied by the principle of conformational selection, which has been documented extensively for protein-mediated ligand interactions. Fundamental riboswitch investigations of the bound and free states have advanced our understanding of RNA folding, ligand recognition, and how these factors culminate in communication between an aptamer and its expression platform. An understanding of these topics is essential to comprehend riboswitch gene regulation at the molecular level, which has already provided a basis to understand the mechanism of action of natural antimicrobials.

  15. Orphan receptor ligand discovery by pickpocketing pharmacological neighbors.

    PubMed

    Ngo, Tony; Ilatovskiy, Andrey V; Stewart, Alastair G; Coleman, James L J; McRobb, Fiona M; Riek, R Peter; Graham, Robert M; Abagyan, Ruben; Kufareva, Irina; Smith, Nicola J

    2017-02-01

    Understanding the pharmacological similarity of G protein-coupled receptors (GPCRs) is paramount for predicting ligand off-target effects, drug repurposing, and ligand discovery for orphan receptors. Phylogenetic relationships do not always correctly capture pharmacological similarity. Previous family-wide attempts to define pharmacological relationships were based on three-dimensional structures and/or known receptor-ligand pairings, both unavailable for orphan GPCRs. Here, we present GPCR-CoINPocket, a novel contact-informed neighboring pocket metric of GPCR binding-site similarity that is informed by patterns of ligand-residue interactions observed in crystallographically characterized GPCRs. GPCR-CoINPocket is applicable to receptors with unknown structure or ligands and accurately captures known pharmacological relationships between GPCRs, even those undetected by phylogeny. When applied to orphan receptor GPR37L1, GPCR-CoINPocket identified its pharmacological neighbors, and transfer of their pharmacology aided in discovery of the first surrogate ligands for this orphan with a 30% success rate. Although primarily designed for GPCRs, the method is easily transferable to other protein families.

  16. Lyar Is a New Ligand for Retinal Pigment Epithelial Phagocytosis.

    PubMed

    Guo, Feiye; Ding, Ying; Caberoy, Nora B; Alvarado, Gabriela; Liu, Robert; Shen, Chen; Yu, Jisu; Zhou, Yixiong; Salero, Enrique; LeBlanc, Michelle E; Wang, Weiwen; Li, Wei

    2015-10-01

    Phagocytosis is critical to tissue homeostasis, as highlighted by phagocytosis defect of retinal pigment epithelial (RPE) cells with debris accumulation, photoreceptor degeneration and blindness. Phagocytosis ligands are the key to delineating molecular mechanisms and functional roles of phagocytes, but are traditionally identified in individual cases with technical challenges. We recently developed open reading frame phage display (OPD) for phagocytosis-based functional cloning (PFC) to identify unknown ligands. One of the identified ligands was Ly-1 antibody reactive clone (Lyar) with functions poorly defined. Herein, we characterized Lyar as a new ligand to stimulate RPE phagocytosis. In contrast to its reported nucleolar expression, immunohistochemistry showed that Lyar was highly expressed in photoreceptor outer segments (POSs) of the retina. Cytoplasmic Lyar was released from apoptotic cells, and selectively bound to shed POSs and apoptotic cells, but not healthy cells. POS vesicles engulfed through Lyar-dependent pathway were targeted to phagosomes and colocalized with phagosome marker Rab7. These results suggest that Lyar is a genuine RPE phagocytosis ligand, which in turn supports the validity of OPD/PFC as the only available approach for unbiased identification of phagocytosis ligands with broad applicability to various phagocytes.

  17. Cell mechanosensory recognizes ligand compliance at biomaterial interface.

    PubMed

    Cosenza, Chiara; Lettera, Vincenzo; Causa, Filippo; Scognamiglio, Pasqualina Liana; Battista, Edmondo; Netti, Paolo Antonio

    2016-01-01

    Cells activate signalling through ligand-receptor bonds by sensing the mechanical properties of the surrounding extracellular matrix (ECM). Ligands, indeed, have to withstand the pulling force elicited by cell receptors through focal adhesions (FAs). On this basis, we developed functional ligands to be simply adsorbed on surfaces and constituted by a two-domain peptide: one derived from ECM proteins and available to receptors to offer biochemical cues, and another adsorbed on material to withstand the tension upon receptor engagement. Tuneable compliance of the anchoring domain of the peptide ligand was verified by single peptide analysis through molecular dynamics and adsorption measurements. We showed that the highest adsorbed peptides combined with integrin cell-binding motifs allow for the cell recognition and polarization with larger mature FA areas. On the contrary, the lowest adsorbed sequences did not provide mechanical resistance to the integrin pulling action, leading to more rounded cells with smaller FA areas. This evidence demonstrates that cell mechanosensory can discriminate ligands on surfaces and should be considered as a criterion in ligand design for material bioactivation.

  18. Ligand binding analysis and screening by chemical denaturation shift.

    PubMed

    Schön, Arne; Brown, Richard K; Hutchins, Burleigh M; Freire, Ernesto

    2013-12-01

    The identification of small molecule ligands is an important first step in drug development, especially drugs that target proteins with no intrinsic activity. Toward this goal, it is important to have access to technologies that are able to measure binding affinities for a large number of potential ligands in a fast and accurate way. Because ligand binding stabilizes the protein structure in a manner dependent on concentration and binding affinity, the magnitude of the protein stabilization effect elicited by binding can be used to identify and characterize ligands. For example, the shift in protein denaturation temperature (Tm shift) has become a popular approach to identify potential ligands. However, Tm shifts cannot be readily transformed into binding affinities, and the ligand rank order obtained at denaturation temperatures (≥60°C) does not necessarily coincide with the rank order at physiological temperature. An alternative approach is the use of chemical denaturation, which can be implemented at any temperature. Chemical denaturation shifts allow accurate determination of binding affinities with a surprisingly wide dynamic range (high micromolar to sub nanomolar) and in situations where binding changes the cooperativity of the unfolding transition. In this article, we develop the basic analytical equations and provide several experimental examples.

  19. Phage Selection of Chemically Stabilized α-Helical Peptide Ligands.

    PubMed

    Diderich, Philippe; Bertoldo, Davide; Dessen, Pierre; Khan, Maola M; Pizzitola, Irene; Held, Werner; Huelsken, Joerg; Heinis, Christian

    2016-05-20

    Short α-helical peptides stabilized by linkages between constituent amino acids offer an attractive format for ligand development. In recent years, a range of excellent ligands based on stabilized α-helices were generated by rational design using α-helical peptides of natural proteins as templates. Herein, we developed a method to engineer chemically stabilized α-helical ligands in a combinatorial fashion. In brief, peptides containing cysteines in position i and i + 4 are genetically encoded by phage display, the cysteines are modified with chemical bridges to impose α-helical conformations, and binders are isolated by affinity selection. We applied the strategy to affinity mature an α-helical peptide binding β-catenin. We succeeded in developing ligands with Kd's as low as 5.2 nM, having >200-fold improved affinity. The strategy is generally applicable for affinity maturation of any α-helical peptide. Compared to hydrocarbon stapled peptides, the herein evolved thioether-bridged peptide ligands can be synthesized more easily, as no unnatural amino acids are required and the cyclization reaction is more efficient and yields no stereoisomers. A further advantage of the thioether-bridged peptide ligands is that they can be expressed recombinantly as fusion proteins.

  20. Ligand exchange in quaternary alloyed nanocrystals--a spectroscopic study.

    PubMed

    Gabka, Grzegorz; Bujak, Piotr; Giedyk, Kamila; Kotwica, Kamil; Ostrowski, Andrzej; Malinowska, Karolina; Lisowski, Wojciech; Sobczak, Janusz W; Pron, Adam

    2014-11-14

    Exchange of initial, predominantly stearate ligands for pyridine in the first step and butylamine (BA) or 11-mercaptoundecanoic acid (MUA) in the second one was studied for alloyed quaternary Cu-In-Zn-S nanocrystals. The NMR results enabled us to demonstrate, for the first time, direct binding of the pyridine labile ligand to the nanocrystal surface as evidenced by paramagnetic shifts of the three signals attributed to its protons to 7.58, 7.95 and 8.75 ppm. XPS investigations indicated, in turn, a significant change in the composition of the nanocrystal surface upon the exchange of initial ligands for pyridine, which being enriched in indium in the 'as prepared' form became enriched in zinc after pyridine binding. This finding indicated that the first step of ligand exchange had to involve the removal of the surface layer enriched in indium with simultaneous exposure of a new, zinc-enriched layer. In the second ligand exchange step (replacement of pyridine with BA or MUA) the changes in the nanocrystal surface compositions were much less significant. The presence of zinc in the nanocrystal surface layer turned out necessary for effective binding of pyridine as shown by a comparative study of ligand exchange in Cu-In-Zn-S, Ag-In-Zn-S and CuInS2, carried out by complementary XPS and NMR investigations.

  1. Limited proteolysis for assaying ligand binding affinities of nuclear receptors.

    PubMed

    Benkoussa, M; Nominé, B; Mouchon, A; Lefebvre, B; Bernardon, J M; Formstecher, P; Lefebvre, P

    1997-01-01

    The binding of natural or synthetic ligands to nuclear receptors is the triggering event leading to gene transcription activation or repression. Ligand binding to the ligand binding domain of these receptors induces conformational changes that are evidenced by an increased resistance of this domain to proteases. In vitro labeled receptors were incubated with various synthetic or natural agonists or antagonists and submitted to trypsin digestion. Proteolysis products were separated by SDS-PAGE and quantified. The amount of trypsin-resistant fragments was proportional to receptor occupancy by the ligand, and allowed the determination of dissociation constants (kDa). Using the wild-type or mutated human retinoic acid receptor alpha as a model, kDa values determined by classical competition binding assays using tritiated ligands are in agreement with those measured by the proteolytic assay. This method was successfully extended to human retinoic X receptor alpha, glucocorticoid receptor, and progesterone receptor, thus providing a basis for a new, faster assay to determine simultaneously the affinity and conformation of receptors when bound to a given ligand.

  2. Ligand and interfacial dynamics in a homodimeric hemoglobin

    PubMed Central

    Gupta, Prashant Kumar; Meuwly, Markus

    2016-01-01

    The structural dynamics of dimeric hemoglobin (HbI) from Scapharca inaequivalvis in different ligand-binding states is studied from atomistic simulations on the μs time scale. The intermediates are between the fully ligand-bound (R) and ligand-free (T) states. Tertiary structural changes, such as rotation of the side chain of Phe97, breaking of the Lys96–heme salt bridge, and the Fe–Fe separation, are characterized and the water dynamics along the R-T transition is analyzed. All these properties for the intermediates are bracketed by those determined experimentally for the fully ligand-bound and ligand-free proteins, respectively. The dynamics of the two monomers is asymmetric on the 100 ns timescale. Several spontaneous rotations of the Phe97 side chain are observed which suggest a typical time scale of 50–100 ns for this process. Ligand migration pathways include regions between the B/G and C/G helices and, if observed, take place in the 100 ns time scale. PMID:26958581

  3. FXR and its ligands inhibit the function of platelets

    PubMed Central

    Vaiyapuri, Sakthivel; Ali, Marfoua S.; Sasikumar, Parvathy; Sage, Tanya; Flora, Gagan D; Bye, Alex P; Kriek, Neline; Dorchies, Emilie; Molendi-Coste, Olivier; Dombrowicz, David; Staels, Bart; Bishop-Bailey, David

    2016-01-01

    Objective While initially seemingly paradoxical due to the lack of nucleus, platelets possess a number of transcription factors that regulate their function through DNA-independent mechanisms. These include the Farnesoid X Receptor (FXR), a member of the superfamily of ligand-activated transcription factors that has been identified as a bile acid receptor. In this study, we show that FXR is present in human platelets and FXR ligands, GW4064 and 6-ECDCA, modulate platelet activation nongenomically. Approach and Results FXR ligands inhibited the activation of platelets in response to stimulation of collagen or thrombin receptors, resulting in diminished intracellular calcium mobilization and secretion, fibrinogen binding and aggregation. Exposure to FXR ligands also reduced integrin αIIbβ3 outside-in signaling and thereby reduced the ability of platelets to spread and to stimulate clot retraction. FXR function in platelets was found to be associated with the modulation of cGMP levels in platelets and associated downstream inhibitory signaling. Platelets from FXR-deficient mice were refractory to the actions of FXR agonists on platelet function and cyclic nucleotide signaling, firmly linking the non-genomic actions of these ligands to the FXR receptor. Conclusion This study provides support for the ability of FXR ligands to modulate platelet activation. The athero-protective effects of GW4064, with its novel antiplatelet effects, indicate FXR as a potential target for prevention of athero-thrombotic disease. PMID:27758768

  4. Database of Ligand-Receptor Partners, a DIP subset

    DOE Data Explorer

    Graeber, Thomas G.; Eisenberg, David

    The Database of Ligand-Receptor Partners (DLRP) is a subset of DIP (Database of Interacting Proteins). The DLRP is a database of protein ligand and protein receptor pairs that are known to interact with each other. By interact we mean that the ligand and receptor are members of a ligand-receptor complex and, unless otherwise noted, transduce a signal. In some instances the ligand and/or receptor may form a heterocomplex with other ligands/receptors in order to be functional. We have entered the majority of interactions in DLRP as full DIP entries, with links to references and additional information (see the DIP User's Guide). DLRP is a web supplement for: Thomas G. Graeber and David Eisenberg. Bioinformatic identification of potential autocrine signaling loops in cancers from gene expression profiles. Nature Genetics, 29(3):295-300 (November 2001). [Quoted from the DLRP homepage at http://dip.doe-mbi.ucla.edu/dip/DLRP.cgi] Also available from this page is the DLRP chemokine subset.

  5. Predicting Efficient Antenna Ligands for Tb(III) Emission

    SciTech Connect

    Samuel, Amanda P.S.; Xu, Jide; Raymond, Kenneth

    2008-10-06

    A series of highly luminescent Tb(III) complexes of para-substituted 2-hydroxyisophthalamide ligands (5LI-IAM-X) has been prepared (X = H, CH{sub 3}, (C=O)NHCH{sub 3}, SO{sub 3}{sup -}, NO{sub 2}, OCH{sub 3}, F, Cl, Br) to probe the effect of substituting the isophthalamide ring on ligand and Tb(III) emission in order to establish a method for predicting the effects of chromophore modification on Tb(III) luminescence. The energies of the ligand singlet and triplet excited states are found to increase linearly with the {pi}-withdrawing ability of the substituent. The experimental results are supported by time-dependent density functional theory (TD-DFT) calculations performed on model systems, which predict ligand singlet and triplet energies within {approx}5% of the experimental values. The quantum yield ({Phi}) values of the Tb(III) complex increases with the triplet energy of the ligand, which is in part due to the decreased non-radiative deactivation caused by thermal repopulation of the triplet. Together, the experimental and theoretical results serve as a predictive tool that can be used to guide the synthesis of ligands used to sensitize lanthanide luminescence.

  6. Discovery of GPCR ligands for probing signal transduction pathways

    PubMed Central

    Brogi, Simone; Tafi, Andrea; Désaubry, Laurent; Nebigil, Canan G.

    2014-01-01

    G protein-coupled receptors (GPCRs) are seven integral transmembrane proteins that are the primary targets of almost 30% of approved drugs and continue to represent a major focus of pharmaceutical research. All of GPCR targeted medicines were discovered by classical medicinal chemistry approaches. After the first GPCR crystal structures were determined, the docking screens using these structures lead to discovery of more novel and potent ligands. There are over 360 pharmaceutically relevant GPCRs in the human genome and to date about only 30 of structures have been determined. For these reasons, computational techniques such as homology modeling and molecular dynamics simulations have proven their usefulness to explore the structure and function of GPCRs. Furthermore, structure-based drug design and in silico screening (High Throughput Docking) are still the most common computational procedures in GPCRs drug discovery. Moreover, ligand-based methods such as three-dimensional quantitative structure–selectivity relationships, are the ideal molecular modeling approaches to rationalize the activity of tested GPCR ligands and identify novel GPCR ligands. In this review, we discuss the most recent advances for the computational approaches to effectively guide selectivity and affinity of ligands. We also describe novel approaches in medicinal chemistry, such as the development of biased agonists, allosteric modulators, and bivalent ligands for class A GPCRs. Furthermore, we highlight some knockout mice models in discovering biased signaling selectivity. PMID:25506327

  7. Ligands Slow Down Pure-Dephasing in Semiconductor Quantum Dots.

    PubMed

    Liu, Jin; Kilina, Svetlana V; Tretiak, Sergei; Prezhdo, Oleg V

    2015-09-22

    It is well-known experimentally and theoretically that surface ligands provide additional pathways for energy relaxation in colloidal semiconductor quantum dots (QDs). They increase the rate of inelastic charge-phonon scattering and provide trap sites for the charges. We show that, surprisingly, ligands have the opposite effect on elastic electron-phonon scattering. Our simulations demonstrate that elastic scattering slows down in CdSe QDs passivated with ligands compared to that in bare QDs. As a result, the pure-dephasing time is increased, and the homogeneous luminescence line width is decreased in the presence of ligands. The lifetime of quantum superpositions of single and multiple excitons increases as well, providing favorable conditions for multiple excitons generation (MEG). Ligands reduce the pure-dephasing rates by decreasing phonon-induced fluctuations of the electronic energy levels. Surface atoms are most mobile in QDs, and therefore, they contribute greatly to the electronic energy fluctuations. The mobility is reduced by interaction with ligands. A simple analytical model suggests that the differences between the bare and passivated QDs persist for up to 5 nm diameters. Both low-frequency acoustic and high-frequency optical phonons participate in the dephasing processes in bare QDs, while low-frequency acoustic modes dominate in passivated QDs. The theoretical predictions regarding the pure-dephasing time, luminescence line width, and MEG can be verified experimentally by studying QDs with different surface passivation.

  8. Rule of five in 2015 and beyond: Target and ligand structural limitations, ligand chemistry structure and drug discovery project decisions.

    PubMed

    Lipinski, Christopher A

    2016-06-01

    The rule of five (Ro5), based on physicochemical profiles of phase II drugs, is consistent with structural limitations in protein targets and the drug target ligands. Three of four parameters in Ro5 are fundamental to the structure of both target and drug binding sites. The chemical structure of the drug ligand depends on the ligand chemistry and design philosophy. Two extremes of chemical structure and design philosophy exist; ligands constructed in the medicinal chemistry synthesis laboratory without input from natural selection and natural product (NP) metabolites biosynthesized based on evolutionary selection. Exceptions to Ro5 are found mostly among NPs. Chemistry chameleon-like behavior of some NPs due to intra-molecular hydrogen bonding as exemplified by cyclosporine A is a strong contributor to NP Ro5 outliers. The fragment derived, drug Navitoclax is an example of the extensive expertise, resources, time and key decisions required for the rare discovery of a non-NP Ro5 outlier.

  9. A Ferrocene-Based Catecholamide Ligand: the Consequences of Ligand Swivel for Directed Supramolecular Self-Assembly

    SciTech Connect

    Mugridge, Jeffrey; Fiedler, Dorothea; Raymond, Kenneth

    2010-02-04

    A ferrocene-based biscatecholamide ligand was prepared and investigated for the formation of metal-ligand supramolecular assemblies with different metals. Reaction with Ge(IV) resulted in the formation of a variety of Ge{sub n}L{sub m} coordination complexes, including [Ge{sub 2}L{sub 3}]{sup 4-} and [Ge{sub 2}L{sub 2}({mu}-OMe){sub 2}]{sup 2-}. The ligand's ability to swivel about the ferrocenyl linker and adopt different conformations accounts for formation of many different Ge{sub n}L{sub m} species. This study demonstrates why conformational ligand rigidity is essential in the rational design and directed self-assembly of supramolecular complexes.

  10. Multipurpose ligand, DAKLI (Dynorphin A-analogue Kappa LIgand), with high affinity and selectivity for dynorphin (. kappa. opioid) binding sites

    SciTech Connect

    Goldstein, A.; Nestor, J.J. Jr.; Naidu, A.; Newman, S.R. )

    1988-10-01

    The authors describe a synthetic ligand, DALKI (Dynorphin A-analogue Kappa LIgand), related to the opioid peptide dynorphin A. A single reactive amino group at the extended carboxyl terminus permits various reporter groups to be attached, such as {sup 125}I-labeled Bolton-Hunter reagent, fluorescein isothiocyanate, or biotin. These derivatives have high affinity and selectivity for the dynorphin ({kappa} opioid) receptor. An incidental finding is that untreated guinea pig brain membranes have saturable avidin binding sites.

