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Sample records for acyclic ditopic ligand

  1. Kinetic Studies of the Coordination of Mono- and Ditopic Ligands with First Row Transition Metal Ions.

    PubMed

    Munzert, Stefanie Martina; Schwarz, Guntram; Kurth, Dirk G

    2016-03-01

    The reactions of the ditopic ligand 1,4-bis(2,2':6',2″-terpyridin-4'-yl)benzene (1) as well as the monotopic ligands 4'-phenyl-2,2':6',2″-terpyridine (2) and 2,2':6',2″-terpyridine (3) with Fe(2+), Co(2+), and Ni(2+) in solution are studied. While the reaction of 1 with Fe(2+), Co(2+), and Ni(2+) results in metallo-supramolecular coordination polyelectrolytes (MEPEs), ligands 2 and 3 give mononuclear complexes. All compounds are analyzed by UV/vis and fluorescence spectroscopy. Fluorescence spectroscopy indicates that protonation as well as coordination to Zn(2+) leads to an enhanced fluorescence of the terpyridine ligands. In contrast, Fe(2+), Co(2+), or Ni(2+) quench the fluorescence of the ligands. The kinetics of the reactions are studied by stopped-flow fluorescence spectroscopy. Analysis of the measured data is presented and the full kinetic rate laws for the coordination of the terpyridine ligands 1, 2, and 3 to Fe(2+), Co(2+), and Ni(2+) are presented. The coordination occurs within a few seconds, and the rate constant increases in the order Ni(2+) < Co(2+) < Fe(2+). With the rate constants at hand, the polymer growth of Ni-MEPE is computed.

  2. 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

  3. Synthesis and reactivity of metal complexes with acyclic (amino)(ylide)carbene ligands.

    PubMed

    González-Fernández, Elisa; Rust, Jörg; Alcarazo, Manuel

    2013-10-18

    No cycle required: The straightforward synthesis of acyclic (amino)(ylide)carbene gold complexes was achieved by reaction of isocyanide gold complexes with phosphorus and arsenic ylides as well as electron-rich olefins. Their ability to form bimetallic species and to act as ligand-transfer reagents has also been established. PMID:24038894

  4. Synthesis and reactivity of metal complexes with acyclic (amino)(ylide)carbene ligands.

    PubMed

    González-Fernández, Elisa; Rust, Jörg; Alcarazo, Manuel

    2013-10-18

    No cycle required: The straightforward synthesis of acyclic (amino)(ylide)carbene gold complexes was achieved by reaction of isocyanide gold complexes with phosphorus and arsenic ylides as well as electron-rich olefins. Their ability to form bimetallic species and to act as ligand-transfer reagents has also been established.

  5. 1,1'-Bis(N-benzimidazolylidene)ferrocene: synthesis and study of a novel ditopic ligand and its transition metal complexes.

    PubMed

    Varnado, C Daniel; Lynch, Vincent M; Bielawski, Christopher W

    2009-09-21

    Diiridum complexes containing 1,1'-bis(N-benzimidazolylidene)ferrocene, a novel ditopic ligand comprised of two N-heterocyclic carbenes (NHCs) linked directly via their N-substituents to each cyclopentadienyl ring of a ferrocene moiety, were synthesized. Crystallographic analyses of these C(2)-symmetric bimetallic complexes revealed the benzimidazolylidene moieties were intramolecularly stacked in nearly opposing orientations, effectively forming Janus-type bis(NHC) structures in the solid state. Using a variety of electrochemical techniques, the oxidation potentials of the ferrocenyl groups in these complexes were found to depend on the auxillary ligands coordinated to the Ir centers (i.e., 1,5-cyclooctadiene vs. carbonyl). Similarly, the nu(CO) of carbonyls ligated to the Ir centers varied in accord with the oxidation state of the ferrocene contained with the bis(NHC) ligand. These results suggest that the Ir and Fe centers in these complexes are electronically coupled and that the electron donating ability of the bis(NHC) ligand reported herein can be tuned electrochemically.

  6. Redox-Active-Ligand-Mediated Formation of an Acyclic Trinuclear Ruthenium Complex with Bridging Nitrido Ligands.

    PubMed

    Bagh, Bidraha; Broere, Daniël L J; Siegler, Maxime A; van der Vlugt, Jarl Ivar

    2016-07-11

    Coordination of a redox-active pyridine aminophenol ligand to Ru(II) followed by aerobic oxidation generates two diamagnetic Ru(III) species [1 a (cis) and 1 b (trans)] with ligand-centered radicals. The reaction of 1 a/1 b with excess NaN3 under inert atmosphere resulted in the formation of a rare bis(nitrido)-bridged trinuclear ruthenium complex with two nonlinear asymmetrical Ru-N-Ru fragments. The spontaneous reduction of the ligand centered radical in the parent 1 a/1 b supports the oxidation of a nitride (N(3-) ) to half an equivalent of N2 . The trinuclear omplex is reactive toward TEMPO-H, tin hydrides, thiols, and dihydrogen. PMID:27321547

  7. Synthesis, spectroscopic characterization and crystal structure of novel NNNN-donor μ-bis(bidentate) tetraaza acyclic Schiff base ligands

    NASA Astrophysics Data System (ADS)

    Habibi, Mohammad Hossein; Shojaee, Elahe; Nichol, Gary S.

    2012-12-01

    Novel NNNN-donor μ-bis(bidentate) tetraaza acyclic Schiff base ligands with different substituents (CF3, N(CH3)2 or OH groups) were synthesized by the condensation reaction of triethylenetetramine with 4-substituted benzaldehydes. Triethylenetetramine tris(4-trifluoromethylbenzylidene) (TTFMB), triethylenetetramine tris(4-dimethylaminobenzylidene) (TTDMB) and triethylenetetramine tris(2,4-dihydroxybenzylidene) (TTDHB) were formed as N4 donor ligands. The formation of a five-membered imidazolidine ring from the ethylenediamine backbone as a spacer-cumbridging unit gives rise to a new type of imidazolidine ligand. The structure of the TTFMB and TTDMB were determined by single crystal X-ray crystallography. The synthesized ligands have been characterized on the basis of the results of cyclic voltammetry (CV) and spectroscopic studies viz. FT-IR spectroscopy (FT-IR), mass spectroscopy (MS) and UV-Vis spectroscopy (UV-Vis).

  8. Synthesis, spectroscopic characterization and crystal structure of novel NNNN-donor μ-bis(bidentate) tetraaza acyclic Schiff base ligands.

    PubMed

    Habibi, Mohammad Hossein; Shojaee, Elahe; Nichol, Gary S

    2012-12-01

    Novel NNNN-donor μ-bis(bidentate) tetraaza acyclic Schiff base ligands with different substituents (CF(3), N(CH(3))(2) or OH groups) were synthesized by the condensation reaction of triethylenetetramine with 4-substituted benzaldehydes. Triethylenetetramine tris(4-trifluoromethylbenzylidene) (TTFMB), triethylenetetramine tris(4-dimethylaminobenzylidene) (TTDMB) and triethylenetetramine tris(2,4-dihydroxybenzylidene) (TTDHB) were formed as N(4) donor ligands. The formation of a five-membered imidazolidine ring from the ethylenediamine backbone as a spacer-cumbridging unit gives rise to a new type of imidazolidine ligand. The structure of the TTFMB and TTDMB were determined by single crystal X-ray crystallography. The synthesized ligands have been characterized on the basis of the results of cyclic voltammetry (CV) and spectroscopic studies viz. FT-IR spectroscopy (FT-IR), mass spectroscopy (MS) and UV-Vis spectroscopy (UV-Vis).

  9. Structural diversity in manganese, iron and cobalt complexes of the ditopic 1,2-bis(2,2'-bipyridyl-6-yl)ethyne ligand and observation of epoxidation and catalase activity of manganese compounds.