  11. electronic Ligand Builder and Optimisation Workbench (eLBOW): A tool for ligand coordinate and restraint generation

    SciTech Connect

    Moriarty, Nigel; Grosse-Kunstleve, Ralf; Adams, Paul

    2009-07-01

    The electronic Ligand Builder and Optimisation Workbench (eLBOW) is a program module of the PHENIX suite of computational crystallographic software. It's designed to be a flexible procedure using simple and fast quantum chemical techniques to provide chemically accurate information for novel and known ligands alike. A variety of input formats and options allow for the attainment of a number of diverse goals including geometry optimisation and generation of restraints.

  12. The biotic ligand model: a historical overview.

    PubMed

    Paquin, Paul R; Gorsuch, Joseph W; Apte, Simon; Batley, Graeme E; Bowles, Karl C; Campbell, Peter G C; Delos, Charles G; Di Toro, Dominic M; Dwyer, Robert L; Galvez, Fernando; Gensemer, Robert W; Goss, Gregory G; Hostrand, Christer; Janssen, Colin R; McGeer, James C; Naddy, Rami B; Playle, Richard C; Santore, Robert C; Schneider, Uwe; Stubblefield, William A; Wood, Chris M; Wu, Kuen Benjamin

    2002-09-01

    During recent years, the biotic ligand model (BLM) has been proposed as a tool to evaluate quantitatively the manner in which water chemistry affects the speciation and biological availability of metals in aquatic systems. This is an important consideration because it is the bioavailability and bioreactivity of metals that control their potential to cause adverse effects. The BLM approach has gained widespread interest amongst the scientific, regulated and regulatory communities because of its potential for use in developing water quality criteria (WQC) and in performing aquatic risk assessments for metals. Specifically, the BLM does this in a way that considers the important influences of site-specific water quality. This journal issue includes papers that describe recent advances with regard to the development of the BLM approach. Here, the current status of the BLM development effort is described in the context of the longer-term history of advances in the understanding of metal interactions in the environment upon which the BLM is based. Early developments in the aquatic chemistry of metals, the physiology of aquatic organisms and aquatic toxicology are reviewed first, and the degree to which each of these disciplines influenced the development of water quality regulations is discussed. The early scientific advances that took place in each of these fields were not well coordinated, making it difficult for regulatory authorities to take full advantage of the potential utility of what had been learned. However, this has now changed, with the BLM serving as a useful interface amongst these scientific disciplines, and within the regulatory arena as well. The more recent events that have led to the present situation are reviewed, and consideration is given to some of the future needs and developments related to the BLM that are envisioned. The research results that are described in the papers found in this journal issue represent a distinct milestone in the ongoing

  13. Quantitative analysis of protein-ligand interactions by NMR.

    PubMed

    Furukawa, Ayako; Konuma, Tsuyoshi; Yanaka, Saeko; Sugase, Kenji

    2016-08-01

    Protein-ligand interactions have been commonly studied through static structures of the protein-ligand complex. Recently, however, there has been increasing interest in investigating the dynamics of protein-ligand interactions both for fundamental understanding of the underlying mechanisms and for drug development. NMR is a versatile and powerful tool, especially because it provides site-specific quantitative information. NMR has widely been used to determine the dissociation constant (KD), in particular, for relatively weak interactions. The simplest NMR method is a chemical-shift titration experiment, in which the chemical-shift changes of a protein in response to ligand titration are measured. There are other quantitative NMR methods, but they mostly apply only to interactions in the fast-exchange regime. These methods derive the dissociation constant from population-averaged NMR quantities of the free and bound states of a protein or ligand. In contrast, the recent advent of new relaxation-based experiments, including R2 relaxation dispersion and ZZ-exchange, has enabled us to obtain kinetic information on protein-ligand interactions in the intermediate- and slow-exchange regimes. Based on R2 dispersion or ZZ-exchange, methods that can determine the association rate, kon, dissociation rate, koff, and KD have been developed. In these approaches, R2 dispersion or ZZ-exchange curves are measured for multiple samples with different protein and/or ligand concentration ratios, and the relaxation data are fitted to theoretical kinetic models. It is critical to choose an appropriate kinetic model, such as the two- or three-state exchange model, to derive the correct kinetic information. The R2 dispersion and ZZ-exchange methods are suitable for the analysis of protein-ligand interactions with a micromolar or sub-micromolar dissociation constant but not for very weak interactions, which are typical in very fast exchange. This contrasts with the NMR methods that are used

  14. Evaluating ligands for use in polymer ligand film (PLF) for plutonium and uranium extraction

    SciTech Connect

    Rim, Jung H.; Peterson, Dominic S.; Armenta, Claudine E.; Gonzales, Edward R.; Ünlü, Kenan

    2015-05-08

    We describe a new analyte extraction technique using Polymer Ligand Film (PLF). PLFs were synthesized to perform direct sorption of analytes onto its surface for direct counting using alpha spectroscopy. The main focus of the new technique is to shorten and simplify the procedure for chemically isolating radionuclides for determination through a radiometric technique. 4'(5')-di-t-butylcyclohexano 18-crown-6 (DtBuCH18C6) and 2-ethylhexylphosphonic acid (HEH[EHP]) were examined for plutonium extraction. Di(2-ethyl hexyl) phosphoric acid (HDEHP) were examined for plutonium and uranium extraction. DtBuCH18C6 and HEH[EHP] were not effective in plutonium extraction. HDEHP PLFs were effective for plutonium but not for uranium.

  15. Evaluating ligands for use in polymer ligand film (PLF) for plutonium and uranium extraction

    DOE PAGES

    Rim, Jung H.; Peterson, Dominic S.; Armenta, Claudine E.; ...

    2015-05-08

    We describe a new analyte extraction technique using Polymer Ligand Film (PLF). PLFs were synthesized to perform direct sorption of analytes onto its surface for direct counting using alpha spectroscopy. The main focus of the new technique is to shorten and simplify the procedure for chemically isolating radionuclides for determination through a radiometric technique. 4'(5')-di-t-butylcyclohexano 18-crown-6 (DtBuCH18C6) and 2-ethylhexylphosphonic acid (HEH[EHP]) were examined for plutonium extraction. Di(2-ethyl hexyl) phosphoric acid (HDEHP) were examined for plutonium and uranium extraction. DtBuCH18C6 and HEH[EHP] were not effective in plutonium extraction. HDEHP PLFs were effective for plutonium but not for uranium.

  16. Triple bioaffinity mass spectrometry concept for thyroid transporter ligands.

    PubMed

    Aqai, Payam; Fryganas, Christos; Mizuguchi, Mineyuki; Haasnoot, Willem; Nielen, Michel W F

    2012-08-07

    For the analysis of thyroid transporter ligands, a triple bioaffinity mass spectrometry (BioMS) concept was developed, with the aim at three different analytical objectives: rapid screening of any ligand, confirmation of known ligands in accordance with legislative requirements, and identification of emerging yet unknown ligands. These three purposes share the same biorecognition element, recombinant thyroid transport protein transthyretin (rTTR), and dedicated modes of liquid chromatography-mass spectrometry (LC-MS). For screening, a rapid and radiolabel-free competitive inhibition MS binding assay was developed with fast ultrahigh performance-liquid chromatography-electrospray ionization-triple-quadrupole-MS (UPLC-QqQ-MS) as the readout system. It uses the nonradioactive stable isotopic thyroid hormone (13)C(6)-L-thyroxine as the label of which the binding to rTTR is inhibited by any ligand such as thyroid drugs and thyroid endocrine disrupting chemicals (EDCs). To this end, rTTR is either used in solution or immobilized on paramagnetic microbeads. The concentration-dependent inhibition of the label by the natural thyroid hormone l-thyroxine (T4), as a model analyte, is demonstrated in water at part-per-trillion and in urine at part-per-billion level. For confirmation of identity of known ligands, rTTR was used for bioaffinity purification for confirmation of naturally present free T4 in urine. As a demonstrator for identification of unknown ligands, the same rTTR was used again but in combination with nano-UPLC-quadrupole time-of-flight-MS (nLC-Q-TOF-MS) and urine samples spiked with the model "unknown" EDCs triclosan and tetrabromobisphenol-A. This study highlights the potential of BioMS using one affinity system, both for rapid screening and for confirmation and identification of known and unknown emerging thyroid EDCs.

  17. Ligand-based virtual screening under partial shape constraints.

    PubMed

    von Behren, Mathias M; Rarey, Matthias

    2017-04-01

    Ligand-based virtual screening has proven to be a viable technology during the search for new lead structures in drug discovery. Despite the rapidly increasing number of published methods, meaningful shape matching as well as ligand and target flexibility still remain open challenges. In this work, we analyze the influence of knowledge-based sterical constraints on the performance of the recently published ligand-based virtual screening method mRAISE. We introduce the concept of partial shape matching enabling a more differentiated view on chemical structure. The new method is integrated into the LBVS tool mRAISE providing multiple options for such constraints. The applied constraints can either be derived automatically from a protein-ligand complex structure or by manual selection of ligand atoms. In this way, the descriptor directly encodes the fit of a ligand into the binding site. Furthermore, the conservation of close contacts between the binding site surface and the query ligand can be enforced. We validated our new method on the DUD and DUD-E datasets. Although the statistical performance remains on the same level, detailed analysis reveal that for certain and especially very flexible targets a significant improvement can be achieved. This is further highlighted looking at the quality of calculated molecular alignments using the recently introduced mRAISE dataset. The new partial shape constraints improved the overall quality of molecular alignments especially for difficult targets with highly flexible or different sized molecules. The software tool mRAISE is freely available on Linux operating systems for evaluation purposes and academic use (see http://www.zbh.uni-hamburg.de/raise ).

  18. Ligand-based virtual screening under partial shape constraints

    NASA Astrophysics Data System (ADS)

    von Behren, Mathias M.; Rarey, Matthias

    2017-03-01

    Ligand-based virtual screening has proven to be a viable technology during the search for new lead structures in drug discovery. Despite the rapidly increasing number of published methods, meaningful shape matching as well as ligand and target flexibility still remain open challenges. In this work, we analyze the influence of knowledge-based sterical constraints on the performance of the recently published ligand-based virtual screening method mRAISE. We introduce the concept of partial shape matching enabling a more differentiated view on chemical structure. The new method is integrated into the LBVS tool mRAISE providing multiple options for such constraints. The applied constraints can either be derived automatically from a protein-ligand complex structure or by manual selection of ligand atoms. In this way, the descriptor directly encodes the fit of a ligand into the binding site. Furthermore, the conservation of close contacts between the binding site surface and the query ligand can be enforced. We validated our new method on the DUD and DUD-E datasets. Although the statistical performance remains on the same level, detailed analysis reveal that for certain and especially very flexible targets a significant improvement can be achieved. This is further highlighted looking at the quality of calculated molecular alignments using the recently introduced mRAISE dataset. The new partial shape constraints improved the overall quality of molecular alignments especially for difficult targets with highly flexible or different sized molecules. The software tool mRAISE is freely available on Linux operating systems for evaluation purposes and academic use (see http://www.zbh.uni-hamburg.de/raise).

  19. Dimolybdenum cyclopentadienyl complexes with bridging chalcogenophosphinidene ligands.

    PubMed

    Alvarez, Belén; Alvarez, M Angeles; Amor, Inmaculada; García, M Esther; García-Vivó, Daniel; Suárez, Jaime; Ruiz, Miguel A

    2012-07-16

    The reactions of the phosphinidene-bridged complex [Mo(2)Cp(2)(μ-PH)(η(6)-HMes*)(CO)(2)] (1), the arylphosphinidene complexes [Mo(2)Cp(2)(μ-κ(1):κ(1),η(6)-PMes*)(CO)(2)] (2), [Mo(2)Cp(2)(μ-κ(1):κ(1),η(4)-PMes*)(CO)(3)] (3), [Mo(2)Cp(2)(μ-κ(1):κ(1),η(4)-PMes*)(CO)(2)(CN(t)Bu)] (4), and the cyclopentadienylidene-phosphinidene complex [Mo(2)Cp(μ-κ(1):κ(1),η(5)-PC(5)H(4))(η(6)-HMes*)(CO)(2)] (5) toward different sources of chalcogen atoms were investigated (Mes* = 2,4,6-C(6)H(2)(t)Bu(3); Cp = η(5)-C(5)H(5)). The bare elements were appropriate sources in all cases except for oxygen, in which case dimethyldioxirane gave the best results. Complex 1 reacted with the mentioned chalcogen sources at low temperature, to give the corresponding chalcogenophosphinidene derivatives [Mo(2)Cp(2){μ-κ(2)(P,Z):κ(1)(P)-ZPH}(η(6)-HMes*)(CO)(2)] (Z = O, S, Se, Te; P-Se = 2.199(2) Å). The arylphosphinidene complex 2 was the least reactive substrate and gave only chalcogenophosphinidene derivatives [Mo(2)Cp(2)(μ-κ(2)(P,Z):κ(1)(P),η(6)-ZPMes*)(CO)(2)] for Z = O and S (P-O = 1.565(2) Å), along with small amounts of the dithiophosphorane complex [Mo(2)Cp(2)(μ-κ(2)(P,S):κ(1)(S'),η(6)-S(2)PMes*)(CO)(2)], in the reaction with sulfur. The η(4)-complexes 3 and 4 reacted with sulfur and gray selenium to give the corresponding derivatives [Mo(2)Cp(2)(μ-κ(2)(P,Z):κ(1)(P),η(4)-ZPMes*)(CO)(2)L] (L = CO, CN(t)Bu), obtained respectively as syn (Z = Se; P-Se = 2.190(1) Å for L = CO) or a mixture of syn and anti isomers (Z = S; P-S = 2.034(1)-2.043(1) Å), with these diastereoisomers differing in the relative positioning of the chalcogen atom and the terminal ligand at the metallocene fragment, relative to the Mo(2)P plane. The cyclopentadienylidene compound 5 reacted with all chalcogens, and gave with good yields the chalcogenophosphinidene derivatives [Mo(2)Cp(μ-κ(2)(P,Z):κ(1)(P),η(5)-ZPC(5)H(4))(η(6)-HMes*)(CO)(2)] (Z = S, Se, Te), these displaying in solution

  20. Ligand Migration and Binding in Myoglobin Mutant L29W

    NASA Astrophysics Data System (ADS)

    Nienhaus, G. Ulrich; Waschipky, Robert; Nienhaus, Karin; Minkow, Oleksandr; Ostermann, Andreas; Parak, Fritz G.

    2001-09-01

    Myoglobin, a small globular heme protein that binds gaseous ligands such as O2, CO, and NO reversibly at the heme iron, has for many years been a paradigm for studying the effects of structure and dynamics on protein reactions. Time-resolved spectroscopic measurements after photodissociation of the ligand reveal a complex ligand binding reaction with multiple kinetic intermediates, resulting from protein relaxation and movements of the ligand within the protein. To observe structural changes induced by ligand dissociation, we have investigated carbonmonoxy myoglobin (MbCO) mutant L29W using time-resolved infrared spectroscopy in combination with x-ray crystallography. The presence of two distinct infrared stretch bands of the bound CO, AI at 1945 cm-1 and AII at 1955 cm-1, implies that L29W MbCO assumes two different conformations at neutral pH. Low-temperature flash photolysis experiments with monitoring of the absorption changes in the individual CO lines reveal markedly different rebinding properties. While recombination in AII is conceptually simple and well described by a two-state transition involving a distribution of enthalpy barriers, recombination in AI is more complicated: Besides a fast kinetic component, a second, slower kinetic component appears; its population grows with increasing temperature. X-ray crystallography of crystals illuminated below 180 K to photodissociate the CO reveals that the slow component arises from ligands that have migrated from their initial docking site to a remote site within the distal heme pocket. This process occurs in an essentially immobilized, frozen protein. Subsequently, ligands rebind by thermal activation over a barrier that is much higher than the barrier for recombination from the initial docking site. Upon photodissociation above 180 K, ligands escape from the distal pocket, aided by protein fluctuations that transiently open exit channels. The x-ray structure shows a large proportion of ligands in a cavity on

  1. Using chemical shift perturbation to characterise ligand binding.

    PubMed

    Williamson, Mike P

    2013-08-01

    Chemical shift perturbation (CSP, chemical shift mapping or complexation-induced changes in chemical shift, CIS) follows changes in the chemical shifts of a protein when a ligand is added, and uses these to determine the location of the binding site, the affinity of the ligand, and/or possibly the structure of the complex. A key factor in determining the appearance of spectra during a titration is the exchange rate between free and bound, or more specifically the off-rate koff. When koff is greater than the chemical shift difference between free and bound, which typically equates to an affinity Kd weaker than about 3μM, then exchange is fast on the chemical shift timescale. Under these circumstances, the observed shift is the population-weighted average of free and bound, which allows Kd to be determined from measurement of peak positions, provided the measurements are made appropriately. (1)H shifts are influenced to a large extent by through-space interactions, whereas (13)Cα and (13)Cβ shifts are influenced more by through-bond effects. (15)N and (13)C' shifts are influenced both by through-bond and by through-space (hydrogen bonding) interactions. For determining the location of a bound ligand on the basis of shift change, the most appropriate method is therefore usually to measure (15)N HSQC spectra, calculate the geometrical distance moved by the peak, weighting (15)N shifts by a factor of about 0.14 compared to (1)H shifts, and select those residues for which the weighted shift change is larger than the standard deviation of the shift for all residues. Other methods are discussed, in particular the measurement of (13)CH3 signals. Slow to intermediate exchange rates lead to line broadening, and make Kd values very difficult to obtain. There is no good way to distinguish changes in chemical shift due to direct binding of the ligand from changes in chemical shift due to allosteric change. Ligand binding at multiple sites can often be characterised, by

  2. Ligand-Receptor Binding Measured by Laser-Scanning Imaging

    NASA Astrophysics Data System (ADS)

    Zuck, Paul; Lao, Zhege; Skwish, Stephen; Fraser Glickman, J.; Yang, Ke; Burbaum, Jonathan; Inglese, James

    1999-09-01

    This report describes the integration of laser-scanning fluorometric cytometry and nonseparation ligand-binding techniques to provide new assay methods adaptable to miniaturization and high-throughput screening. Receptor-bound, cyanine dye-labeled ligands, [Cy]ligands, were discriminated from those free in solution by measuring the accumulated fluorescence associated with a receptor-containing particle. To illustrate the various binding formats accommodated by this technique, saturation- and competition-binding analyses were performed with [Cy]ligands and their cognate receptors expressed in CHO cells or as fusion proteins coated on polystyrene microspheres. We have successfully applied this technique to the analysis of G protein-coupled receptors, cytokine receptors, and SH2 domains. Multiparameter readouts from ligands labeled separately with Cy5 and Cy5.5 demonstrate the simultaneous analysis of two target receptors in a single well. In addition, laser-scanning cytometry has been used to assay enzymes such as phosphatases and in the development of single-step fluorescent immunoassays.