    PubMed

    Madhu, Vedichi; Ekambaram, Balaraman; Shimon, Linda J W; Diskin, Yael; Leitus, Gregory; Neumann, Ronny

    2010-08-21

    A ditopic 1,2-bis(2,2'-bipyridyl-6-yl)ethyne ligand, L, has been synthesized for the first time by consecutive Suzuki and Sonogashira coupling reactions either in a one- or two-step synthesis. Coordination of L with some first-row transition metals, Fe, Mn and Co showed a very rich structural diversity that can be obtained with this ligand. Reaction of L with Mn(II)(OAc)(2) yielded a dimanganese(II) complex, [Mn(2)L(mu-OAc)(3)]PF(6), (1) where the two somewhat inequivalent trigonal-bipyramidal Mn atoms separated by 3.381 A are bridged by L and three acetate moieties. A similar reaction of L with Mn(III)(OAc)(3) yielded a very different dimanganese complex [Mn(2)L'(OH)(OAc)(2)(DMF)(2)]PF(6) x DMF (2) where L' is a E-1,2-bis(2,2'-bipyridyl-6-yl)ethene fragment that was formed in situ. The L' ligand bridges between the two Mn centers, despite its trans configuration, which leads to a very strained ethene bridging moiety. The Mn atoms are also bridged by two acetate ligands and a hydroxy group that bridges between the Mn atoms and the ethene fragment; DMF completes the octahedral coordination around each Mn atom which are separated by 3.351 A. A comproportionation reaction of L with Mn(II)(OAc)(2) and n-Bu(4)NMnO(4) yielded a tetramanganese compound, [Mn(4)(mu(3)-O)(2)(OAc)(4)(H(2)O)(2)L(2)](PF(6))(2) x 2 CH(3)CN (3). Compound 3 has a dimer of dimers structure of the tetranuclear Mn core that consists of binuclear [Mn(2)O(OAc)(2)L](+) fragment and a PF(6) anion. BVS calculations indicate that 3 is a mixed-valent 2Mn(II) plus 2Mn(III) compound where two [Mn(II)(2)O(OAc)(2)L](+) fragments are held together by Mn(III)-O inter-fragment linkers which have a distorted octahedral geometry. The Mn atoms in the [Mn(2)O(OAc)(2)L](+) fragments have a capped square-pyramid configuration where an aqua ligand is capped on one of the faces. Although the aqua ligand is well within a bonding distance to a carbon atom of the proximal ethyne bridge, there does not appear to be an oxygen

  10. 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

    2015-08-01

    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. PMID:26200923

  11. Influence of terminal acryloyl arms on the coordination chemistry of a ditopic pyrimidine-hydrazone ligand: comparison of Pb(II), Zn(II), Cu(II), and Ag(I) complexes.

    PubMed

    Hutchinson, Daniel J; Hanton, Lyall R; Moratti, Stephen C

    2013-03-01

    A new ditopic pyrimidine-hydrazone ligand, 6-hydroxymethylacryloyl-2-pyridinecarboxaldehyde, 2,2'-[2,2'-(2-methyl-4,6-pyrimidinediyl)bis(1-methylhydrazone)] (L2), was synthesized with terminal acryloyl functional groups to allow incorporation into copolymer gel actuators. NMR spectroscopy was used to show that L2 adopted a horseshoe shape with transoid-transoid pym-hyz-py linkages. Metal complexation studies were performed with L2 and salts of Pb(II), Zn(II), Cu(II), and Ag(I) ions in CH3CN in a variety of metal to ligand ratios. Reacting L2 with an excess amount of any of the metal ions resulted in linear complexes where the pym-hyz-py linkages were rotated to a cisoid-cisoid conformation. NMR spectroscopy showed that the acryloyl arms of L2 did not interact with the bound metal ions in solution. Seven of the linear complexes (1-7) were crystallized and analyzed by X-ray diffraction. Most of these complexes (4-7) also showed no coordination between the acryloyl arms and the metal ions; however, complexes 1-3 showed some interactions. Both of the acryloyl arms were coordinated to Pb(II) ions in [Pb2L2(SO3CF3)4] (1), one through the carbonyl oxygen donor and the other through the alkoxy oxygen donor. One of the acryloyl arms of [Cu2L2(CH3CN)3](SO3CF3)4 (2) was coordinated to one of the Cu(II) ions through the carbonyl oxygen donor. There appeared to be a weak association between the alkoxy donors of the acryloyl arms and the Pb(II) ions of [Pb2L2(ClO4)4]·CH3CN (3). Reaction of excess AgSO3CF3 with L2 was repeated in CD3NO2, resulting in crystals of {[Ag7(L2)2(SO3CF3)6(H2O)2] SO3CF3}∞ (8), the polymeric structure of which resulted from coordination between the carbonyl donors of the acryloyl arms and the Ag(I) ions. In all cases the coordination and steric effects of the acryloyl arms did not inhibit isomerization of the pym-hyz bonds of L2 or the core shape of the linear complexes.

  12. Synergistic growth inhibition of human hepatocellular carcinoma cells by acyclic retinoid and GW4064, a farnesoid X receptor ligand.

    PubMed

    Ohno, Tomohiko; Shirakami, Yohei; Shimizu, Masahito; Kubota, Masaya; Sakai, Hiroyasu; Yasuda, Yoichi; Kochi, Takahiro; Tsurumi, Hisashi; Moriwaki, Hisataka

    2012-10-28

    Abnormalities in the expression and function of retinoid X receptor (RXR), a master regulator of the nuclear receptor superfamily, are associated with the development of hepatocellular carcinoma (HCC). Dysfunction of farnesoid X receptor (FXR), one of the nuclear receptors that forms a heterodimer with RXR, also plays a role in liver carcinogenesis. In the present study, we examined the effects of acyclic retinoid (ACR), a synthetic retinoid targeting RXRα, plus GW4064, a ligand for FXR, on the growth of human HCC cells. We found that ACR and GW4064 preferentially inhibited the growth of HLE, HLF, and Huh7 human HCC cells in comparison with Hc normal hepatocytes. The combination of 1μM ACR plus 1μM GW4064 synergistically inhibited the growth of HLE cells by inducing apoptosis. The combined treatment with these agents acted cooperatively to induce cell cycle arrest in the G(0)/G(1) phase and inhibit the phosphorylation of RXRα, which is regarded as a critical factor for liver carcinogenesis, through inhibition of ERK and Stat3 phosphorylation. This combination also increased the expression levels of p21(CIP1) and SHP mRNA, while decreasing the levels of c-myc and cyclin D1 mRNA in HLE cells. In addition, a reporter assay indicated that the FXRE promoter activity was significantly increased by treatment with ACR plus GW4064. Our results suggest that ACR and GW4064 cooperatively inhibit RXRα phosphorylation, modulate the expression of FXR-regulated genes, thus resulting in the induction of apoptosis and the inhibition of growth in HCC cells. This combination might therefore be effective for the chemoprevention and chemotherapy of HCC.

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

    PubMed

    Abou-Hussein, A A; Linert, Wolfgang

    2015-04-15

    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, (1)H-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, (1)H-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.

  14. 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.

  15. Lanthanide-directed synthesis of luminescent self-assembly supramolecular structures and mechanically bonded systems from acyclic coordinating organic ligands.

    PubMed

    Barry, Dawn E; Caffrey, David F; Gunnlaugsson, Thorfinnur

    2016-06-01

    Herein some examples of the use of lanthanide ions (f-metal ions) to direct the synthesis of luminescent self-assembly systems (architectures) will be discussed. This area of lanthanide supramolecular chemistry is fast growing, thanks to the unique physical (magnetic and luminescent) and coordination properties of the lanthanides, which are often transferred to the resulting supermolecule. The emphasis herein will be on systems that are luminescent, and hence, generated by using either visibly emitting ions (such as Eu(III), Tb(III) and Sm(III)) or near infrared emitting ions (like Nd(III), Yb(III) and Er(III)), formed through the use of templating chemistry, by employing structurally simple ligands, possessing oxygen and nitrogen coordinating moieties. As the lanthanides have high coordination requirements, their use often allows for the formation of coordination compounds and supramolecular systems such as bundles, grids, helicates and interlocked molecules that are not synthetically accessible through the use of other commonly used templating ions such as transition metal ions. Hence, the use of the rare-earth metal ions can lead to the formation of unique and stable species in both solution and in the solid state, as well as functional and responsive structures.