  3. Thiophene-Core Estrogen Receptor Ligands Having Superagonist Activity

    PubMed Central

    Min, Jian; Wang, Pengcheng; Srinivasan, Sathish; Nwachukwu, Jerome C.; Guo, Pu; Huang, Minjian; Carlson, Kathryn E.; Katzenellenbogen, John A.; Nettles, Kendall W.; Zhou, Hai-Bing

    2013-01-01

    To probe the importance of the heterocyclic core of estrogen receptor (ER) ligands, we prepared a series of thiophene-core ligands by Suzuki cross-coupling of aryl boronic acids with bromo-thiophenes, and we assessed their receptor binding and cell biological activities. The disposition of the phenol substituents on the thiophene core, at alternate or adjacent sites, and the nature of substituents on these phenols all contribute to binding affinity and subtype selectivity. Most of the bis(hydroxyphenyl)-thiophenes were ERβ selective, whereas the tris(hydroxyphenyl)-thiophenes were ERα selective; analogous furan-core compounds generally have lower affinity and less selectivity. Some diarylthiophenes show distinct superagonist activity in reporter gene assays, giving maximal activities 2–3 times that of estradiol, and modeling suggests that these ligands have a different interaction with a hydrogen-bonding residue in helix-11. Ligand-core modification may be a new strategy for developing ER ligands whose selectivity is based on having transcriptional activity greater than that of estradiol. PMID:23586645

  4. Cloud computing for protein-ligand binding site comparison.

    PubMed

    Hung, Che-Lun; Hua, Guan-Jie

    2013-01-01

    The proteome-wide analysis of protein-ligand binding sites and their interactions with ligands is important in structure-based drug design and in understanding ligand cross reactivity and toxicity. The well-known and commonly used software, SMAP, has been designed for 3D ligand binding site comparison and similarity searching of a structural proteome. SMAP can also predict drug side effects and reassign existing drugs to new indications. However, the computing scale of SMAP is limited. We have developed a high availability, high performance system that expands the comparison scale of SMAP. This cloud computing service, called Cloud-PLBS, combines the SMAP and Hadoop frameworks and is deployed on a virtual cloud computing platform. To handle the vast amount of experimental data on protein-ligand binding site pairs, Cloud-PLBS exploits the MapReduce paradigm as a management and parallelizing tool. Cloud-PLBS provides a web portal and scalability through which biologists can address a wide range of computer-intensive questions in biology and drug discovery.

  5. Surface Ligand-Mediated Plasmon-Driven Photochemical Reactions.

    PubMed

    Kafle, Bijesh; Poveda, Marisa; Habteyes, Terefe G

    2017-03-02

    Contrary to the general expectation that surface ligands reduce the reactivity of surfaces by blocking the active sites, we present experimental evidence that surface ligands can in fact increase reactivity and induce important reaction pathways in plasmon-driven surface photochemistry. The remarkable effect of surface ligands is demonstrated by comparing the photochemistry of p-aminothiophenol (PATP) on resonant plasmonic gold nanorods (AuNRs) in the presence of citrate, hexadecyltrimethylammonium bromide (CTAB), and no surface ligands under visible light irradiation. The use of AuNRs with citrate and no surface ligand results in the usual azo-coupling reaction. In contrast, CTAB-coated AuNRs oxidize PATP primarily to p-nitrothiophenol (PNTP). Strong correlation has been observed between the N-O and Au-Br vibration band intensities, suggesting that CTAB influences the reaction pathway through the Br(-) counterions that can minimize the electron-hole recombination rate by reacting with the hole and hence increasing the concentration of hot electrons that drive the oxidation reaction.

  6. Ligand specificity and evolution of liver X receptors§

    PubMed Central

    Reschly, Erica J.; Ai, Ni; Welsh, William J.; Ekins, Sean; Hagey, Lee R.; Krasowski, Matthew D.

    2008-01-01

    Liver X receptors (LXRs) are key regulators of lipid and cholesterol metabolism in mammals. Little is known, however, about the function and evolution of LXRs in non-mammalian species. The present study reports the cloning of LXRs from African clawed frog (Xenopus laevis), Western clawed frog (Xenopus tropicalis), and zebrafish (Danio rerio), and their functional characterization and comparison with human and mouse LXRs. Additionally, an ortholog of LXR in the chordate invertebrate Ciona intestinalis was cloned and functionally characterized. Ligand specificities of the frog and zebrafish LXRs were very similar to LXRα and LXRβ from human and mouse. All vertebrate LXRs studied were activated robustly by the synthetic ligands T-0901317 and GW3965 and by a variety of oxysterols. In contrast, Ciona LXR was not activated by T-0901317 or GW3965 but was activated by a limited number of oxysterols, as well as some androstane and pregnane steroids. Pharmacophore analysis, homology modeling, and docking studies of Ciona LXR predict a receptor with a more restricted ligand-binding pocket and less intrinsic disorder in the ligand-binding domain compared to vertebrate LXRs. The results suggest that LXRs have a long evolutionary history, with vertebrate LXRs diverging from invertebrate LXRs in ligand specificity. PMID:18395439

  7. Structural basis for EGFR ligand sequestration by Argos

    SciTech Connect

    Klein, Daryl E.; Stayrook, Steven E.; Shi, Fumin; Narayan, Kartik; Lemmon, Mark A.

    2008-06-26

    Members of the epidermal growth factor receptor (EGFR) or ErbB/HER family and their activating ligands are essential regulators of diverse developmental processes. Inappropriate activation of these receptors is a key feature of many human cancers, and its reversal is an important clinical goal. A natural secreted antagonist of EGFR signalling, called Argos, was identified in Drosophila. We showed previously that Argos functions by directly binding (and sequestering) growth factor ligands that activate EGFR5. Here we describe the 1.6-{angstrom} resolution crystal structure of Argos bound to an EGFR ligand. Contrary to expectations, Argos contains no EGF-like domain. Instead, a trio of closely related domains (resembling a three-finger toxin fold) form a clamp-like structure around the bound EGF ligand. Although structurally unrelated to the receptor, Argos mimics EGFR by using a bipartite binding surface to entrap EGF. The individual Argos domains share unexpected structural similarities with the extracellular ligand-binding regions of transforming growth factor-{beta} family receptors. The three-domain clamp of Argos also resembles the urokinase-type plasminogen activator (uPA) receptor, which uses a similar mechanism to engulf the EGF-like module of uPA. Our results indicate that undiscovered mammalian counterparts of Argos may exist among other poorly characterized structural homologues. In addition, the structures presented here define requirements for the design of artificial EGF-sequestering proteins that would be valuable anti-cancer therapeutics.

  8. A grand unified model for liganded gold clusters

    NASA Astrophysics Data System (ADS)

    Xu, Wen Wu; Zhu, Beien; Zeng, Xiao Cheng; Gao, Yi

    2016-12-01

    A grand unified model (GUM) is developed to achieve fundamental understanding of rich structures of all 71 liganded gold clusters reported to date. Inspired by the quark model by which composite particles (for example, protons and neutrons) are formed by combining three quarks (or flavours), here gold atoms are assigned three `flavours' (namely, bottom, middle and top) to represent three possible valence states. The `composite particles' in GUM are categorized into two groups: variants of triangular elementary block Au3(2e) and tetrahedral elementary block Au4(2e), all satisfying the duet rule (2e) of the valence shell, akin to the octet rule in general chemistry. The elementary blocks, when packed together, form the cores of liganded gold clusters. With the GUM, structures of 71 liganded gold clusters and their growth mechanism can be deciphered altogether. Although GUM is a predictive heuristic and may not be necessarily reflective of the actual electronic structure, several highly stable liganded gold clusters are predicted, thereby offering GUM-guided synthesis of liganded gold clusters by design.

  9. Efficient mapping of ligand migration channel networks in dynamic proteins.

    PubMed

    Lin, Tu-Liang; Song, Guang

    2011-08-01

    For many proteins such as myoglobin, the binding site lies in the interior, and there is no obvious route from the exterior to the binding site in the average structure. Although computer simulations for a limited number of proteins have found some transiently open channels, it is not clear if there exist more channels elsewhere or how the channels are regulated. A systematic approach that can map out the whole ligand migration channel network is lacking. Ligand migration in a dynamic protein resembles closely a well-studied problem in robotics, namely, the navigation of a mobile robot in a dynamic environment. In this work, we present a novel robotic motion planning inspired approach that can map the ligand migration channel network in a dynamic protein. The method combines an efficient spatial mapping of protein inner space with a temporal exploration of protein structural heterogeneity, which is represented by a structure ensemble. The spatial mapping of each conformation in the ensemble produces a partial map of protein inner cavities and their inter-connectivity. These maps are then merged to form a super map that contains all the channels that open dynamically. Results on the pathways in myoglobin for gaseous ligands demonstrate the efficiency of our approach in mapping the ligand migration channel networks. The results, obtained in a significantly less amount of time than trajectory-based approaches, are in agreement with previous simulation results. Additionally, the method clearly illustrates how and what conformational changes open or close a channel.

  10. Protein-Ligand Docking Based on Beta-Shape

    NASA Astrophysics Data System (ADS)

    Kim, Chong-Min; Won, Chung-In; Kim, Jae-Kwan; Ryu, Joonghyun; Bhak, Jong; Kim, Deok-Soo

    Protein-ligand docking is to predict the location and orientation of a ligand with respect to a protein within its binding site, and has been known to be essential for the development of new drugs. The protein-ligand docking problem is usually formulated as an energy minimization problem to identify the docked conformation of the ligand. A ligand usually docks around a depressed region, called a pocket, on the surface of a protein. Presented in this paper is a docking method, called BetaDock, based on the newly developed geometric construct called the β-shape and the β-complex. To cope with the computational intractability, the global minimum of the potential energy function is searched using the genetic algorithm. The proposed algorithm first locates initial chromosomes at some locations within the pocket recognized according to the local shape of the β-shape. Then, the algorithm proceeds generations by taking advantage of powerful properties of the β-shape to achieve an extremely fast and good solution. We claim that the proposed method is much faster than other popular docking softwares including AutoDock.

  11. A grand unified model for liganded gold clusters

    PubMed Central

    Xu, Wen Wu; Zhu, Beien; Zeng, Xiao Cheng; Gao, Yi

    2016-01-01

    A grand unified model (GUM) is developed to achieve fundamental understanding of rich structures of all 71 liganded gold clusters reported to date. Inspired by the quark model by which composite particles (for example, protons and neutrons) are formed by combining three quarks (or flavours), here gold atoms are assigned three ‘flavours' (namely, bottom, middle and top) to represent three possible valence states. The ‘composite particles' in GUM are categorized into two groups: variants of triangular elementary block Au3(2e) and tetrahedral elementary block Au4(2e), all satisfying the duet rule (2e) of the valence shell, akin to the octet rule in general chemistry. The elementary blocks, when packed together, form the cores of liganded gold clusters. With the GUM, structures of 71 liganded gold clusters and their growth mechanism can be deciphered altogether. Although GUM is a predictive heuristic and may not be necessarily reflective of the actual electronic structure, several highly stable liganded gold clusters are predicted, thereby offering GUM-guided synthesis of liganded gold clusters by design. PMID:27910848

  12. A modified fluorescent intercalator displacement assay for RNA ligand discovery

    PubMed Central

    Asare-Okai, Papa Nii; Chow, Christine S.

    2010-01-01

    Fluorescent intercalator displacement (FID) is a convenient and practical tool for identifying new nucleic-acid-binding ligands. The success of FID is based on the fact that it can be fashioned into a versatile screening assay for assessing the relative binding affinities of compounds to nucleic acids. FID is a tagless approach; the target RNAs and the ligands or small molecules under investigation do not have to be modified in order to be examined. In this study, a modified FID assay for screening RNA-binding ligands was established using 3-methyl-2-((1-(3-(trimethylammonio)propyl)-4-quinolinylidene)methyl)benzothiazolium (TO-PRO) as the fluorescent indicator. Electrospray ionization mass spectrometry (ESI-MS) results provide direct evidence that correlates the reduction in fluorescence intensity observed in the FID assay with displacement of the dye molecule from RNA. The assay was successfully applied to screen a variety of RNA-binding ligands with a set of small hairpin RNAs. Ligands that bind with moderate affinity to the chosen RNA constructs (A-site, TAR, h31, and H69) were identified. PMID:20863807

  13. NKG2D ligands mediate immunosurveillance of senescent cells

    PubMed Central

    Moshayev, Zhana; Vadai, Ezra; Wensveen, Felix; Ben-Dor, Shifra; Golani, Ofra; Polic, Bojan; Krizhanovsky, Valery

    2016-01-01

    Cellular senescence is a stress response mechanism that limits tumorigenesis and tissue damage. Induction of cellular senescence commonly coincides with an immunogenic phenotype that promotes self-elimination by components of the immune system, thereby facilitating tumor suppression and limiting excess fibrosis during wound repair. The mechanisms by which senescent cells regulate their immune surveillance are not completely understood. Here we show that ligands of an activating Natural Killer (NK) cell receptor (NKG2D), MICA and ULBP2 are consistently up-regulated following induction of replicative senescence, oncogene-induced senescence and DNA damage - induced senescence. MICA and ULBP2 proteins are necessary for efficient NK-mediated cytotoxicity towards senescent fibroblasts. The mechanisms regulating the initial expression of NKG2D ligands in senescent cells are dependent on a DNA damage response, whilst continuous expression of these ligands is regulated by the ERK signaling pathway. In liver fibrosis, the accumulation of senescent activated stellate cells is increased in mice lacking NKG2D receptor leading to increased fibrosis. Overall, our results provide new insights into the mechanisms regulating the expression of immune ligands in senescent cells and reveal the importance of NKG2D receptor-ligand interaction in protecting against liver fibrosis. PMID:26878797

  14. Structural basis for EGFR ligand sequestration by Argos.

    PubMed

    Klein, Daryl E; Stayrook, Steven E; Shi, Fumin; Narayan, Kartik; Lemmon, Mark A

    2008-06-26

    Members of the epidermal growth factor receptor (EGFR) or ErbB/HER family and their activating ligands are essential regulators of diverse developmental processes. Inappropriate activation of these receptors is a key feature of many human cancers, and its reversal is an important clinical goal. A natural secreted antagonist of EGFR signalling, called Argos, was identified in Drosophila. We showed previously that Argos functions by directly binding (and sequestering) growth factor ligands that activate EGFR. Here we describe the 1.6-A resolution crystal structure of Argos bound to an EGFR ligand. Contrary to expectations, Argos contains no EGF-like domain. Instead, a trio of closely related domains (resembling a three-finger toxin fold) form a clamp-like structure around the bound EGF ligand. Although structurally unrelated to the receptor, Argos mimics EGFR by using a bipartite binding surface to entrap EGF. The individual Argos domains share unexpected structural similarities with the extracellular ligand-binding regions of transforming growth factor-beta family receptors. The three-domain clamp of Argos also resembles the urokinase-type plasminogen activator (uPA) receptor, which uses a similar mechanism to engulf the EGF-like module of uPA. Our results indicate that undiscovered mammalian counterparts of Argos may exist among other poorly characterized structural homologues. In addition, the structures presented here define requirements for the design of artificial EGF-sequestering proteins that would be valuable anti-cancer therapeutics.

  15. Rediscovery of halogen bonds in protein-ligand complexes.

    PubMed

    Zhou, P; Tian, F; Zou, J; Shang, Z

    2010-04-01

    Although the halogen bond has attracted much interest in chemistry and material science communities, its implications for drug design are just now coming to light. The protein-ligand interactions through short halogen-oxygen/nitrogen/sulfur contacts have been observed in crystal structures for a long time, but only in recent years, with the experimental and theoretical progress in weak biological interactions, especially the pioneering works contributed by Ho and co-workers (Auffinger, P.; Hays, F. A.; Westhof, E.; Ho, P. S. Proc. Natl. Acad. Sci. USA 2004, 101, 16789-16794), these short contacts involving halogens in biomolecules were rediscovered and re-recognized as halogen bonds to stress their shared similarities with hydrogen bonds in strength and directionality. Crystal structure determinations of protein complexes with halogenated ligands preliminarily unveiled the functionality of halogen bonds in protein-ligand recogni-tion. Database surveys further revealed a considerable number of short halogen-oxygen contacts between proteins and halogenated ligands. Theoretical calculations on model and real systems eventually gave a quantitative pronouncement for the substantial contribution of halogen bonds to ligand binding. All of these works forebode that the halogen bond can be exploited as a new and versatile tool for rational drug design and bio-crystal engineering.

  16. Organic ligands reduce copper toxicity in Pseudomonas syringae

    SciTech Connect

    Azenha, M.; Vasconcelos, M.T.; Cabral, J.P.S.

    1995-03-01

    Pseudomonas syringae cells were exposed to 100 {mu}M copper alone, or to previously equilibrated copper sulfate-ligand solutions. Ligand concentrations were determined experimentally as those that reduced the free copper concentration to 5 {mu}M (determined with a Cu{sup 2+}-selective electrode). These values were in agreement with those calculated by computational equilibrium simulation based on published stability constants. Exposure of P. syringae cells to copper sulfate, chloride, or nitrate resulted in similar high mortality, suggesting that copper was responsible for cell death. Acetate, succinate, proline, lysine, cysteine, and EDTA significantly reduced both the amount of copper bound to the cells and cell death, indicating that not only strong chelating agents but also weak and moderate copper ligands can effectively antagonize copper toxicity. However, cysteine and EDTA were considerably more effective than acetate, succinate, proline, and lysine, indicating that copper toxicity is not simply a function of free copper concentration but depends on the nature of the ligand. The results suggested that a significant fraction of copper bound to acetate, succinate, proline, or lysine was displaced to the bacteria or, alternatively, mixed copper-ligand-cell complexes could be formed. On the contrary, none of these phenomena occurred for the copper complexes with cysteine or EDTA.

  17. Ligand binding to a high-energy partially unfolded protein.

    PubMed

    Kasper, Joseph R; Park, Chiwook

    2015-01-01

    The conformational energy landscape of a protein determines populations of all possible conformations of the protein and also determines the kinetics of the conversion between the conformations. Interaction with ligands influences the conformational energy landscapes of proteins and shifts populations of proteins in different conformational states. To investigate the effect of ligand binding on partial unfolding of a protein, we use Escherichia coli dihydrofolate reductase (DHFR) and its functional ligand NADP(+) as a model system. We previously identified a partially unfolded form of DHFR that is populated under native conditions. In this report, we determined the free energy for partial unfolding of DHFR at varying concentrations of NADP(+) and found that NADP(+) binds to the partially unfolded form as well as the native form. DHFR unfolds partially without releasing the ligand, though the binding affinity for NADP(+) is diminished upon partial unfolding. Based on known crystallographic structures of NADP(+) -bound DHFR and the model of the partially unfolded protein we previously determined, we propose that the adenosine-binding domain of DHFR remains folded in the partially unfolded form and interacts with the adenosine moiety of NADP(+) . Our result demonstrates that ligand binding may affect the conformational free energy of not only native forms but also high-energy non-native forms.

  18. New synthetic routes toward enantiopure nitrogen donor ligands.

    PubMed

    Sala, Xavier; Rodríguez, Anna M; Rodríguez, Montserrat; Romero, Isabel; Parella, Teodor; von Zelewsky, Alexander; Llobet, Antoni; Benet-Buchholz, Jordi

    2006-12-08

    New polypyridylic chiral ligands, having either C3 or lower symmetry, have been prepared via a de novo construction of the pyridine nucleus by means of Kröhnke methodology in the key step. The chiral moieties of these ligands originate from the monoterpen chiral pool, namely (-)-alpha-pinene ((-)-14, (-)-15) and (-)-myrtenal ((-)-9, (-)-10). Extension of the above-mentioned asymmetric synthesis procedure to the preparation of enantiopure derivatives of some commonly used polypyridylic ligands has been achieved through a new aldehyde building block ((-)-16). As an example, the synthesis of a chiral derivative of N,N-bis(2-pyridylmethyl)ethylamine (bpea) ligand, (-)-19, has been performed to illustrate the viability of the method. The coordinative ability of the ligands has been tested through the synthesis and characterization of complexes [Mn((-)-19)Br2], (-)-20, and [RuCl((-)-10)(bpy)](BF4), (-)-21. Some preliminary results related to the enantioselective catalytic epoxidation of styrene with the ruthenium complex are also presented.

  19. A model for ligand binding to hexacoordinate hemoglobins.

    PubMed

    Trent, J T; Hvitved, A N; Hargrove, M S

    2001-05-22

    Hexacoordinate hemoglobins are heme proteins capable of reversible intramolecular coordination of the ligand binding site by an amino acid side chain from within the heme pocket. Examples of these proteins are found in many living organisms ranging from prokaryotes to humans. The nonsymbiotic hemoglobins (nsHbs) are a class of hexacoordinate heme proteins present in all plants. The nsHb from rice (rHb1) has been used as a model system to develop methods for determining rate constants characterizing binding and dissociation of the His residue responsible for hexacoordination. Measurement of these reactions exploits laser flash photolysis to initiate the reaction from the unligated, pentacoordinate form of the heme protein. A model for ligand binding is presented that incorporates the reaction following rapid mixing with the reaction starting from the pentacoordinate hemoglobin (Hb). This model is based on results indicating that ligand binding to hexacoordinate Hbs is not a simple combination of competing first order (hexacoordination) and second order (exogenous ligand binding) reactions. Ligand binding following rapid mixing is a multiphasic reaction displaying time courses ranging from milliseconds to minutes. The new model incorporates a "closed", slow reacting form of the protein that is not at rapid equilibrium with the reactive conformation. It is also demonstrated that formation of the closed protein species is not dependent on hexacoordination.