  16. Ion-pair triple helicates and mesocates self-assembled from ditopic 2,2 -bipyridine-bis(urea) ligands and Ni(II) and Fe(II) sulfate salts

    SciTech Connect

    Custelcean, Radu; Bonnesen, Peter V; Roach, Benjamin D; Duncan, Nathan C

    2012-01-01

    NiSO{sub 4} and FeSO{sub 4} self-assemble with heteroditopic ligands (L) comprising 2,2{prime}-bipyridine and o-phenylene-(bis)urea cation- and anion-binding sites, respectively, into [ML{sub 3}SO{sub 4}] (M = Ni{sup 2+}, Fe{sup 2+}) triple-stranded ion-pair helicates and mesocates.

  17. 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.

  18. Preparation of tris(spiroorthocarbonate) cyclophanes as back to back ditopic hosts.

    PubMed

    Danjo, Hiroshi; Iwaso, Kazuhisa; Kawahata, Masatoshi; Ohara, Kazuaki; Miyazawa, Toshifumi; Yamaguchi, Kentaro

    2013-05-01

    Twin-bowl-shaped tris(spiroorthocarbonate) cyclophanes were designed and prepared as ditopic hosts for electrically neutral or electron-rich guests. Preparation of the desired cyclophanes was achieved by cyclotrimerization of 2,2',3,3'-tetrahydroxy-1,1'-binaphthyl (THB) via the transesterification of tetraphenyl orthocarbonate or dichlorodiphenoxymethane. In those reactions, bis(spiroorthocarbonate) cyclophane containing two THB units was also formed as the kinetically favored product. The spiroorthocarbonate twin bowl exhibited ditopic molecular recognition toward fullerene C60 in the crystalline state. PMID:23587007

  19. Conformation-selective coordination-driven self-assembly of a ditopic donor with Pd(II) acceptors.

    PubMed

    Howlader, Prodip; Mukherjee, Sandip; Saha, Rajat; Mukherjee, Partha Sarathi

    2015-12-21

    Coordination-driven self-assembly of 3-(5-(pyridin-3-yl)-1H-1,2,4-triazol-3-yl)pyridine (L) was investigated with 90°cis-blocked Pd(II) acceptors and tetratopic Pd(NO3)2. Although the ligand is capable of binding in several different conformations (acting as a ditopic donor through the pyridyl nitrogens), the experimental results (including X-ray structures) showed that it adopts a particular conformation when it binds with 90°cis-blocked Pd(II) acceptors (two available sites) to yield [2 + 2] self-assembled macrocycles. On the other hand, with Pd(NO3)2 (where four available sites are present) a different conformer of the same donor was selectively bound to form a molecular cubic cage. The experimental findings were corroborated well with the density functional theory (B3LYP) calculations. The tetratopic Pd(NO3)2 yielded a [6 + 12] self-assembled Pd6L12 molecular cube, which contains a potential void occupied by nitrate and perchlorate ions. Being a triazole based ligand, the free space inside the cage is enriched with several sp(2) hybridised nitrogen atoms with lone pairs of electrons to act as Lewis basic sites. Knoevenagel condensation reactions of several aromatic aldehydes with active methylene compounds were successfully performed in reasonably high yields in the presence of the cage. PMID:26544720

  20. Towards dipyrrins: oxidation and metalation of acyclic and macrocyclic Schiff-base dipyrromethanes.

    PubMed

    Pankhurst, James R; Cadenbach, Thomas; Betz, Daniel; Finn, Colin; Love, Jason B

    2015-02-01

    Oxidation of acyclic Schiff-base dipyrromethanes cleanly results in dipyrrins, whereas the macrocyclic 'Pacman' analogues either decompose or form new dinuclear copper(ii) complexes that are inert to ligand oxidation; the unhindered hydrogen substituent at the meso-carbon allows new structural motifs to form.

  1. 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.

  2. Minimalistic Ditopic Ligands: An α-S,N-Donor-Substituted Alkyne as Effective Intermetallic Conjugation Linker.

    PubMed

    Rüger, Julia; Timmermann, Christopher; Villinger, Alexander; Hinz, Alexander; Hollmann, Dirk; Seidel, Wolfram W

    2016-08-01

    The capability of donor-substituted alkynes to link different metal ions in a side-on carbon donor-chelate coordination mode is extended from the donor centers S and P to the second period element N. The complex [Tp'W(CO)2 {η(2) -C2 (S)(NHBn)}] (Tp'=hydrido-tris(3,5-dimethylpyrazolyl)borate, Bn=benzyl) bearing a terminal sulfur atom and a secondary amine substituent is accessible by a metal-template synthesis. Subsequent deprotonation allowed the formation of remarkably stable heterobimetallic complexes with the [(η(5) -C5 H5 )Ru(PPh3 )] and the [Ir(ppy)2 ] moiety. Electrochemical and spectroscopic investigations (cyclic voltammetry, IR, UV/Vis, luminescence, EPR), as well as DFT calculations, and X-ray structure determinations of the W-Ru complex in two oxidation states reveal a strong metal-metal coupling but also a limited delocalization of excited states. PMID:27272102

  3. Minimalistic Ditopic Ligands: An α-S,N-Donor-Substituted Alkyne as Effective Intermetallic Conjugation Linker.

    PubMed

    Rüger, Julia; Timmermann, Christopher; Villinger, Alexander; Hinz, Alexander; Hollmann, Dirk; Seidel, Wolfram W

    2016-08-01

    The capability of donor-substituted alkynes to link different metal ions in a side-on carbon donor-chelate coordination mode is extended from the donor centers S and P to the second period element N. The complex [Tp'W(CO)2 {η(2) -C2 (S)(NHBn)}] (Tp'=hydrido-tris(3,5-dimethylpyrazolyl)borate, Bn=benzyl) bearing a terminal sulfur atom and a secondary amine substituent is accessible by a metal-template synthesis. Subsequent deprotonation allowed the formation of remarkably stable heterobimetallic complexes with the [(η(5) -C5 H5 )Ru(PPh3 )] and the [Ir(ppy)2 ] moiety. Electrochemical and spectroscopic investigations (cyclic voltammetry, IR, UV/Vis, luminescence, EPR), as well as DFT calculations, and X-ray structure determinations of the W-Ru complex in two oxidation states reveal a strong metal-metal coupling but also a limited delocalization of excited states.

  4. Pyrrolic tripodal receptors for the molecular recognition of carbohydrates: ditopic receptors for dimannosides.

    PubMed

    Francesconi, Oscar; Nativi, Cristina; Gabrielli, Gabriele; Gentili, Matteo; Palchetti, Marco; Bonora, Beatrice; Roelens, Stefano

    2013-08-26

    Synthetic ditopic receptors, designed for the molecular recognition of dimannosides, have been prepared by bridging two monotopic units effectively recognizing mannosides with linkers of the appropriate size and flexibility, endowed with hydrogen-bonding groups. Affinities toward the α and β glycosides of the biologically relevant Manα(1-2)Man disaccharide were measured by NMR spectroscopy and isothermal titration calorimetry (ITC) in polar organic media (30-40 % DMF in chloroform). Significant selectivities and affinities in the micromolar range were observed in most cases, with two newly designed receptors being the most effective receptors of the set, together with a distinct preference of the dimannosides for the (S) enantiomer of the receptor in all cases. A 3D view of the recognition mode was elucidated by a combined NMR spectroscopic/molecular modeling approach, showing the dimannoside included in the cleft of the receptor. Compared to the monotopic precursors, the ditopic receptors showed markedly improved recognition properties, proving the efficacy of the modular receptor design for the recognition of disaccharides.

  5. 3000 Horsepower super conductive field acyclic motor

    SciTech Connect

    Marshall, R.