  20. KLIFS: a structural kinase-ligand interaction database

    PubMed Central

    Kooistra, Albert J.; Kanev, Georgi K.; van Linden, Oscar P.J.; Leurs, Rob; de Esch, Iwan J.P.; de Graaf, Chris

    2016-01-01

    Protein kinases play a crucial role in cell signaling and are important drug targets in several therapeutic areas. The KLIFS database contains detailed structural kinase-ligand interaction information derived from all (>2900) structures of catalytic domains of human and mouse protein kinases deposited in the Protein Data Bank in order to provide insights into the structural determinants of kinase-ligand binding and selectivity. The kinase structures have been processed in a consistent manner by systematically analyzing the structural features and molecular interaction fingerprints (IFPs) of a predefined set of 85 binding site residues with bound ligands. KLIFS has been completely rebuilt and extended (>65% more structures) since its first release as a data set, including: novel automated annotation methods for (i) the assessment of ligand-targeted subpockets and the analysis of (ii) DFG and (iii) αC-helix conformations; improved and automated protocols for (iv) the generation of sequence/structure alignments, (v) the curation of ligand atom and bond typing for accurate IFP analysis and (vi) weekly database updates. KLIFS is now accessible via a website (http://klifs.vu-compmedchem.nl) that provides a comprehensive visual presentation of different types of chemical, biological and structural chemogenomics data, and allows the user to easily access, compare, search and download the data. PMID:26496949

  1. Insights into Protein–Ligand Interactions: Mechanisms, Models, and Methods

    PubMed Central

    Du, Xing; Li, Yi; Xia, Yuan-Ling; Ai, Shi-Meng; Liang, Jing; Sang, Peng; Ji, Xing-Lai; Liu, Shu-Qun

    2016-01-01

    Molecular recognition, which is the process of biological macromolecules interacting with each other or various small molecules with a high specificity and affinity to form a specific complex, constitutes the basis of all processes in living organisms. Proteins, an important class of biological macromolecules, realize their functions through binding to themselves or other molecules. A detailed understanding of the protein–ligand interactions is therefore central to understanding biology at the molecular level. Moreover, knowledge of the mechanisms responsible for the protein-ligand recognition and binding will also facilitate the discovery, design, and development of drugs. In the present review, first, the physicochemical mechanisms underlying protein–ligand binding, including the binding kinetics, thermodynamic concepts and relationships, and binding driving forces, are introduced and rationalized. Next, three currently existing protein-ligand binding models—the “lock-and-key”, “induced fit”, and “conformational selection”—are described and their underlying thermodynamic mechanisms are discussed. Finally, the methods available for investigating protein–ligand binding affinity, including experimental and theoretical/computational approaches, are introduced, and their advantages, disadvantages, and challenges are discussed. PMID:26821017

  2. Entangled zinc-ditetrazolate frameworks involving in situ ligand synthesis and topological modulation by various secondary N-donor ligands

    SciTech Connect

    Li Yunwu; Chen Weilin; Wang Yonghui; Li Yangguang; Wang Enbo

    2009-04-15

    The introduction of various secondary N-donor ligands into an in situ ditetrazolate-ligand synthesis system of terephthalonitrile, NaN{sub 3} and ZnCl{sub 2} led to the formation of three new entangled frameworks Zn(pdtz)(4,4'-bipy).3H{sub 2}O (1), [Zn(pdtz)(bpp)]{sub 2}.3H{sub 2}O (2) and Zn(pdtz){sub 0.5}(N{sub 3})(2,2'-bipy) (3) (4,4'-bipy=4,4'-bipyridine; bpp=1,3-bis(4-pyridyl)propane; 2,2'-bipy=2,2'-bipyridine; H{sub 2}pdtz=5,5'-1,4-phenylene-ditetrazole). The formation of pdtz{sup 2-} ligand involves the Sharpless [2+3] cycloaddition reaction between terephthalonitrile and NaN{sub 3} in the presence of Zn{sup 2+} ion as a Lewis-acid catalyst under hydrothermal conditions. Compound 1 exhibits a fivefold interpenetrating 3D framework based on the diamondoid topology. Compound 2 displays a twofold parallel interpenetrating framework based on the wavelike individual network. Compound 3 possesses a 2D puckered network. These new Zn-ditetrazolate frameworks are highly dependent on the modulation of different secondary N-donor ligands. Their luminescent properties were investigated. - Graphical abstract: Three new entangled frameworks were prepared by an in situ ditetrazolate-ligand synthesis system assisted with various auxiliary N-donor ligands. The entangled structures can be modulated by different secondary ligands.

  3. Conformational diversity of flexible ligand in metal-organic frameworks controlled by size-matching mixed ligands

    SciTech Connect

    Hua, Xiu-Ni; Qin, Lan; Yan, Xiao-Zhi; Yu, Lei; Xie, Yi-Xin; Han, Lei

    2015-12-15

    Hydrothermal reactions of N-auxiliary flexible exo-bidentate ligand 1,3-bis(4-pyridyl)propane (bpp) and carboxylates ligands naphthalene-2,6-dicarboxylic acid (2,6-H{sub 2}ndc) or 4,4′-(hydroxymethylene)dibenzoic acid (H{sub 2}hmdb), in the presence of cadmium(II) salts have given rise to two novel metal-organic frameworks based on flexible ligands (FL-MOFs), namely, [Cd{sub 2}(2,6-ndc){sub 2}(bpp)(DMF)]·2DMF (1) and [Cd{sub 3}(hmdb){sub 3}(bpp)]·2DMF·2EtOH (2) (DMF=N,N-Dimethylformamide). Single-crystal X-ray diffraction analyses revealed that compound 1 exhibits a three-dimensional self-penetrating 6-connected framework based on dinuclear cluster second building unit. Compound 2 displays an infinite three-dimensional ‘Lucky Clover’ shape (2,10)-connected network based on the trinuclear cluster and V-shaped organic linkers. The flexible bpp ligand displays different conformations in 1 and 2, which are successfully controlled by size-matching mixed ligands during the self-assembly process. - Graphical abstract: Compound 1 exhibits a 3D self-penetrating 6-connected framework based on dinuclear cluster, and 2 displays an infinite 3D ‘Lucky Clover’ shape (2,10)-connected network based on the trinuclear cluster. The flexible 1,3-bis(4-pyridyl)propane ligand displays different conformations in 1 and 2, which successfully controlled by size-matching mixed ligands during the self-assembly process.

  4. Synthesis, structure characterization and biological activity of selected metal complexes of sulfonamide Schiff base as a primary ligand and some mixed ligand complexes with glycine as a secondary ligand

    NASA Astrophysics Data System (ADS)

    Sharaby, Carmen M.; Amine, Mona F.; Hamed, Asmaa A.

    2017-04-01

    The current work reports synthesis of metal complexes and mixed ligand complexes of a novel sulfonamide Schiff base ligand (HL) resulted from the condensation of sulfametrole [N‧-(4-methoxy-1,2,5-thiadiazol-3-yl]sulfanilamide and acetyl-acetone as a primary ligand and glycine as a secondary ligand. The metal complexes and mixed ligand complexes of HL Schiff base ligand were synthesized and characterized using different physicochemical studies as elemental analyses, mass spectra, conductivity measurement, IR spectra, 1H NMR spectra, UV-vis Spectra, solid reflectance, magnetic susceptibility, thermal analyses (TGA and DTA) and their microbial and anticancer activities. The spectroscopic data of the complexes suggest their 1:2(L1:M) complex structures and 1:2:2(L1:L2:M) mixed ligand complex structures, where L1 = HL and L2 = glycine. Also, the spectroscopic studies suggested the octahedral structure for all complexes. The synthesized Schiff base, its metal and mixed ligand complexes were screened for their bacterial, antifungal and anticancer activity. The activity data show that the metal complexes and mixed ligand complexes exhibited promising microbial and anticancer activities than their parent HL Schiff base ligand, also the data show that the mixed ligand complexes more effective than the metal complexes.

  5. Unprecedented coordination modes and demetalation pathways for unbridged polyenyl ligands. Ruthenium eta1,eta4-cycloheptadienyl complexes from allyl/alkyne cycloaddition.

    PubMed

    Older, Christina M; McDonald, Robert; Stryker, Jeffrey M

    2005-10-19

    Cationic (eta6-hexamethylbenzene)ruthenium(II) mediates the [3 + 2 + 2] cycloaddition of allyl and alkyne ligands, leading to the unexpected isolation of eta1,eta4-cycloheptadienyl complexes, an unprecedented coordination mode for transition metal complexes of simple organic rings. The nonconjugated, eta1,eta4-coordinated complex is obtained as the kinetic reaction product from treatment of the unsubstituted allyl complex with excess ethyne; this complex rearranges slowly at 80 degrees C to the thermodynamically more stable conjugated eta5-cycloheptadienyl isomer. The eta1,eta4-coordinated isomer is fluxional at room temperature, undergoing rapid and reversible equilibration with a cycloheptatriene hydride intermediate via facile beta-hydride elimination/reinsertion. The reinsertion process is remarkably regioselective, returning the nonconjugated eta1,eta4-cycloheptadienyl isomer exclusively at room temperature. For reactions incorporating dimethylacetylene dicarboxylate (DMAD) as one or both of the alkyne components, eta1,eta4-coordination appears to be both kinetically and thermodynamically favored, despite undergoing equilibration among all possible eta1,eta4-cycloheptadienyl and cycloheptatriene hydride isomers prior to arriving at one observed eta1,eta4-isomer. For this series, no isomerization to eta5-coordination is observed even upon prolonged heating. In contrast, the cyclization incorporating both DMAD and phenylacetylene proceeds directly to the eta5-cycloheptadienyl isomer at or below room temperature, indicating that eta5-coordination remains energetically accessible to this system. The DMAD-based cyclization reactions produce structurally diverse minor byproducts, including both eta1,eta4-methanocyclohexadiene and acyclic eta3,eta2-heptadienyl isomers, which have been isolated and rigorously characterized. The unusual eta1,eta4-coordination of the seven-membered ring leads to unique new organic products upon oxidative demetalation by iodinolysis

  6. Ligand structure and mechanical properties of single-nanoparticle thick membranes

    SciTech Connect

    Salerno, Kenneth Michael; Bolintineanu, Dan S.; Lane, J. Matthew D.; Grest, Gary S.

    2015-06-16

    We believe that the high mechanical stiffness of single-nanoparticle-thick membranes is the result of the local structure of ligand coatings that mediate interactions between nanoparticles. These ligand structures are not directly observable experimentally. We use molecular dynamics simulations to observe variations in ligand structure and simultaneously measure variations in membrane mechanical properties. We have shown previously that ligand end group has a large impact on ligand structure and membrane mechanical properties. Here we introduce and apply quantitative molecular structure measures to these membranes and extend analysis to multiple nanoparticle core sizes and ligand lengths. Simulations of nanoparticle membranes with a nanoparticle core diameter of 4 or 6 nm, a ligand length of 11 or 17 methylenes, and either carboxyl (COOH) or methyl (CH3) ligand end groups are presented. In carboxyl-terminated ligand systems, structure and interactions are dominated by an end-to-end orientation of ligands. In methyl-terminated ligand systems large ordered ligand structures form, but nanoparticle interactions are dominated by disordered, partially interdigitated ligands. Core size and ligand length also affect both ligand arrangement within the membrane and the membrane's macroscopic mechanical response, but are secondary to the role of the ligand end group. Additionally, the particular end group (COOH or CH3) alters the nature of how ligand length, in turn, affects the membrane properties. The effect of core size does not depend on the ligand end group, with larger cores always leading to stiffer membranes. Asymmetry in the stress and ligand density is observed in membranes during preparation at a water-vapor interface, with the stress asymmetry persisting in all membranes after drying.

  7. Ligand structure and mechanical properties of single-nanoparticle thick membranes

    DOE PAGES

    Salerno, Kenneth Michael; Bolintineanu, Dan S.; Lane, J. Matthew D.; ...

    2015-06-16

    We believe that the high mechanical stiffness of single-nanoparticle-thick membranes is the result of the local structure of ligand coatings that mediate interactions between nanoparticles. These ligand structures are not directly observable experimentally. We use molecular dynamics simulations to observe variations in ligand structure and simultaneously measure variations in membrane mechanical properties. We have shown previously that ligand end group has a large impact on ligand structure and membrane mechanical properties. Here we introduce and apply quantitative molecular structure measures to these membranes and extend analysis to multiple nanoparticle core sizes and ligand lengths. Simulations of nanoparticle membranes with amore » nanoparticle core diameter of 4 or 6 nm, a ligand length of 11 or 17 methylenes, and either carboxyl (COOH) or methyl (CH3) ligand end groups are presented. In carboxyl-terminated ligand systems, structure and interactions are dominated by an end-to-end orientation of ligands. In methyl-terminated ligand systems large ordered ligand structures form, but nanoparticle interactions are dominated by disordered, partially interdigitated ligands. Core size and ligand length also affect both ligand arrangement within the membrane and the membrane's macroscopic mechanical response, but are secondary to the role of the ligand end group. Additionally, the particular end group (COOH or CH3) alters the nature of how ligand length, in turn, affects the membrane properties. The effect of core size does not depend on the ligand end group, with larger cores always leading to stiffer membranes. Asymmetry in the stress and ligand density is observed in membranes during preparation at a water-vapor interface, with the stress asymmetry persisting in all membranes after drying.« less

  8. Noncovalent ligand-to-ligand interactions alter sense of optical chirality in luminescent tris(β-diketonate) lanthanide(III) complexes containing a chiral bis(oxazolinyl) pyridine ligand.

    PubMed

    Yuasa, Junpei; Ohno, Tomoko; Miyata, Kohei; Tsumatori, Hiroyuki; Hasegawa, Yasuchika; Kawai, Tsuyoshi

    2011-06-29

    Highly luminescent tris[β-diketonate (HFA, 1,1,1,5,5,5-hexafluoropentane-2,4-dione)] europium(III) complexes containing a chiral bis(oxazolinyl) pyridine (pybox) ligand--[(Eu(III)(R)-Ph-pybox)(HFA)(3)], [(Eu(III)(R)-i-Pr-pybox)(HFA)(3)], and [(Eu(III)(R)-Me-Ph-pybox)(HFA)(3)])--exhibit strong circularly polarized luminescence (CPL) at the magnetic-dipole ((5)D(0) → (7)F(1)) transition, where the [(Eu(III)(R)-Ph-pybox)(HFA)(3)] complexes show virtually opposite CPL spectra as compared to those with the same chirality of [(Eu(III)(R)-i-Pr-pybox)(HFA)(3)] and [(Eu(III)(R)-Me-Ph-pybox)(HFA)(3)]. Similarly, the [(Tb(III)(R)-Ph-pybox)(HFA)(3)] complexes were found to exhibit CPL signals almost opposite to those of [(Tb(III)(R)-i-Pr-pybox)(HFA)(3)] and [(Tb(III)(R)-Me-Ph-pybox)(HFA)(3)] complexes with the same pybox chirality. Single-crystal X-ray structural analysis revealed ligand-ligand interactions between the pybox ligand and the HFA ligand in each lanthanide(III) complex: π-π stacking interactions in the Eu(III) and Tb(III) complexes with the Ph-pybox ligand, CH/F interactions in those with the i-Pr-pybox ligand, and CH/π interactions in those with the Me-Ph-pybox ligand. The ligand-ligand interactions between the achiral HFA ligands and the chiral pybox results in an asymmetric arrangement of three HFA ligands around the metal center. The metal center geometry varies depending on the types of ligand-ligand interaction.

  9. Ligand-gated Diffusion Across the Bacterial Outer Membrane

    SciTech Connect

    B Lepore; M Indic; H Pham; E Hearn; D Patel; B van den Berg

    2011-12-31

    Ligand-gated channels, in which a substrate transport pathway is formed as a result of the binding of a small-molecule chemical messenger, constitute a diverse class of membrane proteins with important functions in prokaryotic and eukaryotic organisms. Despite their widespread nature, no ligand-gated channels have yet been found within the outer membrane (OM) of Gram-negative bacteria. Here we show, using in vivo transport assays, intrinsic tryptophan fluorescence and X-ray crystallography, that high-affinity (submicromolar) substrate binding to the OM long-chain fatty acid transporter FadL from Escherichia coli causes conformational changes in the N terminus that open up a channel for substrate diffusion. The OM long-chain fatty acid transporter FadL from E. coli is a unique paradigm for OM diffusion-driven transport, in which ligand gating within a {beta}-barrel membrane protein is a prerequisite for channel formation.

  10. Pharmacokinetics and pharmacodynamics of nonsteroidal androgen receptor ligands.

    PubMed

    Gao, Wenqing; Kim, Juhyun; Dalton, James T

    2006-08-01

    Testosterone and structurally related anabolic steroids have been used to treat hypogonadism, muscle wasting, osteoporosis, male contraception, cancer cachexia, anemia, and hormone replacement therapy in aging men or age-related frailty; while antiandrogens may be useful for treatment of conditions like acne, alopecia (male-pattern baldness), hirsutism, benign prostatic hyperplasia (BPH) and prostate cancer. However, the undesirable physicochemical and pharmacokinetic properties of steroidal androgen receptor (AR) ligands limited their clinical use. Nonsteroidal AR ligands with improved pharmacological and pharmacokinetic properties have been developed to overcome these problems. This review focuses on the pharmacokinetics, metabolism, and pharmacology of clinically used and emerging nonsteroidal AR ligands, including antagonists, agonists, and selective androgen receptor modulators.

  11. slate: A method for the superposition of flexible ligands

    NASA Astrophysics Data System (ADS)

    Mills, J. E. J.; de Esch, I. J. P.; Perkins, T. D. J.; Dean, P. M.

    2001-01-01

    A novel program for the superposition of flexible molecules, slate, is presented. It uses simulated annealing to minimise the difference between the distance matrices calculated from the hydrogen-bonding and aromatic-ring properties of two ligands. A method for generating a molecular stack using multiple pairwise matches is illustrated. These stacks are used by the program doh to predict the relative positions of receptor atoms that could form hydrogen bonds to two or more ligands in the dataset. The methodology has been applied to ligands binding to dihydrofolate reductase, thermolysin, H3 histamine receptors, α2 adrenoceptors and 5-HT1D receptors. When there are sufficient numbers and diversity of molecules in the dataset, the prediction of receptor-atom positions is applicable to compound design.

  12. Automated identification of crystallographic ligands using sparse-density representations

    PubMed Central

    Carolan, C. G.; Lamzin, V. S.

    2014-01-01

    A novel procedure for the automatic identification of ligands in macromolecular crystallographic electron-density maps is introduced. It is based on the sparse parameterization of density clusters and the matching of the pseudo-atomic grids thus created to conformationally variant ligands using mathematical descriptors of molecular shape, size and topology. In large-scale tests on experimental data derived from the Protein Data Bank, the procedure could quickly identify the deposited ligand within the top-ranked compounds from a database of candidates. This indicates the suitability of the method for the identification of binding entities in fragment-based drug screening and in model completion in macromolecular structure determination. PMID:25004962

  13. Ligand screening by saturation-transfer difference (STD) NMR spectroscopy.

    SciTech Connect

    Krishnan, V V

    2005-04-26

    NMR based methods to screen for high-affinity ligands have become an indispensable tool for designing rationalized drugs, as these offer a combination of good experimental design of the screening process and data interpretation methods, which together provide unprecedented information on the complex nature of protein-ligand interactions. These methods rely on measuring direct changes in the spectral parameters, that are often simpler than the complex experimental procedures used to study structure and dynamics of proteins. The goal of this review article is to provide the basic details of NMR based ligand-screening methods, with particular focus on the saturation transfer difference (STD) experiment. In addition, we provide an overview of other NMR experimental methods and a practical guide on how to go about designing and implementing them.

  14. GPCR biased ligands as novel heart failure therapeutics.

    PubMed

    Violin, Jonathan D; Soergel, David G; Boerrigter, Guido; Burnett, John C; Lark, Michael W

    2013-10-01

    G protein-coupled receptors have been successfully targeted by numerous therapeutics including drugs that have transformed the management of cardiovascular disease. However, many GPCRs, when activated or blocked by drugs, elicit both beneficial and adverse pharmacology. Recent work has demonstrated that in some cases, the salutary and deleterious signals linked to a specific GPCR can be selectively targeted by "biased ligands" that entrain subsets of a receptor's normal pharmacology. This review briefly summarizes the advances and current state of the biased ligand field, focusing on an example: biased ligands targeting the angiotensin II type 1 receptor. These compounds exhibit unique pharmacology, distinct from classic agonists or antagonists, and one such molecule is now in clinical development for the treatment of acute heart failure.

  15. Memetic algorithms for ligand expulsion from protein cavities

    NASA Astrophysics Data System (ADS)

    Rydzewski, J.; Nowak, W.

    2015-09-01

    Ligand diffusion through a protein interior is a fundamental process governing biological signaling and enzymatic catalysis. A complex topology of channels in proteins leads often to difficulties in modeling ligand escape pathways by classical molecular dynamics simulations. In this paper, two novel memetic methods for searching the exit paths and cavity space exploration are proposed: Memory Enhanced Random Acceleration (MERA) Molecular Dynamics (MD) and Immune Algorithm (IA). In MERA, a pheromone concept is introduced to optimize an expulsion force. In IA, hybrid learning protocols are exploited to predict ligand exit paths. They are tested on three protein channels with increasing complexity: M2 muscarinic G-protein-coupled receptor, enzyme nitrile hydratase, and heme-protein cytochrome P450cam. In these cases, the memetic methods outperform simulated annealing and random acceleration molecular dynamics. The proposed algorithms are general and appropriate in all problems where an accelerated transport of an object through a network of channels is studied.

  16. Ligand reorganization and activation energies in nonadiabatic electron transfer reactions

    NASA Astrophysics Data System (ADS)

    Zhu, Jianjun; Wang, Jianji; Stell, George

    2006-10-01

    The activation energy and ligand reorganization energy for nonadiabatic electron transfer reactions in chemical and biological systems are investigated in this paper. The free energy surfaces and the activation energy are derived exactly in the general case in which the ligand vibration frequencies are not equal. The activation energy is derived by free energy minimization at the transition state. Our formulation leads to the Marcus-Hush [J. Chem. Phys. 24, 979 (1956); 98, 7170 (1994); 28, 962 (1958)] results in the equal-frequency limit and also generalizes the Marcus-Sumi [J. Chem. Phys. 84, 4894 (1986)] model in the context of studying the solvent dynamic effect on electron transfer reactions. It is found that when the ligand vibration frequencies are different, the activation energy derived from the Marcus-Hush formula deviates by 5%-10% from the exact value. If the reduced reorganization energy approximation is introduced in the Marcus-Hush formula, the result is almost exact.

  17. Coordination chemistry of N-heterocyclic nitrenium-based ligands.

    PubMed

    Tulchinsky, Yuri; Kozuch, Sebastian; Saha, Prasenjit; Mauda, Assaf; Nisnevich, Gennady; Botoshansky, Mark; Shimon, Linda J W; Gandelman, Mark

    2015-05-04

    Comprehensive studies on the coordination properties of tridentate nitrenium-based ligands are presented. N-heterocyclic nitrenium ions demonstrate general and versatile binding abilities to various transition metals, as exemplified by the synthesis and characterization of Rh(I) , Rh(III) , Mo(0) , Ru(0) , Ru(II) , Pd(II) , Pt(II) , Pt(IV) , and Ag(I) complexes based on these unusual ligands. Formation of nitrenium-metal bonds is unambiguously confirmed both in solution by selective (15) N-labeling experiments and in the solid state by X-ray crystallography. The generality of N-heterocyclic nitrenium as a ligand is also validated by a systematic DFT study of its affinity towards all second-row transition and post-transition metals (Y-Cd) in terms of the corresponding bond-dissociation energies.

  18. Quantitation of Membrane-Ligand Interactions Using Backscattering Interferometry

    PubMed Central

    Baksh, Michael M.; Kussrow, Amanda K.; Mileni, Mauro; Finn, M.G.; Bornhop, Darryl J.

    2011-01-01

    Though membrane-associated proteins are ubiquitous within all living organisms and represent the majority of drug targets, a general method for direct, label-free measurement of ligand binding to native membranes has not been reported. Here we show backscattering interferometry (BSI) to be a viable technique for quantifying ligand-receptor binding affinities in a variety of membrane environments. By detecting minute changes in the refractive index of a solution, BSI allows binding interactions of proteins with their ligands to be measured at picomolar concentrations. Equilibrium binding constants in the micromolar to picomolar range were obtained for small- and large-molecule interactions in both synthetic- and cell-derived membranes without the use of labels or supporting substrates. The simple and low-cost hardware, high sensitivity, and label-free nature of BSI should make it readily applicable to the study of many membrane-associated proteins of biochemical and pharmacological interest. PMID:21399645

  19. Ligand Binding Thermodynamics in Drug Discovery: Still a Hot Tip?

    PubMed

    Geschwindner, Stefan; Ulander, Johan; Johansson, Patrik

    2015-08-27

    The use of ligand binding thermodynamics has been proposed as a potential success factor to accelerate drug discovery. However, despite the intuitive appeal of optimizing binding enthalpy, a number of factors complicate routine use of thermodynamic data. On a macroscopic level, a range of experimental parameters including temperature and buffer choice significantly influence the observed thermodynamic signatures. On a microscopic level, solute effects, structural flexibility, and cooperativity lead to nonlinear changes in enthalpy. This multifactorial character hides essential enthalpy contributions of intermolecular contacts, making them experimentally nonobservable. In this perspective, we present three case studies, reflect on some key factors affecting thermodynamic signatures, and investigate their relation to the hydrophobic effect, enthalpy-entropy compensation, lipophilic ligand efficiency, and promiscuity. The studies highlight that enthalpy and entropy cannot be used as direct end points but can together with calculations increase our understanding of ligand binding and identify interesting outliers that do not behave as expected.

  20. Protein-Observed Fluorine NMR Is a Complementary Ligand Discovery Method to (1)H CPMG Ligand-Observed NMR.

    PubMed

    Urick, Andrew K; Calle, Luis Pablo; Espinosa, Juan F; Hu, Haitao; Pomerantz, William C K

    2016-11-18

    To evaluate its potential as a ligand discovery tool, we compare a newly developed 1D protein-observed fluorine NMR (PrOF NMR) screening method with the well-characterized ligand-observed (1)H CPMG NMR screen. We selected the first bromodomain of Brd4 as a model system to benchmark PrOF NMR because of the high ligandability of Brd4 and the need for small molecule inhibitors of related epigenetic regulatory proteins. We compare the two methods' hit sensitivity, triaging ability, experiment speed, material consumption, and the potential for false positives and negatives. To this end, we screened 930 fragment molecules against Brd4 in mixtures of five and followed up these studies with mixture deconvolution and affinity characterization of the top hits. In selected examples, we also compare the environmental responsiveness of the (19)F chemical shift to (1)H in 1D-protein observed (1)H NMR experiments. To address concerns of perturbations from fluorine incorporation, ligand binding trends and affinities were verified via thermal shift assays and isothermal titration calorimetry. We conclude that for the protein understudy here, PrOF NMR and (1)H CPMG have similar sensitivity, with both being effective tools for ligand discovery. In cases where an unlabeled protein can be used, 1D protein-observed (1)H NMR may also be effective; however, the (19)F chemical shift remains significantly more responsive.

  1. Improved Estimation of Protein-Ligand Binding Free Energy by Using the Ligand-Entropy and Mobility of Water Molecules

    PubMed Central

    Fukunishi, Yoshifumi; Nakamura, Haruki

    2013-01-01

    We previously developed the direct interaction approximation (DIA) method to estimate the protein-ligand binding free energy (ΔG). The DIA method estimates the ΔG value based on the direct van der Waals and electrostatic interaction energies between the protein and the ligand. In the current study, the effect of the entropy of the ligand was introduced with protein dynamic properties by molecular dynamics simulations, and the interaction between each residue of the protein and the ligand was also weighted considering the hydration of each residue. The molecular dynamics simulation of the apo target protein gave the hydration effect of each residue, under the assumption that the residues, which strongly bind the water molecules, are important in the protein-ligand binding. These two effects improved the reliability of the DIA method. In fact, the parameters used in the DIA became independent of the target protein. The averaged error of ΔG estimation was 1.3 kcal/mol and the correlation coefficient between the experimental ΔG value and the calculated ΔG value was 0.75. PMID:24276169

  2. Complexation of trivalent americium and lanthanides with terdentate 'N' donor ligands: the role of rigidity in the ligand structure.

    PubMed

    Bhattacharyya, Arunasis; Gadly, Trilochan; Pathak, Priyanath; Ghosh, Sunil K; Mohapatra, Manoj; Ghanty, Tapan K; Mohapatra, Prasanta K

    2014-08-28

    A systematic study on the Ln(3+) complexation behaviour with two terdentate 'N' donor ligands of varying structural rigidity, viz. 5,6-dimethyl-(1,2,4)-triazinylbipyridine (Me2TBipy) and 5,6-dimethyl-(1,2,4)-triazinylphenanthroline (Me2TPhen), is performed in the present work by UV-Vis spectrophotometry, time resolved fluorescence spectroscopy (TRFS) and electrospray ionization mass spectrometric (ESI-MS) studies. These studies indicate the formation of a 1 : 1 complex of La(3+), 1 : 2 complexes of Eu(3+) and Er(3+) with both the ligands. Density functional theoretical (DFT) study is carried out to determine the solution phase structure of the Eu(3+) complex considering the species (from UV-Vis spectrophotometry) and C2v site symmetry around the Eu(3+) ion (from TRFS study). Me2TPhen is found to be a stronger complexing ligand as compared to Me2TBipy irrespective of the Ln(3+) ions. The solid state crystal structure of the La(3+) complex of Me2TPhen is determined using the single crystal X-ray diffraction (SCXRD) technique. The complexation of the trivalent Am(3+) ion is also studied with both these ligands using UV-Vis spectrophotometric titrations which show the formation of 1 : 2 complexes with higher complexation constant values as compared to all the Ln(3+) ions studied, indicating the selectivity of these ligands for the trivalent actinides over the lanthanides.

  3. SODOCK: swarm optimization for highly flexible protein-ligand docking.

    PubMed

    Chen, Hung-Ming; Liu, Bo-Fu; Huang, Hui-Ling; Hwang, Shiow-Fen; Ho, Shinn-Ying

    2007-01-30

    Protein-ligand docking can be formulated as a parameter optimization problem associated with an accurate scoring function, which aims to identify the translation, orientation, and conformation of a docked ligand with the lowest energy. The parameter optimization problem for highly flexible ligands with many rotatable bonds is more difficult than that for less flexible ligands using genetic algorithm (GA)-based approaches, due to the large numbers of parameters and high correlations among these parameters. This investigation presents a novel optimization algorithm SODOCK based on particle swarm optimization (PSO) for solving flexible protein-ligand docking problems. To improve efficiency and robustness of PSO, an efficient local search strategy is incorporated into SODOCK. The implementation of SODOCK adopts the environment and energy function of AutoDock 3.05. Computer simulation results reveal that SODOCK is superior to the Lamarckian genetic algorithm (LGA) of AutoDock, in terms of convergence performance, robustness, and obtained energy, especially for highly flexible ligands. The results also reveal that PSO is more suitable than the conventional GA in dealing with flexible docking problems with high correlations among parameters. This investigation also compared SODOCK with four state-of-the-art docking methods, namely GOLD 1.2, DOCK 4.0, FlexX 1.8, and LGA of AutoDock 3.05. SODOCK obtained the smallest RMSD in 19 of 37 cases. The average 2.29 A of the 37 RMSD values of SODOCK was better than those of other docking programs, which were all above 3.0 A.

  4. Estrogen Receptor Ligands: A Review (2013–2015)

    PubMed Central

    Farzaneh, Shabnam; Zarghi, Afshin

    2016-01-01

    Estrogen receptors (ERs) are a group of compounds named for their importance in both menstrual and estrous reproductive cycles. They are involved in the regulation of various processes ranging from tissue growth maintenance to reproduction. Their action is mediated through ER nuclear receptors. Two subtypes of the estrogen receptor, ERα and ERβ, exist and exhibit distinct cellular and tissue distribution patterns. In humans, both receptor subtypes are expressed in many cells and tissues, and they control key physiological functions in various organ systems. Estrogens attract great attention due to their wide applications in female reproductive functions and treatment of some estrogen-dependent cancers and osteoporosis. This paper provides a general review of ER ligands published in international journals patented between 2013 and 2015. The broad physiological profile of estrogens has attracted the attention of many researchers to develop new estrogen ligands as therapeutic molecules for various clinical purposes. After the discovery of the ERβ receptor, subtype-selective ligands could be used to elicit beneficial estrogen-like activities and reduce adverse side effects, based on the different distributions and relative levels of the two ER subtypes in different estrogen target tissues. Therefore, recent literature has focused on selective estrogen ligands as highly promising agents for the treatment of some types of cancer, as well as for cardiovascular, inflammatory, and neurodegenerative diseases. Estrogen receptors are nuclear transcription factors that are involved in the regulation of many complex physiological functions in humans. Selective estrogen ligands are highly promising targets for treatment of some types of cancer, as well as for cardiovascular, inflammatory and neurodegenerative diseases. Extensive structure-activity relationship studies of ER ligands based on small molecules indicate that many different structural scaffolds may provide high

  5. Evaluation of nanoparticle-ligand distributions to determine nanoparticle concentration.

    PubMed

    Uddayasankar, Uvaraj; Shergill, Ravi T; Krull, Ulrich J

    2015-01-20

    The concentration of nanoparticles in solution is an important, yet challenging, parameter to quantify. In this work, a facile strategy for the determination of nanoparticle concentration is presented. The method relies on the quantitative analysis of the inherent distribution of nanoparticle-ligand conjugates that are generated when nanoparticles are functionalized with ligands. Validation of the method was accomplished by applying it to gold nanoparticles and semiconductor nanoparticles (CdSe/ZnS; core/shell). Poly(ethylene glycol) based ligands, with functional groups that quantitatively react with the nanoparticles, were incubated with the nanoparticles at varying equivalences. Agarose gel electrophoresis was subsequently used to separate and quantify the nanoparticle-ligand conjugates of varying valences. The distribution in the nanoparticle-ligand conjugates agreed well with that predicted by the Poisson model. A protocol was then developed, where a series of only eight different ligand amounts could provide an estimate of the nanoparticle concentration that spans 3 orders of magnitude (1 μM to 1 mM). For the gold nanoparticles and semiconductor nanoparticles, the measured concentrations were found to deviate by only 7% and 2%, respectively, from those determined by UV-vis spectroscopy. The precision of the assay was evaluated, resulting in a coefficient of variation of 5-7%. Finally, the protocol was used to determine the extinction coefficient of alloyed semiconductor nanoparticles (CdSxSe1-x/ZnS), for which a reliable estimate is currently unavailable, of three different emission wavelengths (525, 575, and 630 nm). The extinction coefficient of the nanoparticles of all emission wavelengths was similar and was found to be 2.1 × 10(5) M(-1)cm(-1).

  6. Designing simple tridentate ligands for highly luminescent europium complexes.

    PubMed

    Shavaleev, Nail M; Eliseeva, Svetlana V; Scopelliti, Rosario; Bünzli, Jean-Claude G

    2009-10-19

    A series of tridentate benzimidazole-substituted pyridine-2-carboxylic acids have been prepared with a halogen, methyl or alkoxy group in the 6-position of the benzimidazole ring, which additionally contains a solubilising N-alkyl chain. The ligands form neutral homoleptic nine-coordinate lanthanum, europium and terbium complexes as established from X-ray crystallographic analysis of eight structures. The coordination polyhedron around the lanthanide ion is close to a tricapped trigonal prism with ligands arranged in an up-up-down fashion. The coordinated ligands serve as light-harvesting chromophores in the complexes with absorption maxima in the range 321-341 nm (epsilon=(4.9-6.0)x10(4) M(-1) cm(-1)) and triplet-state energies between 21 300 and 18 800 cm(-1); the largest redshifts occur for bromine and electron-donor alkoxy substituents. The ligands efficiently sensitise europium luminescence with overall quantum yields (Q(L)(Eu)) and observed lifetimes (tau(obs)) reaching 71 % and 3.00 ms, respectively, in the solid state and 52 % and 2.81 ms, respectively, in CH(2)Cl(2) at room temperature. The radiative lifetimes of the Eu((5)D(0)) level amount to tau(rad)=3.6-4.6 ms and the sensitisation efficiency eta(sens)=Q(L)(Eu)(tau(rad)/tau(obs)) is close to unity for most of the complexes in the solid state and equal to approximately 80 % in solution. The photophysical parameters of the complexes correlate with the triplet energy of the ligands, which in turn is determined by the nature of the benzimidazole substituent. Facile modification of the ligands makes them promising for the development of brightly emissive europium-containing materials.

  7. Protein-ligand docking with multiple flexible side chains

    NASA Astrophysics Data System (ADS)

    Zhao, Yong; Sanner, Michel F.

    2008-09-01

    In this work, we validate and analyze the results of previously published cross docking experiments and classify failed dockings based on the conformational changes observed in the receptors. We show that a majority of failed experiments (i.e. 25 out of 33, involving four different receptors: cAPK, CDK2, Ricin and HIVp) are due to conformational changes in side chains near the active site. For these cases, we identify the side chains to be made flexible during docking calculation by superimposing receptors and analyzing steric overlap between various ligands and receptor side chains. We demonstrate that allowing these side chains to assume rotameric conformations enables the successful cross docking of 19 complexes (ligand all atom RMSD < 2.0 Å) using our docking software FLIPDock. The number of side receptor side chains interacting with a ligand can vary according to the ligand's size and shape. Hence, when starting from a complex with a particular ligand one might have to extend the region of potential interacting side chains beyond the ones interacting with the known ligand. We discuss distance-based methods for selecting additional side chains in the neighborhood of the known active site. We show that while using the molecular surface to grow the neighborhood is more efficient than Euclidian-distance selection, the number of side chains selected by these methods often remains too large and additional methods for reducing their count are needed. Despite these difficulties, using geometric constraints obtained from the network of bonded and non-bonded interactions to rank residues and allowing the top ranked side chains to be flexible during docking makes 22 out of 25 complexes successful.

  8. Luminescent cyclometallated iridium(III) complexes having acetylide ligands

    DOEpatents

    Thompson, Mark E.; Bossi, Alberto; Djurovich, Peter Ivan

    2014-09-02

    The present invention relates to phosphorescent (triplet-emitting) organometallic materials. The phosphorescent materials of the present invention comprise Ir(III)cyclometallated alkynyl complexes for use as triplet light-emitting materials. The Ir(III)cyclometallated alkynyl complexes comprise at least one cyclometallating ligand and at least one alkynyl ligand bonded to the iridium. Also provided is an organic light emitting device comprising an anode, a cathode and an emissive layer between the anode and the cathode, wherein the emissive layer comprises a Ir(III)cyclometallated alkynyl complex as a triplet emitting material.

  9. Structural Basis of Cooperative Ligand Binding by the Glycine Riboswitch

    SciTech Connect

    E Butler; J Wang; Y Xiong; S Strobel

    2011-12-31

    The glycine riboswitch regulates gene expression through the cooperative recognition of its amino acid ligand by a tandem pair of aptamers. A 3.6 {angstrom} crystal structure of the tandem riboswitch from the glycine permease operon of Fusobacterium nucleatum reveals the glycine binding sites and an extensive network of interactions, largely mediated by asymmetric A-minor contacts, that serve to communicate ligand binding status between the aptamers. These interactions provide a structural basis for how the glycine riboswitch cooperatively regulates gene expression.