    1983-05-01

    A 3000 hp acyclic motor was assembled and tested utilizing superconducting field coils. The magnet assembly is designed as a quadrupole magnet, utilizing a multifilamentary niobium titanium superconductor. Each magnet coil is 18 inches in diameter and 10 inches long, and operates at rated current of 200 amperes, providing 5.8 tesla in the bore of the coils in the motor configuration. The average winding current density is 10,600 A/cm/sup 2/. The acyclic motor is of a drum-type design with liquid metal current collectors, and is designed to model full-scale machinery for ship propulsion applications. Laboratory test data verified the electrical and electromagnetic design to be within three percent of the calculated values.

  6. Polar reactions of acyclic conjugated bisallenes

    PubMed Central

    Stamm, Reiner

    2013-01-01

    Summary The chemical behaviour of various alkyl-substituted, acyclic conjugated bisallenes in reactions involving polar intermediates and/or transition states has been investigated on a broad scale for the first time. The reactions studied include lithiation, reaction of the thus formed organolithium salts with various electrophiles (among others, allyl bromide, DMF and acetone), oxidation to cyclopentenones and epoxides, hydrohalogenation (HCl, HBr addition), halogenation (Br2 and I2 addition), and [2 + 2] cycloaddition with chlorosulfonyl isocyanate. The resulting adducts were fully characterized by spectroscopic and analytical methods; they constitute interesting substrates for further organic transformations. PMID:23400309

  7. Stabilization of a two-coordinate, acyclic diaminosilylene (ADASi): completion of the series of isolable diaminotetrylenes, :E(NR(2))(2) (E = group 14 element).

    PubMed

    Hadlington, Terrance J; Abdalla, Joseph A B; Tirfoin, Rémi; Aldridge, Simon; Jones, Cameron

    2016-01-28

    An extremely bulky boryl-amide ligand, [N(SiMe3){B(DAB)}](-) (TBoN; DAB = (DipNCH)2, Dip = C6H3Pr(i)2-2,6), has been utilised in the preparation of the first isolable, two-coordinate acyclic diaminosilylene (ADASi), viz. :Si(TBoN)2. This is shown to have a frontier orbital energy separation, and presumed level of reactivity, intermediate between those of the two classes of previously reported isolable two-coordinate, acyclic silylenes. PMID:26666776

  8. Synthesis and structures of acyclic monoanionic tetradentate aza beta-diketiminate complexes of magnesium, zinc, and cadmium.

    PubMed

    Fritsch, Joseph M; Thoreson, Kristen A; McNeill, Kristopher

    2006-10-28

    An acyclic monoanionic tetradentate nitrogen ligand was prepared through the condensation of 2-(4-tolyl)-malondialdehyde and 8-aminoquinoline to give (BDI(QQ))H where (BDI(QQ))H = (8-quinolyl)-NCHC(4-tolyl)CHNH-(8-quinolyl). Metal complexes, (BDI(QQ))MX, were prepared where MX = MgBr 2, ZnCl 3, and CdOAc 4. The spectroscopic and crystallographic properties of compounds 2, 3, and 4 were explored. Structures of complexes 2, 3, 4, and the tridentate ligand, (BDI(Q))OH, 5, are reported. PMID:17033706