  10. Discovery of Potent Dual PPARα Agonists/CB1 Ligands.

    PubMed

    Pérez-Fernández, Ruth; Fresno, Nieves; Macías-González, Manuel; Elguero, José; Decara, Juan; Girón, Rocío; Rodríguez-Álvarez, Ana; Martín, María Isabel; Rodríguez de Fonseca, Fernando; Goya, Pilar

    2011-11-10

    This letter describes the synthesis and in vitro and in vivo evaluation of dual ligands targeting the cannabinoid and peroxisome proliferator-activated receptors (PPAR). These compounds were obtained from fusing the pharmacophores of fibrates and the diarylpyrazole rimonabant, a cannabinoid receptor antagonist. They are the first examples of dual compounds with nanomolar affinity for both PPARα and cannabinoid receptors. Besides, lead compound 2 proved to be CB1 selective. Unexpectedly, the phenol intermediates tested were equipotent (compound 1 as compared to 2) or even more potent (compound 3 as compared with 4). This discovery opens the way to design new dual ligands.

  11. Development of catalysts and ligands for enantioselective gold catalysis.

    PubMed

    Wang, Yi-Ming; Lackner, Aaron D; Toste, F Dean

    2014-03-18

    During the past decade, the use of Au(I) complexes for the catalytic activation of C-C π-bonds has been investigated intensely. Over this time period, the development of homogeneous gold catalysis has been extraordinarily rapid and has yielded a host of mild and selective methods for the formation of carbon-carbon and carbon-heteroatom bonds. The facile formation of new bonds facilitated by gold naturally led to efforts toward rendering these transformations enantioselective. In this Account, we survey the development of catalysts and ligands for enantioselective gold catalysis by our research group as well as related work by others. We also discuss some of our strategies to address the challenges of enantioselective gold(I) catalysis. Early on, our work with enantioselective gold-catalyzed transformations focused on bis(phosphinegold) complexes derived from axially chiral scaffolds. Although these complexes were highly successful in some reactions like cyclopropanation, the careful choice of the weakly coordinating ligand (or counterion) was necessary to obtain high levels of enantioselectivity for the case of allene hydroamination. These counterion effects led us to use the anion itself as a source of chirality, which was successful in the case of allene hydroalkoxylation. In general, these tactics enhance the steric influence around the reactive gold center beyond the two-coordinate ligand environment. The use of binuclear complexes allowed us to use the second gold center and its associated ligand (or counterion) to exert a further steric influence. In a similar vein, we employed a chiral anion (in place of or in addition to a chiral ligand) to move the chiral information closer to the reactive center. In order to expand the scope of reactions amenable to enantioselective gold catalysis to cycloadditions and other carbocyclization processes, we also developed a new class of mononuclear phosphite and phosphoramidite ligands to supplement the previously widely

  12. Ultrafast electron trapping in ligand-exchanged quantum dot assemblies.

    PubMed

    Turk, Michael E; Vora, Patrick M; Fafarman, Aaron T; Diroll, Benjamin T; Murray, Christopher B; Kagan, Cherie R; Kikkawa, James M

    2015-02-24

    We use time-integrated and time-resolved photoluminescence and absorption to characterize the low-temperature optical properties of CdSe quantum dot solids after exchanging native aliphatic ligands for thiocyanate and subsequent thermal annealing. In contrast to trends established at room temperature, our data show that at low temperature the band-edge absorptive bleach is dominated by 1S3/2h hole occupation in the quantum dot interior. We find that our ligand treatments, which bring enhanced interparticle coupling, lead to faster surface state electron trapping, a greater proportion of surface-related photoluminescence, and decreased band-edge photoluminescence lifetimes.

  13. Isothermal Titration Calorimetry: Assisted Crystallization of RNA-Ligand Complexes.

    PubMed

    Da Veiga, Cyrielle; Mezher, Joelle; Dumas, Philippe; Ennifar, Eric

    2016-01-01

    The success rate of nucleic acids/ligands co-crystallization can be significantly improved by performing preliminary biophysical analyses. Among suitable biophysical approaches, isothermal titration calorimetry (ITC) is certainly a method of choice. ITC can be used in a wide range of experimental conditions to monitor in real time the formation of the RNA- or DNA-ligand complex, with the advantage of providing in addition the complete binding profile of the interaction. Following the ITC experiment, the complex is ready to be concentrated for crystallization trials. This chapter describes a detailed experimental protocol for using ITC as a tool for monitoring RNA/small molecule binding, followed by co-crystallization.

  14. Double-ligand modulation for engineering magnetic nanoclusters

    PubMed Central

    2013-01-01

    Magnetic nanoclusters (MNCs) are agglomerated individual magnetic nanoparticles (MNPs) that show great promise in increasing magnetic resonance imaging (MRI) sensitivity. Here, we report an effective strategy to engineer MNCs based on double-ligand modulation to enhance MRI sensitivity. The oleic acid-coated individual MNPs self-assembled and then were enveloped by polysorbate 80, using a nanoemulsion method to prepare MNCs. By modulating the amounts of the two ligands, and thus the size and magnetic content of the resultant MNCs, we were able to enormously improve MRI sensitivity. PMID:23433032

  15. [Determining the parameters for receptor-ligand interaction by serial dilution method for the case when the ligand and receptor are in a pre-existing mixture].

    PubMed

    Bobrovnik, S A

    2005-01-01

    New methods of determining the binding parameters for ligand-receptor interaction are considered. The considered approaches are based on the earlier suggested method of serial dilution and application of so-called coordinates of dilution. It was shown that the suggested methods allow to evaluate affinity constant and ligand concentration even for the case, when the receptor and corresponding ligand of unknown concentration are in a mixture and their separation from each other is impossible. In this connection the suggested methods are especially useful for studying the ligand-receptor interaction if the receptor is very liable and its purification from the ligand would cause drastic changes of its binding properties.

  16. From α4β2 Nicotinic Ligands to the Discovery of σ1 Receptor Ligands: Pharmacophore Analysis and Rational Design.

    PubMed

    Yu, Li-Fang; Zhang, Han-Kun; Gunosewoyo, Hendra; Kozikowski, Alan P

    2012-12-13

    Comparative analyses of the pharmacophoric elements required for σ1 and nicotinic ligands led to the identification of a potent and selective σ1 ligand (15). Compound 15 displayed high selectivity for the σ1 receptor (Ki, σ1 = 4.1 nM, Ki, σ2 = 1312 nM) with moderate binding affinity for the DAT (Ki = 373 nM) and NET (Ki = 203 nM) in the PDSP broad screening panel of common CNS neurotransmitter transporters and receptors. The key finding in this present work is that a subtle structural modifica tion could be used as a tool to switch a ligand's selectivity between nAChRs and sigma receptors.

  17. Predicting Electrophoretic Mobility of Protein-Ligand Complexes for Ligands from DNA-Encoded Libraries of Small Molecules.

    PubMed

    Bao, Jiayin; Krylova, Svetlana M; Cherney, Leonid T; Hale, Robert L; Belyanskaya, Svetlana L; Chiu, Cynthia H; Shaginian, Alex; Arico-Muendel, Christopher C; Krylov, Sergey N

    2016-05-17

    Selection of target-binding ligands from DNA-encoded libraries of small molecules (DELSMs) is a rapidly developing approach in drug-lead discovery. Methods of kinetic capillary electrophoresis (KCE) may facilitate highly efficient homogeneous selection of ligands from DELSMs. However, KCE methods require accurate prediction of electrophoretic mobilities of protein-ligand complexes. Such prediction, in turn, requires a theory that would be applicable to DNA tags of different structures used in different DELSMs. Here we present such a theory. It utilizes a model of a globular protein connected, through a single point (small molecule), to a linear DNA tag containing a combination of alternating double-stranded and single-stranded DNA (dsDNA and ssDNA) regions of varying lengths. The theory links the unknown electrophoretic mobility of protein-DNA complex with experimentally determined electrophoretic mobilities of the protein and DNA. Mobility prediction was initially tested by using a protein interacting with 18 ligands of various combinations of dsDNA and ssDNA regions, which mimicked different DELSMs. For all studied ligands, deviation of the predicted mobility from the experimentally determined value was within 11%. Finally, the prediction was tested for two proteins and two ligands with a DNA tag identical to those of DELSM manufactured by GlaxoSmithKline. Deviation between the predicted and experimentally determined mobilities did not exceed 5%. These results confirm the accuracy and robustness of our model, which makes KCE methods one step closer to their practical use in selection of drug leads, and diagnostic probes from DELSMs.

  18. Glucagon-Like Peptide-1 Receptor Ligand Interactions: Structural Cross Talk between Ligands and the Extracellular Domain

    PubMed Central

    West, Graham M.; Willard, Francis S.; Sloop, Kyle W.; Showalter, Aaron D.; Pascal, Bruce D.; Griffin, Patrick R.

    2014-01-01

    Activation of the glucagon-like peptide-1 receptor (GLP-1R) in pancreatic β-cells potentiates insulin production and is a current therapeutic target for the treatment of type 2 diabetes mellitus (T2DM). Like other class B G protein-coupled receptors (GPCRs), the GLP-1R contains an N-terminal extracellular ligand binding domain. N-terminal truncations on the peptide agonist generate antagonists capable of binding to the extracellular domain, but not capable of activating full length receptor. The main objective of this study was to use Hydrogen/deuterium exchange (HDX) to identify how the amide hydrogen bonding network of peptide ligands and the extracellular domain of GLP-1R (nGLP-1R) were altered by binding interactions and to then use this platform to validate direct binding events for putative GLP-1R small molecule ligands. The HDX studies presented here for two glucagon-like peptide-1 receptor (GLP-1R) peptide ligands indicates that the antagonist exendin-4[9-39] is significantly destabilized in the presence of nonionic detergents as compared to the agonist exendin-4. Furthermore, HDX can detect stabilization of exendin-4 and exendin-4[9-39] hydrogen bonding networks at the N-terminal helix [Val19 to Lys27] upon binding to the N-terminal extracellular domain of GLP-1R (nGLP-1R). In addition we show hydrogen bonding network stabilization on nGLP-1R in response to ligand binding, and validate direct binding events with the extracellular domain of the receptor for putative GLP-1R small molecule ligands. PMID:25180755

  19. Synthesis, structure and reactivity of rare-earth metal complexes containing anionic phosphorus ligands.

    PubMed

    Li, Tianshu; Kaercher, Sabrina; Roesky, Peter W

    2014-01-07

    A comprehensive review of structurally characterized rare-earth metal complexes containing anionic phosphorus ligands is presented. Since rare-earth elements form hard ions and phosphorus is considered as a soft ligand, the rare-earth metal phosphorus coordination is regarded as a less favorite combination. Three classes of phosphorus ligands, (1) the monoanionic organophosphide ligands (PR2(-)) bearing one negative charge on the phosphorus atom; (2) the dianionic phosphinidene (PR(2-)) and P(3-) ligands; and (3) the pure inorganic polyphosphide ligands (Pn(x-)), are included here. Particular attention has been paid to the synthesis, structure, and reactivity of the rare-earth metal phosphides.

  20. SANS Study on the Behaviors of Polymeric Ligands on the Nanoparticle Surfaces

    NASA Astrophysics Data System (ADS)

    Kim, Seyong; Choi, Soo-Hyung; Huh, June; Bang, Joona

    2015-03-01

    In this work, we employed small angle neutron scattering (SANS) and contrast variation technique to characterize the behaviors of polymer ligands on the nanoparticle (NPs) surfaces. The Janus-type Au NPs were coated with a mixture of two different ligands, PMMA-SH and deuterated PS-SH, and the Au NPs coated only with P(MMA-r-dS)-SH were also prepared for the control case of NPs with homogeneous ligands. From the SANS analysis, it was observed that the ligands become phase separated with increasing the molecular weight of ligands. Furthermore, computational simulation was performed to examine how ligands are phase separated on the curved NPs surfaces.

  1. Secondary ligand-directed assembly of Co(II) coordination polymers based on a pyridine carboxylate ligand

    SciTech Connect

    Cao, Ke-Li; Zhang, Yi-Ping; Cai, Yi-Ni; Xu, Xiao-Wei; Feng, Yun-Long

    2014-07-01

    To investigate the influence of hydrogen bonds and secondary ligands on the structures and properties of the resulting frameworks, five new Co(II) compounds have been synthesized by the reactions of Co(II) salts and 3,5-bis(pyridin-4-ylmethoxy)benzoic acid (HL) with four rationally selected dicarboxylic acid ligands. Without secondary ligand, we got one compound [CoL{sub 2}(H{sub 2}O){sub 2}]{sub n}·2nH{sub 2}O (1), which possesses a 1D chain structure. In the presence of ancillary ligands, namely, 1,3-adamantanedicarboxylic acid (H{sub 2}adbc), terephthalic acid (H{sub 2}tpa), thiophene-2,5-dicarboxylic acid (H{sub 2}tdc) and 1,4-benzenedithioacetic acid (H{sub 2}bdtc), four 3D structures [Co{sub 2}L{sub 2}(adbc)]{sub n}·nH{sub 2}O (2), [Co{sub 2}L{sub 2}(tpa)]{sub n} (3), [Co{sub 2}L{sub 2}(tdc)]{sub n} (4), [Co{sub 2}L{sub 2}(bdtc)(H{sub 2}O)]{sub n} (5) were obtained, respectively. It can be observed from the architectures of 1–5 that hydrogen bonds and secondary ligands both have great effects on the spatial connective fashions, resulting in the formation of various dimensional compounds. The XRPD, TGA data of title polymers and the magnetic properties for 2 and 5 have also been investigated. - Graphical abstract: The structural differences show that the ancillary ligands have great effects on the spatial connective fashions, resulting in the formation of various dimensional compounds. - Highlights: • Five new Co(II) coordination polymers have been synthesized by solvothermal reactions based on 3,5-bis(pyridin-4-ylmethoxy)benzoic acid (HL). • The long-flexible ligand (HL) is a good candidate to produce interpenetrating architectures. • The secondary dicarboxylic acid ligands play important roles in the spatial connective fashions and the formation of various dimensional compounds. • The magnetism studies show that both 2 and 5 exhibit antiferromagnetic interactions.

  2. Rhodium complexes bearing tetradentate diamine-bis(phenolate) ligands

    SciTech Connect

    Liu, Xiang Y; Lokare, Kapil S; Ganesh, Somesh K; Gonzales, Jason M; Oxgaard, Jonas; Goddard, William A; Periana, Roy A

    2011-01-01

    Using tetradentate, dianionic ligands, several new rhodium complexes have been prepared. Some of these diamine-bis(phenolate) compounds, are active for C–H activation of benzene. These complexes are air and thermally stable. All four complexes were characterized by X-ray diffraction.

  3. Selective Electrocatalytic Activity of Ligand Stabilized Copper Oxide Nanoparticles

    SciTech Connect

    Kauffman, Douglas R; Ohodnicki, Paul R; Kail, Brian W; Matranga, Christopher

    2011-01-01

    Ligand stabilization can influence the surface chemistry of Cu oxide nanoparticles (NPs) and provide unique product distributions for electrocatalytic methanol (MeOH) oxidation and CO{sub 2} reduction reactions. Oleic acid (OA) stabilized Cu{sub 2}O and CuO NPs promote the MeOH oxidation reaction with 88% and 99.97% selective HCOH formation, respectively. Alternatively, CO{sub 2} is the only reaction product detected for bulk Cu oxides and Cu oxide NPs with no ligands or weakly interacting ligands. We also demonstrate that OA stabilized Cu oxide NPs can reduce CO{sub 2} into CO with a {approx}1.7-fold increase in CO/H{sub 2} production ratios compared to bulk Cu oxides. The OA stabilized Cu oxide NPs also show 7.6 and 9.1-fold increases in CO/H{sub 2} production ratios compared to weakly stabilized and non-stabilized Cu oxide NPs, respectively. Our data illustrates that the presence and type of surface ligand can substantially influence the catalytic product selectivity of Cu oxide NPs.

  4. Ultrafast Electron Trapping in Ligand-Exchanged Quantum Dot Assemblies

    NASA Astrophysics Data System (ADS)

    Kikkawa, J. M.; Turk, M. E.; Vora, P. M.; Fafarman, A. T.; Diroll, B. T.; Murray, C. B.; Kagan, C. R.

    2015-03-01

    We use time-integrated and time-resolved photoluminescence and absorption to characterize the low-temperature (10 K) optical properties of CdSe quantum dot (QD) solids with different ligand and annealing preparation. Close-packed CdSe quantum dot solids are prepared with native aliphatic ligands and with thiocyanate with and without thermal annealing. Using sub-picosecond, broadband time-resolved photoluminescence and absorption, we find that ligand exchange increases the rate of carrier surface trapping. We further determine that holes within the QD core, rather than electrons, can bleach the band-edge transition in these samples at low temperature, a finding that comes as a surprise given what is known about the surface treatment in these QDs. We find that our ligand treatments lead to faster electron trapping to the quantum dot surface, a greater proportion of surface photoluminescence, and an increased rate of nonradiative decay due to enhanced interparticle coupling upon exchange and annealing. All aspects of this work supported by the U.S. Department of Energy Office of Basic Energy Sciences, Division of Materials Science and Engineering, under Award No. DE-SC0002158.

  5. Local Innate Responses to TLR Ligands in the Chicken Trachea

    PubMed Central

    Barjesteh, Neda; Alkie, Tamiru Negash; Hodgins, Douglas C.; Nagy, Éva; Sharif, Shayan

    2016-01-01

    The chicken upper respiratory tract is the portal of entry for respiratory pathogens, such as avian influenza virus (AIV). The presence of microorganisms is sensed by pathogen recognition receptors (such as Toll-like receptors (TLRs)) of the innate immune defenses. Innate responses are essential for subsequent induction of potent adaptive immune responses, but little information is available about innate antiviral responses of the chicken trachea. We hypothesized that TLR ligands induce innate antiviral responses in the chicken trachea. Tracheal organ cultures (TOC) were used to investigate localized innate responses to TLR ligands. Expression of candidate genes, which play a role in antiviral responses, was quantified. To confirm the antiviral responses of stimulated TOC, chicken macrophages were treated with supernatants from stimulated TOC, prior to infection with AIV. The results demonstrated that TLR ligands induced the expression of pro-inflammatory cytokines, type I interferons and interferon stimulated genes in the chicken trachea. In conclusion, TLR ligands induce functional antiviral responses in the chicken trachea, which may act against some pathogens, such as AIV. PMID:27455308

  6. The Principles of Ligand Specificity on beta-2-adrenergic receptor

    PubMed Central

    Chan, H. C. Stephen; Filipek, Slawomir; Yuan, Shuguang

    2016-01-01

    G protein-coupled receptors are recognized as one of the largest families of membrane proteins. Despite sharing a characteristic seven-transmembrane topology, G protein-coupled receptors regulate a wide range of cellular signaling pathways in response to various physical and chemical stimuli, and prevail as an important target for drug discovery. Notably, the recent progress in crystallographic methods led to a breakthrough in elucidating the structures of membrane proteins. The structures of β2-adrenergic receptor bound with a variety of ligands provide atomic details of the binding modes of agonists, antagonists and inverse agonists. In this study, we selected four representative molecules from each functional class of ligands and investigated their impacts on β2-adrenergic receptor through a total of 12 × 100 ns molecular dynamics simulations. From the obtained trajectories, we generated molecular fingerprints exemplifying propensities of protein-ligand interactions. For each functional class of compounds, we characterized and compared the fluctuation of the protein backbone, the volumes in the intracellular pockets, the water densities in the receptors, the domain interaction networks as well as the movements of transmembrane helices. We discovered that each class of ligands exhibits a distinct mode of interactions with mainly TM5 and TM6, altering the shape and eventually the state of the receptor. Our findings provide insightful prospective into GPCR targeted structure-based drug discoveries. PMID:27703221

  7. Spin-dependent mechanism for diatomic ligand binding to heme

    NASA Astrophysics Data System (ADS)

    Franzen, Stefan

    2002-12-01

    The nature of diatomic ligand recombination in heme proteins is elucidated by using a Landau-Zener model for the electronic coupling in the recombination rate constant. The model is developed by means of explicit potential energy surfaces calculated by using density functional theory (DFT). The interaction of all possible spin states of the three common diatomic ligands, CO, NO, and O2, and high-spin heme iron is compared. The electronic coupling, rebinding barrier, and Landau-Zener force terms can be obtained and used to demonstrate significant differences among the ligands. In particular the intermediate spin states of NO (S = 3/2) and O2 (S = 1) are shown to be bound states. Rapid recombination occurs from these bound states in agreement with experimental data. The slower phases of O2 recombination can be explained by the presence of two higher spin states, S = 2 and S = 3, which have a small and relatively large barrier to ligand recombination, respectively. By contrast, the intermediate spin state for CO is not a bound state, and the only recombination pathway for CO involves direct recombination from the S = 2 state. This process is significantly slower according to the Landau-Zener model. Quantitative estimates of the parameters used in the rate constants provide a complete description that explains rebinding rates that range from femtoseconds to milliseconds at ambient temperature.

  8. Analyzing Ligand Depletion in a Saturation Equilibrium Binding Experiment

    ERIC Educational Resources Information Center

    Claro, Enrique

    2006-01-01

    I present a proposal for a laboratory practice to generate and analyze data from a saturation equilibrium binding experiment addressed to advanced undergraduate students. [[superscript 3]H]Quinuclidinyl benzilate is a nonselective muscarinic ligand with very high affinity and very low nonspecific binding to brain membranes, which contain a high…

  9. Trapping of palindromic ligands within native transthyretin prevents amyloid formation

    PubMed Central

    Kolstoe, Simon E.; Mangione, Palma P.; Bellotti, Vittorio; Taylor, Graham W.; Tennent, Glenys A.; Deroo, Stéphanie; Morrison, Angus J.; Cobb, Alexander J. A.; Coyne, Anthony; McCammon, Margaret G.; Warner, Timothy D.; Mitchell, Jane; Gill, Raj; Smith, Martin D.; Ley, Steven V.; Robinson, Carol V.; Wood, Stephen P.; Pepys, Mark B.

    2010-01-01

    Transthyretin (TTR) amyloidosis is a fatal disease for which new therapeutic approaches are urgently needed. We have designed two palindromic ligands, 2,2'-(4,4'-(heptane-1,7-diylbis(oxy))bis(3,5-dichloro-4,1-phenylene)) bis(azanediyl)dibenzoic acid (mds84) and 2,2'-(4,4'-(undecane-1,11-diylbis(oxy))bis(3,5-dichloro-4,1-phenylene)) bis(azanediyl)dibenzoic acid (4ajm15), that are rapidly bound by native wild-type TTR in whole serum and even more avidly by amyloidogenic TTR variants. One to one stoichiometry, demonstrable in solution and by MS, was confirmed by X-ray crystallographic analysis showing simultaneous occupation of both T4 binding sites in each tetrameric TTR molecule by the pair of ligand head groups. Ligand binding by native TTR was irreversible under physiological conditions, and it stabilized the tetrameric assembly and inhibited amyloidogenic aggregation more potently than other known ligands. These superstabilizers are orally bioavailable and exhibit low inhibitory activity against cyclooxygenase (COX). They offer a promising platform for development of drugs to treat and prevent TTR amyloidosis. PMID:21059958

  10. Photocontrol over cooperative porphyrin self-assembly with phenylazopyridine ligands.

    PubMed

    Hirose, Takashi; Helmich, Floris; Meijer, E W

    2013-01-02

    The cooperative self-assembly of chiral zinc porphyrins is regulated by a photoresponsive phenylazopyridine ligand. Porphyrin stacks depolymerize into dimers upon axial ligation and the strength of the coordination is regulated by its photoinduced isomerization, which shows more than 95 % conversion ratio for both photostationary states.

  11. Ligand influences on homoleptic Group 12 m-terphenyl complexes.

    PubMed

    Blundell, Toby J; Hastings, Fiona R; Gridley, Benjamin M; Moxey, Graeme J; Lewis, William; Blake, Alexander J; Kays, Deborah L

    2014-10-14

    Three m-terphenyl ligands 2,6-Ar2C6H3(-) [Ar = 2,6-Me2C6H3 (2,6-Xyl); 3,5-Me2C6H3 (3,5-Xyl); 2,3,4,5,6-Me5C6 (Pmp)] have been used to stabilise three series of two-coordinate Group 12 diaryl complexes; (2,6-Ar2C6H3)2M [M = Zn, Cd, Hg, Ar = 2,6-Xyl 1-3, 3,5-Xyl 4-6, Pmp 7-9], where differing steric demands on the metal centres are imparted. These are the first homoleptic d-block complexes featuring any of these ligands. Complexes 1-9 have been characterised in solution and the solid state; the analysis of structural changes produced by differences in ligand properties is reported. In particular, complexes 4-6 show smaller C-M-C bond angles and contain secondary ligand interactions that are not seen in the analogous complexes 1-3 and 7-9.

  12. Phosphite-oxazole/imidazole ligands in asymmetric intermolecular Heck reaction.

    PubMed

    Mazuela, Javier; Tolstoy, Paivi; Pàmies, Oscar; Andersson, Pher G; Diéguez, Montserrat

    2011-02-07

    We describe the application of a new class of ligands--the phosphite-oxazole/imidazole (L1-L5a-g)--in asymmetric intermolecular Pd-catalyzed Heck reactions under thermal and microwave conditions. These ligands combine the advantages of the oxazole/imidazole moiety with those of the phosphite moiety: they are more stable than their oxazoline counterparts, less sensitive to air and other oxidizing agents than phosphines and phosphinites, and easy to synthesize from readily available alcohols. The results indicate that activities, regio- and enantioselectivities, are highly influenced by the type of nitrogen donor group (oxazole or imidazole), the oxazole and biaryl-phosphite substituents and the axial chirality of the biaryl moiety of the ligand. By carefully selecting the ligand components, we achieved high activities, regio- (up to 99%) and enantioselectivities (up to 99%) using several triflate sources. Under microwave-irradiation conditions, reaction times were considerably shorter (from 24 h to 30 min) and regio- and enantioselectivities were still excellent.

  13. REACTIVITY PROFILE OF CONFORMATIONALLY-FLEXIBLE RETINOID RECEPTOR LIGANDS

    EPA Science Inventory

    Retinoids and associated derivatives represent a class of endogenousr hormones that bind to and activate different families of retinoic acid receptors (RARs, RXRs), and control many aspects of normal vertebrate development. Identification of potential RAR and RXRs ligands is of i...

  14. Theoretical investigations of silver clusters and silver-ligand systems.

    SciTech Connect

    Jellinek, J.; Salian, U.; Srinivas, S.

    1999-05-19

    Studies directed at understanding structural and electronic properties of silver clusters have been and remain the subject of an active theoretical [1-22] and experimental [23- 38] effort. One of the reasons is the (still) important role these systems play in the photographic process. Investigations of interactions of silver clusters with different atoms and molecules are motivated primarily by a possible utility of these clusters in catalytic processes. The important role of silver in the selective oxidation of ethylene into ethylene oxide, the feedstock for polyester production, is well-known [39]. Possible variations in chemical reactivity with the cluster size and understanding of the mechanisms of interactions with different ligands may lead to new and more efficient applications. Investigations of cluster-ligand systems also contribute a great deal to a better understanding of gas-surface interactions. Accordingly, theoretical studies of silver clusters and cluster-ligand systems [40-44] fall into two categories--those that use clusters as models for silver surfaces [40], and those that target clusters and cluster-ligand interactions as subjects in their own right [41-44]. The common goal of all these studies is to elucidate the nature of the interatomic interactions and bonding at the microscopic level and thereby arrive at a fundamental understanding and description of the various structural and electronic properties.

  15. Development of Benzophenone-Alkyne Bifunctional Sigma Receptor Ligands

    PubMed Central

    Guo, Lian-Wang; Hajipour, Abdol R.; Karaoglu, Kerim; Mavlyutov, Timur A.; Ruoho, Arnold E.

    2012-01-01

    Sigma (σ) receptors represent unique non-opioid binding sites that are associated with a broad range of disease states. Sigma-2 receptors provide a promising target for diagnostic imaging and pharmacological interventions to curb tumor progression. Most recently, the progesterone receptor (PGRMC1, 25 kDa) has been identified to contain σ2 receptor-like binding properties, highlighting the need to understand the biological function of an 18-kDa protein that exhibits σ2-like photoaffinity labeling (herein denoted as σ2-18k) but the amino acid sequence of which is not known. In order to provide novel tools for the study of the σ2-18k protein, we have developed bifunctional sigma receptor ligands that bear a benzophenone photo-crosslinking moiety and an alkyne group, to which an azide-containing biotin affinity tag can be covalently attached via click chemistry following photo-crosslink. While several compounds showed favorable σ2 binding properties, compound 22 exhibited the highest affinity (2 nM) and the greatest potency in blocking photolabeling of the σ2-18k by a radioactive photoaffinity ligand. Thus, these benzophenone-alkyne sigma receptor ligands may be amenable for studying the σ2-18k protein via chemical biology approaches. To our knowledge, these compounds represent the first reported benzophenone-containing clickable sigma receptor ligands, which may potentially serve broad applications by “plugging” in various tags. PMID:23001760

  16. The imidazoline receptors and ligands in pain modulation

    PubMed Central

    Bektas, Nurcan; Nemutlu, Dilara; Arslan, Rana

    2015-01-01

    Pain is an unpleasant experience and effects daily routine negatively. Although there are various drugs, many of them are not entirely successful in relieving pain, since pain modulation is a complex process involving numerous mediators and receptors. Therefore, it is a rational approach to identify the factors involved in the complex process and develop new agents that act on these pain producing mechanisms. In this respect, the involvement of the imidazoline receptors in pain modulation has drawn attention in recent years. In this review, it is aimed to focus on the imidazoline receptors and their ligands which contribute to the pain modulation. It is demonstrated that imidazoline-2 (I2) receptors are steady new drug targets for analgesics. Even if the mechanism of I2 receptor is not well known in the modulation of pain, it is known that it plays a role in tonic and chronic pain but not in acute phasic pain. Moreover, the I2 receptor ligands increase the analgesic effects of opioids in both acute and chronic pain and prevent the development of opioid tolerance. So, they are valuable for the chronic pain treatment and also therapeutic coadjuvants in the management of chronic pain with opiate drugs due to the attenuation of opioid tolerance and addiction. Thus, the use of the ligands which bind to the imidazoline receptors is an effective strategy for relieving pain. This educational forum exhibits the role of imidazoline receptors and ligands in pain process by utilizing experimental studies. PMID:26600633

  17. Nonsteroidal Androgen Receptor Ligands: Versatile Syntheses and Biological Data

    PubMed Central

    2012-01-01

    We report herein a stereoselective and straightforward methodology for the synthesis of new androgen receptor ligands with (anti)-agonistic activities. Oxygen–nitrogen replacement in bicalutamide-like structures paves the way to the disclosure of a new class of analogues, including cyclized/nitrogen-substituted derivatives, with promising antiandrogen (or anabolic) activity. PMID:24900495

  18. Role of sulfide and ligand strength in controlling nanosilver toxicity.

    PubMed

    Choi, Okkyoung; Clevenger, Thomas E; Deng, Baolin; Surampalli, Rao Y; Ross, Louis; Hu, Zhiqiang

    2009-04-01

    Nanosilver has been used broadly in nanotechnology enhanced consumer products because of its strong antimicrobial properties. Silver nanoparticles (AgNPs) released from these products will likely enter wastewater collection and treatment systems. This research evaluated the role of sulfide and ligand strength in controlling nanosilver toxicity to nitrifying bacteria that are important in wastewater treatment. The nanosilver toxicity in the absence and presence of ligands (SO(4)(2-), S(2-), Cl(-), PO(4)(3-), and EDTA(-)) commonly present in wastewater was determined from the oxygen uptake rate measurements. Sulfide appeared to be the only ligand to effectively reduce nanosilver toxicity. By adding a small aliquot of sulfide that was stoichiometrically complexed with AgNPs, the nanosilver toxicity to nitrifying organisms was reduced by up to 80%. Scanning electron microscopy coupled with energy dispersive X-ray analysis indicated that AgNPs were highly reactive with sulfide to form new Ag(x)S(y) complexes or precipitates. These complexes were not oxidized after a prolonged period of aeration (18h). This information is useful for wastewater treatment design and operation to reduce nanosilver toxicity via sulfide complexation. While the biotic ligand model was successful in predicting the toxicity of Ag(+) ions, it could not accurately predict the toxicity of AgNPs. Nevertheless, it could be one of the many tools useful in predicting and controlling nanosilver toxicity to wastewater microorganisms.

  19. Protein flexibility and ligand recognition: challenges for molecular modeling.

    PubMed

    Spyrakis, Francesca; BidonChanal, Axel; Barril, Xavier; Luque, F Javier

    2011-01-01

    The intrinsic dynamics of macromolecules is an essential property to relate the structure of biomolecular systems with their function in the cell. In the field of ligand-receptor recognition, numerous evidences have revealed the limitations of the lock-and-key theory, and the need to elaborate models that take into account the inherent plasticity of biomolecules, such as the induced-fit model or the existence of an ensemble of pre-equilibrated conformations. Depending on the nature of the target system, ligand binding can be associated with small local adjustments in side chains or even the backbone to large-scale motions of structural fragments, domains or even subunits. Reproducing the inherent flexibility of biomolecules has thus become one of the most challenging issues in molecular modeling and simulation studies, as it has direct implications in our understanding of the structure-function relationships, but even in areas such as virtual screening and structure-based drug discovery. Given the intrinsic limitation of conventional simulation tools, only events occurring in short time scales can be reproduced at a high accuracy level through all-atom techniques such as Molecular Dynamics simulations. However, larger structural rearrangements demand the use of enhanced sampling methods relying on modified descriptions of the biomolecular system or the potential surface. This review illustrates the crucial role that structural plasticity plays in mediating ligand recognition through representative examples. In addition, it discusses some of the most powerful computational tools developed to characterize the conformational flexibility in ligand-receptor complexes.

  20. Supramolecular coordination and antimicrobial activities of constructed mixed ligand complexes

    NASA Astrophysics Data System (ADS)

    El-Sonbati, A. Z.; Diab, M. A.; El-Bindary, A. A.; Abou-Dobara, M. I.; Seyam, H. A.

    2013-03-01

    A novel series of copper(II) and palladium(II) with 4-derivatives benzaldehyde pyrazolone (Ln) were synthesized. The mixed ligand complexes were prepared by using 1,10-phenanthroline (Phen) as second ligand. The structure of these complexes was identified and confirm by elemental analysis, molar conductivity, UV-Vis, IR and 1H NMR spectroscopy and magnetic moment measurements as well as thermal analysis. The ligand behaves as a neutral bidentate ligand through ON donor sites. ESR spectra show the simultaneous presence of a planar trans and a nearly planar cis isomers in the 1:2 ratio for all N,O complexes [Cu(Ln)2]Cl2ṡ2H2O. Schiff bases (Ln) were tested against bacterial species; namely two Gram positive bacteria (Staphylococcus aureus and Bacillus cereus) and two Gram negative bacteria (Escherichia coli and Klebsiella pneumoniae) and fungal species (Aspergillus niger, Fusarium oxysporium, Penicillium italicum and Alternaria alternata). The tested compounds have antibacterial activity against S. aureus, B. cereus and K. pneumoniae.

  1. Central nicotinic receptors: structure, function, ligands, and therapeutic potential.

    PubMed

    Romanelli, M Novella; Gratteri, Paola; Guandalini, Luca; Martini, Elisabetta; Bonaccini, Claudia; Gualtieri, Fulvio

    2007-06-01

    The growing interest in nicotinic receptors, because of their wide expression in neuronal and non-neuronal tissues and their involvement in several important CNS pathologies, has stimulated the synthesis of a high number of ligands able to modulate their function. These membrane proteins appear to be highly heterogeneous, and still only incomplete information is available on their structure, subunit composition, and stoichiometry. This is due to the lack of selective ligands to study the role of nAChR under physiological or pathological conditions; so far, only compounds showing selectivity between alpha4beta2 and alpha7 receptors have been obtained. The nicotinic receptor ligands have been designed starting from lead compounds from natural sources such as nicotine, cytisine, or epibatidine, and, more recently, through the high-throughput screening of chemical libraries. This review focuses on the structure of the new agonists, antagonists, and allosteric ligands of nicotinic receptors, it highlights the current knowledge on the binding site models as a molecular modeling approach to design new compounds, and it discusses the nAChR modulators which have entered clinical trials.

  2. RXR function requires binding to an endogenous terpenoid ligand

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The issue of whether the nuclear receptor RXR must bind to an endogenous, nanomolar affinity ligand in order to perform its natural function is still unsettled (1). On the basis of our previous studies establishing that the Drosophilamelanogaster ortholog of the retinoid X receptor ("ultraspiracle,"...

  3. Multifunctional ligand for use as a diagnostic or therapeutic pharmaceutical

    DOEpatents

    Katti, Kattesh V.; Volkert, Wynn A.; Ketring, Alan R.; Singh, Prahlad R.

    1996-01-01

    A compound and method of making a compound for use as a diagnostic or therapeutic pharmaceutical comprises either a phosphorous or germanium core and at least two hydrazine groups forming a ligand for bonding to a metal extending from the phosphorous or germanium core.

  4. Ligand Pose and Orientational Sampling in Molecular Docking

    PubMed Central

    Coleman, Ryan G.; Carchia, Michael; Sterling, Teague; Irwin, John J.; Shoichet, Brian K.

    2013-01-01

    Molecular docking remains an important tool for structure-based screening to find new ligands and chemical probes. As docking ambitions grow to include new scoring function terms, and to address ever more targets, the reliability and extendability of the orientation sampling, and the throughput of the method, become pressing. Here we explore sampling techniques that eliminate stochastic behavior in DOCK3.6, allowing us to optimize the method for regularly variable sampling of orientations. This also enabled a focused effort to optimize the code for efficiency, with a three-fold increase in the speed of the program. This, in turn, facilitated extensive testing of the method on the 102 targets, 22,805 ligands and 1,411,214 decoys of the Directory of Useful Decoys - Enhanced (DUD-E) benchmarking set, at multiple levels of sampling. Encouragingly, we observe that as sampling increases from 50 to 500 to 2000 to 5000 to 20000 molecular orientations in the binding site (and so from about 1×1010 to 4×1010 to 1×1011 to 2×1011 to 5×1011 mean atoms scored per target, since multiple conformations are sampled per orientation), the enrichment of ligands over decoys monotonically increases for most DUD-E targets. Meanwhile, including internal electrostatics in the evaluation ligand conformational energies, and restricting aromatic hydroxyls to low energy rotamers, further improved enrichment values. Several of the strategies used here to improve the efficiency of the code are broadly applicable in the field. PMID:24098414

  5. Hierarchical Docking of Databases of Multiple Ligand Conformations

    PubMed Central

    Lorber, David M.; Shoichet, Brian K.

    2006-01-01

    Ligand flexibility is an important problem in molecular docking and virtual screening. To address this challenge, we investigate a hierarchical pre-organization of multiple conformations of small molecules. Such organization of pre-calculated conformations removes the exploration of ligand conformational space from the docking calculation and allows for concise representation of what can be thousands of conformations. The hierarchy also recognizes and prunes incompatible conformations early in the calculation, eliminating redundant calculations of fit. We investigate the method by docking the MDL Drug Data Report (MDDR), an annotated database of 100,000 molecules, into apo and holo forms of seven unrelated targets. This annotated database allows us to track the ranking of tens to hundreds of annotated ligands in each of the docking systems. The binding sites and database are prepared in an automated fashion in an attempt to remove some human bias from the calculations. Many thousands of explicit and implicit ligand conformations may be docked in calculations not much longer than required for single conformer docking. As long as internal energies are not considered, recombination with the hierarchy is additive as the number of degrees of freedom is increased. Molecules with even millions of conformations can be docked in a few minutes on a single desktop computer. PMID:16101414

  6. Synthesis and Characterization of Metal Complexes with Schiff Base Ligands

    ERIC Educational Resources Information Center

    Wilkinson, Shane M.; Sheedy, Timothy M.; New, Elizabeth J.

    2016-01-01

    In order for undergraduate laboratory experiments to reflect modern research practice, it is essential that they include a range of elements, and that synthetic tasks are accompanied by characterization and analysis. This intermediate general chemistry laboratory exercise runs over 2 weeks, and involves the preparation of a Schiff base ligand and…

  7. A Guided Inquiry Activity for Teaching Ligand Field Theory

    ERIC Educational Resources Information Center

    Johnson, Brian J.; Graham, Kate J.

    2015-01-01

    This paper will describe a guided inquiry activity for teaching ligand field theory. Previous research suggests the guided inquiry approach is highly effective for student learning. This activity familiarizes students with the key concepts of molecular orbital theory applied to coordination complexes. Students will learn to identify factors that…

  8. Docking validation resources: protein family and ligand flexibility experiments.

    PubMed

    Mukherjee, Sudipto; Balius, Trent E; Rizzo, Robert C

    2010-11-22

    A database consisting of 780 ligand-receptor complexes, termed SB2010, has been derived from the Protein Databank to evaluate the accuracy of docking protocols for regenerating bound ligand conformations. The goal is to provide easily accessible community resources for development of improved procedures to aid virtual screening for ligands with a wide range of flexibilities. Three core experiments using the program DOCK, which employ rigid (RGD), fixed anchor (FAD), and flexible (FLX) protocols, were used to gauge performance by several different metrics: (1) global results, (2) ligand flexibility, (3) protein family, and (4) cross-docking. Global spectrum plots of successes and failures vs rmsd reveal well-defined inflection regions, which suggest the commonly used 2 Å criteria is a reasonable choice for defining success. Across all 780 systems, success tracks with the relative difficulty of the calculations: RGD (82.3%) > FAD (78.1%) > FLX (63.8%). In general, failures due to scoring strongly outweigh those due to sampling. Subsets of SB2010 grouped by ligand flexibility (7-or-less, 8-to-15, and 15-plus rotatable bonds) reveal that success degrades linearly for FAD and FLX protocols, in contrast to RGD, which remains constant. Despite the challenges associated with FLX anchor orientation and on-the-fly flexible growth, success rates for the 7-or-less (74.5%) and, in particular, the 8-to-15 (55.2%) subset are encouraging. Poorer results for the very flexible 15-plus set (39.3%) indicate substantial room for improvement. Family-based success appears largely independent of ligand flexibility, suggesting a strong dependence on the binding site environment. For example, zinc-containing proteins are generally problematic, despite moderately flexible ligands. Finally, representative cross-docking examples, for carbonic anhydrase, thermolysin, and neuraminidase families, show the utility of family-based analysis for rapid identification of particularly good or bad

  9. Magnesium incorporation in calcite in the presence of organic ligands

    NASA Astrophysics Data System (ADS)

    Mavromatis, Vasileios; Baldermann, Andre; Purgstaller, Bettina; Dietzel, Martin

    2015-04-01

    The formation of authigenic Mg-calcites in marine early diagenetic environments is commonly driven by a bio-induced process, the anaerobic oxidation of methane (AOM), which provides inorganic carbon required for the precipitation of such authigenic carbonates. In such settings the availability of major and/or trace divalent metal cations (Me2+) incorporated in calcite and their aqueous speciation are controlled by the presence of aqueous organic molecules that are produced either as (by-)products of biological activity (i.e. exopolymeric substances) or during degradation of allochthonous organic matter in the sediments. Despite the fact that the presence of aqueous organic ligands strongly affects the growth rates and the mineralogy of precipitating CaCO3 polymorphs, till now no study addresses the role of Me2+-ligand aqueous complexes on the extent of Mg and/or other trace element content of Mg-calcites. In order to shed light on this process, relevant to authigenic calcite formation in organic-rich marine sediments and continental soils, we precipitated calcite in the presence of aqueous Mg and a variety of low molecular weight carboxylic- and aminoacids. Our experimental data indicate that the presence of organic ligands augments significantly the saturation state of calcite in the parent fluid during its precipitation. Moreover, they suggest that the higher the ligand concentration, the higher the obtained distribution coefficient of Mg in calcite. The latter is directly proportional to the ratio of Mg2+/Ca2+ aqueous ions for all ligands used. Hydrogeochemical modelling of the aqueous fluids indicate that the observed correlation can be explained by the stronger complexation of Ca2+ with organic ligands compared to Mg2+, which results in higher availability of Mg2+ vs. Ca2+ aqueous ions. Overall the obtained results suggest that the higher the organic ligand aqueous concentration the higher the Mg content of calcite forming from this fluid. These findings are

  10. IDENTIFICATION OF VDR ANTAGONISTS AMONG NUCLEAR RECEPTOR LIGANDS USING VIRTUAL SCREENING

    PubMed Central

    Teske, Kelly; Nandhikonda, Premchendar; Bogart, Jonathan W.; Feleke, Belaynesh; Sidhu, Preetpal; Yuan, Nina; Preston, Joshua; Goy, Robin; Han, Lanlan; Silvaggi, Nicholas R; Singh, Rakesh K.; Bikle, Daniel D.; Cook, James M.; Arnold, Leggy A.

    2014-01-01

    Herein, we described the development of two virtual screens to identify new vitamin D receptor (VDR) antagonists among nuclear receptor (NR) ligands. Therefore, a database of 14330 nuclear receptor ligands and their NR affinities was assembled using the online available “Binding Database”. Two different virtual screens were carried out in conjunction with a reported VDR crystal structure applying a stringent and less stringent pharmacophore model to filter docked NR ligand conformations. The pharmacophore models were based on the spatial orientation of the hydroxyl functionalities of VDR’s natural ligands 1,25(OH2)D3 and 25(OH2)D3. The first virtual screen identified 32 NR ligands with a calculate free energy of VDR binding of more than −6.0 kJ/mol. All but nordihydroguaiaretic acid (NDGA) are VDR ligands, which inhibited the interaction between VDR and coactivator peptide SRC2-3 with an IC50 value of 15.8 µM. The second screen identified 162 NR ligands with a calculate free energy of VDR binding of more than −6.0 kJ/mol. More than half of these ligands were developed to bind VDR followed by ERα/β ligands (26%), TRα/β ligands (7%) and LxRα/β ligands (7%). The binding between VDR and ERα ligand H6036 as well as TRα/β ligand triiodothyronine and a homoserine analog thereof was confirmed by fluorescence polarization. PMID:25419525

  11. Ligands located within a cholesterol domain enhance gene delivery to the target tissue

    PubMed Central

    Xu, Long; Betker, Jamie; Yin, Hao; Anchordoquy, Thomas J.

    2012-01-01

    Targeted gene delivery provides enormous potential for clinical treatment of many incurable diseases. Liposomes formulated with targeting ligands have been tested extensively both in vitro and in vivo, and many studies have strived to identify more efficacious ligands. However, the environment of the ligand within the delivery vehicle is generally not considered, and this study assesses the effect of ligand micoenvironment by utilizing a lipoplex possessing a cholesterol domain. Our recent work has shown that the presence of the targeting ligand within the cholesterol domain promotes more productive transfection in cultured cells. In the present study, lipoplexes having the identical lipid composition were formulated with different conjugates of the folate ligand such that the ligand was included in, or excluded from, the cholesterol domain. The effect of locating the ligand within the cholesterol domain was then tested in a xenograft tumor model in mice. Lipoplexes that included the ligand within the cholesterol domain showed significantly higher luciferase expression and plasmid accumulation in tumors as compared to lipoplexes in which the ligand was excluded from the domain. These results demonstrate that the microenvironment of the ligand can affect gene delivery to tumors, and show that ligand-mediated delivery can be enhanced by locating targeting ligands within a cholesterol domain. PMID:22440429

  12. Dinuclear Metallacycles with Single M-X-M Bridges (X = Cl(-), Br(-); M = Fe(II), Co(II), Ni(II), Cu(II), Zn(II), Cd(II)): Strong Antiferromagnetic Superexchange Interactions.

    PubMed

    Reger, Daniel L; Pascui, Andrea E; Foley, Elizabeth A; Smith, Mark D; Jezierska, Julia; Wojciechowska, Agnieszka; Stoian, Sebastian A; Ozarowski, Andrew

    2017-03-06

    A series of monochloride-bridged, dinuclear metallacycles of the general formula [M2(μ-Cl)(μ-L)2](ClO4)3 have been prepared using the third-generation, ditopic bis(pyrazolyl)methane ligands L = m-bis[bis(1-pyrazolyl)methyl]benzene (Lm), M = Cu(II), Zn(II), and L = m-bis[bis(3,5-dimethyl-1-pyrazolyl)methyl]benzene (Lm*), M = Fe(II), Co(II), Ni(II), Cu(II), Zn(II), Cd(II). These complexes were synthesized from the direct reactions of M(ClO4)2·6H2O, MCl2, and the ligand, Lm or Lm*, in the appropriate stoichiometric amounts. Three analogous complexes of the formula [M2(μ-Cl)(μ-L)2](BF4)3, L = Lm, M = Cu(II), and L = Lm*, M = Co(II), Cu(II), were prepared from the reaction of [M2(μ-F)(μ-L)2](BF4)3 and (CH3)3SiCl. The bromide-bridged complex [Cu2(μ-Br)(μ-Lm*)2](ClO4)3 was prepared by the first method. Three acyclic complexes, [Co2(μ-Lm)μ-Cl4], [Co2(μ-Lm*)Cl4], and [Co2(μ-Lm*)Br4], were also prepared. The structures of all [M2(μ-X)(μ-L)2](3+) (X = Cl(-), Br(-)) complexes have two ditopic bis(pyrazolyl)methane ligands bridging two metals in a metallacyclic arrangement. The fifth coordination site of the distorted trigonal bipyramidal metal centers is filled by a bridging halide ligand that has an unusual linear or nearly linear M-X-M angle. The NMR spectra of [Zn2(μ-Cl)(μ-Lm*)2](ClO4)3 and especially [Cd2(μ-Cl)(μ-Lm*)2](ClO4)3 demonstrate that the metallacycle structure is maintained in solution. Solid state magnetic susceptibility data for the copper(II) compounds show very strong antiferromagnetic exchange interactions, with -J values of 536 cm(-1) for [Cu2(μ-Cl)(μ-Lm)2](ClO4)3·xCH3CN, 720 cm(-1) for [Cu2(μ-Cl)(μ-Lm*)2](ClO4)3, and 945 cm(-1) for [Cu2(μ-Br)(μ-Lm*)2](ClO4)3·2CH3CN. Smaller but still substantial antiferromagnetic interactions are observed with other first row transition metals, with -J values of 98 cm(-1) for [Ni2(μ-Cl)(μ-Lm*)2](ClO4)3, 55 cm(-1) for [Co2(μ-Cl)(μ-Lm*)2](ClO4)3, and 34 cm(-1) for [Fe2(μ-Cl)(μ-Lm*)2](ClO4

  13. Constitutive and ligand-induced nuclear localization of oxytocin receptor.

    PubMed

    Kinsey, Conan G; Bussolati, Gianni; Bosco, Martino; Kimura, Tadashi; Pizzorno, Marie C; Chernin, Mitchell I; Cassoni, Paola; Novak, Josef F

    2007-01-01

    Oxytocin receptor (OTR) is a membrane protein known to mediate oxytocin (OT) effects, in both normal and neoplastic cells. We report here that human osteosarcoma (U2OS, MG63, OS15 and SaOS2), breast cancer (MCF7), and primary human fibroblastic cells (HFF) all exhibit OTR not only on the cell membrane, but also in the various nuclear compartments including the nucleolus. Both an OTR-GFP fusion protein and the native OTR appear to be localized to the nucleus as detected by transfection and/or confocal immunofluorescence, respectively. Treatment with oxytocin causes internalization of OTR and the resulting vesicles accumulate in the vicinity of the nucleus and some of the perinuclear OTR enters the nucleus. Western blots indicate that OTR in the nucleus and on the plasma membrane are likely to be the same biochemical and immunological entities. It appears that OTR is first visible in the nucleoli and subsequently disperses within the nucleus into 4-20 spots while some of the OTR diffuses throughout the nucleoplasm. The behaviour and kinetics of OTR-GFP and OTR are different, indicating interference by GFP in both OTR entrance into the nucleus and subsequent relocalization of OTR within the nucleus. There are important differences among the tested cells, such as the requirement of a ligand for transfer of OTR in nuclei. A constitutive internalization of OTR was found only in osteosarcoma cells, while the nuclear localization in all other tested cells was dependent on ligand binding. The amount of OTR-positive material within and in the vicinity of the nucleus increased following a treatment with oxytocin in both constitutive and ligand-dependent type of cells. The evidence of OTR compartmentalization at the cell nucleus (either ligand-dependent or constitutive) in different cell types suggests still unknown biological functions of this protein or its ligand and adds this G-protein-coupled receptor to other heptahelical receptors displaying this atypical and unexpected

  14. Investigations into the synthesis and fluorescence properties of Tb(III) complexes of a novel bis-β-diketone-type ligand and a novel bispyrazole ligand

    NASA Astrophysics Data System (ADS)

    Xiao, Lin-Xiang; Luo, Yi-Ming; Chen, Zhe; Li, Jun; Tang, Rui-Ren

    2008-11-01

    A novel bis-β-diketone organic ligand, 1,1'-(2,6-bispyridyl)bis-3-( p-methoxyphenyl)-1,3-propanedione (L 1) and its derivatives, a novel bispyrazole ligand, 2,6-bis(5-(4-methoxyphenyl)-1H-pyrazol-3-yl)pyridine (L 2) were designed and synthesized and their complexes with Tb(III) ion were successfully prepared. The ligands and the corresponding metal complexes were characterized by elemental analysis, infrared, proton nuclear magnetic resonance spectroscopy and TG-DTA. Analysis of the IR spectra suggested that the lanthanide metal ion Tb(III) coordinated to the ligands via the nitrogen atom of the pyridine ring and the carbonyl oxygen atoms for ligand L 1 and the nitrogen atom of the pyrazole ring for ligand L 2. The fluorescence properties of the two complexes in solid state were investigated and it was discovered that the Tb(III) ions could be sensitized by both the ligand (L 1) and ligand (L 2) to some extent. In particular, the complex of ligand (L 2) is a better green luminescent material that could be used as a candidate material in organic light-emitting devices (OLEDs) since it could be much better sensitized by the ligand (L 2), and the fluorescence intensity of Tb(III) complex of L 2 are almost as twice strong as L 1's.

  15. Investigations into the synthesis and fluorescence properties of Tb(III) complexes of a novel bis-beta-diketone-type ligand and a novel bispyrazole ligand.

    PubMed

    Xiao, Lin-Xiang; Luo, Yi-Ming; Chen, Zhe; Li, Jun; Tang, Rui-Ren

    2008-11-15

    A novel bis-beta-diketone organic ligand, 1,1'-(2,6-bispyridyl)bis-3-(p-methoxyphenyl)-1,3-propanedione (L1) and its derivatives, a novel bispyrazole ligand, 2,6-bis(5-(4-methoxyphenyl)-1H-pyrazol-3-yl)pyridine (L2) were designed and synthesized and their complexes with Tb(III) ion were successfully prepared. The ligands and the corresponding metal complexes were characterized by elemental analysis, infrared, proton nuclear magnetic resonance spectroscopy and TG-DTA. Analysis of the IR spectra suggested that the lanthanide metal ion Tb(III) coordinated to the ligands via the nitrogen atom of the pyridine ring and the carbonyl oxygen atoms for ligand L1 and the nitrogen atom of the pyrazole ring for ligand L2. The fluorescence properties of the two complexes in solid state were investigated and it was discovered that the Tb(III) ions could be sensitized by both the ligand (L1) and ligand (L2) to some extent. In particular, the complex of ligand (L2) is a better green luminescent material that could be used as a candidate material in organic light-emitting devices (OLEDs) since it could be much better sensitized by the ligand (L2), and the fluorescence intensity of Tb(III) complex of L2 are almost as twice strong as L1's.

  16. Effect of complexing ligands on the adsorption of Cu(II) onto the silica gel surface. 1: Adsorption of ligands

    SciTech Connect

    Park, Y.J.; Jung, K.H.; Park, K.K.; Park, K.K.

    1995-04-01

    The adsorption of several ligands on silica gel was investigated in aqueous solutions. The ligands used were 2,2{prime},6{prime},2{double_prime}-terpyridine, pyridine, 3,4-lutidine, 2-aminomethyl pyridine, 2-pyridine methanol, picolinic acid, salicylic acid, and 5-sulfosalicylic acid. The adsorption behaviors of these ligands were interpreted by means of three adsorption modes: ion exchange, hydrogen bonding, and hydrophobic interaction. For 2,2{prime},6{prime},2{double_prime}-terpyridine, pyridine, and 3,4-lutidine, the adsorption maxima appeared near their respective pK{sub a} values and were found to be due mainly to ion exchange, whereas the adsorption of these ligands at low pH was strongly attributed to hydrophobic interaction. The adsorption of 2-aminomethyl pyridine increased with increasing pH over the entire pH range investigated and was due mainly to ion exchange. Picolinic acid was adsorbed mainly by hydrogen bonding either via pyridine N atoms at low pH or via carboxylic O atoms at high pH. 2-Pyridine methanol was adsorbed by hydrophobic interaction at low pH and by hydrogen bonding at high pH. The adsorptions of salicylic and 5-sulfosalicylic acid were very small over the entire pH ranges investigated. For the adsorption mechanism, the Stern model was used to fit adsorption data.

  17. A sandwich-type triple-decker lanthanide complex with mixed phthalocyanine and Schiff base ligands.

    PubMed

    Gao, Feng; Li, Yu-Yang; Liu, Cai-Ming; Li, Yi-Zhi; Zuo, Jing-Lin

    2013-08-21

    A new triple-decker dinuclear sandwich-type dysprosium complex based on both the phthalocyanine ligand and the tetradentate Schiff base ligand was synthesized, which is of interest for synthetic chemistry and also shows single-molecule magnetic behaviour.

  18. Deprotonation of C-alkyl groups of cationic N-heterocyclic ligands.

    PubMed

    Cabeza, Javier A; García-Álvarez, Pablo; Pérez-Carreño, Enrique; Pruneda, Vanessa

    2012-04-21

    The C-alkyl groups of C-alkylpyrazinium-derived ligands have been selectively deprotonated by K[N(SiMe(3))(2)], through charge-controlled processes, to give neutral products that contain C-alkylidenepyrazine-derived ligands.

  19. Notch Ligand Endocytosis Generates Mechanical Pulling Force Dependent on Dynamin, Epsins and Actin

    PubMed Central

    Meloty-Kapella, Laurence; Shergill, Bhupinder; Kuon, Jane; Botvinick, Elliot; Weinmaster, Gerry

    2012-01-01

    SUMMARY Notch signaling induced by cell surface ligands is critical to development and maintenance of many eukaryotic organisms. Notch and its ligands are integral membrane proteins that facilitate direct cell-cell interactions to activate Notch proteolysis and release the intracellular domain that directs Notch-specific cellular responses. Genetic studies suggest Notch ligands require endocytosis, ubiquitylation and epsin endocytic adaptors to activate signaling, yet the exact role ligand endocytosis serves remains unresolved. Here we characterize a molecularly distinct mode of clathrin-mediated endocytosis requiring ligand ubiquitylation, epsins and actin for ligand cells to activate signaling in Notch cells. Using a cell-bead optical tweezers system, we obtained evidence for cell-mediated mechanical force dependent on this distinct mode of ligand endocytosis. We propose mechanical pulling force produced by endocytosis of Notch-bound ligand drives conformational changes in Notch that permit activating proteolysis. PMID:22658936

  20. Reactivity of halide and pseudohalide ligands in transition-metal complexes

    SciTech Connect

    Kukushkin, Yu.N.; Kukushkin, V.Yu.

    1985-10-01

    The experimental material on the reactions of coordinated halide ligands, as well as cyanide, azido, thiocyanato, and cyanato ligands, in transition-metal complexes has been generalized in this review.