  9. Ion pair complexes and anion binding in the solution of a ditopic receptor.

    PubMed

    Mäkelä, T; Rissanen, K

    2016-04-21

    The synthesis and crystal structures with alkali halides of a ditopic benzo-15-crown-5 bis-urea receptor have been presented. In addition, the anion binding properties of and its alkali metal complexes in solution are presented. A comprehensive single-crystal X-ray crystallographic study of , all together 13 crystal structures, including the ion pair complexes with NaCl, NaBr, NaI, KF, KCl, KBr, KI, RbF, RbCl, and RbI, give a detailed view of how behaves in the solid-state with different alkali halides depending on the size of the cation and anion. In the solid-state forms a 1 : 1 complex with a sodium cation and the anion is complexed as a contact (NaCl) or a separate ion pair (NaBr, NaI). With larger potassium and rubidium cations assembles into a 2 : 1 complex and forms a separated ion pair complex with the anion. Reflecting the crystal structures the forms a 1 : 1 complex with Na(+) in solution, and a 2 : 1 complex with K(+), which were verified by Job's plot analysis in 4 : 1 CDCl3/dimethyl sulfoxide. The binding strength of the monomeric [·Na](+) and the dimeric [2·K](+) toward chloride, bromide and iodide anions was studied by (1)H NMR titrations in 4 : 1 CDCl3/DMSO, and a clear turn-on effect of the cation complexation compared to the neutral receptor alone (Ka with for Cl(-), Br(-) and I(-) being 832, 174 and 32 M(-1), respectively) was observed. The monomeric [·Na](+) binds chloride 9, bromide 8, and iodide 12 times stronger than , while for the dimeric [2K](+) the corresponding increase in binding is 51 (Cl(-)), 84 (Br(-)), and 22 (I(-)) times with the same stoichiometric ratios as observed for the ion pair complexes in the solid-state. PMID:26953675

  10. Polytopic bis(oxazoline)-based ligands for recoverable catalytic systems applied to the enantioselective Henry reaction.

    PubMed

    Angulo, Beatriz; García, José I; Herrerías, Clara I; Mayoral, José A; Miñana, Ana C

    2015-09-21

    Several kinds of polytopic chiral ligands (including ditopic, tritopic and tetratopic), based on the bis(oxazoline) and azabis(oxazoline) motifs, have been tested in the preparation of recoverable catalytic systems for the Henry reaction. The results obtained with the different ligands are, in general, good, but they point to the existence of a delicate balance between the coordinating ability of the ligand, the catalytic activity and the recovery of the catalyst by formation of the coordination polymer, related to the easiness to form oligomeric species in solution.

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

    SciTech Connect

    Gel'man, Boris D

    2010-12-07

    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.

  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. Potent norovirus inhibitors based on the acyclic sulfamide scaffold

    PubMed Central

    Dou, Dengfeng; Tiew, Kok-Chuan; Rao Mandadapu, Sivakoteswara; Reddy Gunnam, Mallikarjuna; Alliston, Kevin R.; Kim, Yunjeong; Chang, Kyeong-Ok; Groutas, William C.

    2013-01-01

    The development of small molecule therapeutics to combat norovirus infection is of considerable interest from a public health perspective because of the highly contagious nature of noroviruses. A series of amino acid-derived acyclic sulfamide-based norovirus inhibitors has been synthesized and evaluated using a cell-based replicon system. Several compounds were found to display potent anti-norovirus activity, low toxicity, and good aqueous solubility. These compounds are suitable for further optimization of pharmacological and ADMET properties. PMID:22356738

  14. Cycloaddition of P-C Single Bonds: Stereoselective Formation of Benzo-1,3,6,2-trioxaphosphepine Complexes via a Ditopic van der Waals Complex.

    PubMed

    Malik, Payal; Espinosa Ferao, Arturo; Schnakenburg, Gregor; Streubel, Rainer

    2016-10-01

    While phosphaalkenes and phosphanes are known to participate in [4+n] cycloaddition reactions, P-C single bonds are inert in this respect. Herein, reactions of oxaphosphirane complexes with tetrachloro-ortho-benzoquinone are presented that reveal a stereoselective reaction of the endocyclic P-C bond to afford benzo-1,3,6,2-trioxaphosphepine complexes. High-level DFT calculations provide evidence that the final product is derived from a sequence of three consecutive steps involving a ditopic van der Waals complex.

  15. Cycloaddition of P-C Single Bonds: Stereoselective Formation of Benzo-1,3,6,2-trioxaphosphepine Complexes via a Ditopic van der Waals Complex.

    PubMed

    Malik, Payal; Espinosa Ferao, Arturo; Schnakenburg, Gregor; Streubel, Rainer

    2016-10-01

    While phosphaalkenes and phosphanes are known to participate in [4+n] cycloaddition reactions, P-C single bonds are inert in this respect. Herein, reactions of oxaphosphirane complexes with tetrachloro-ortho-benzoquinone are presented that reveal a stereoselective reaction of the endocyclic P-C bond to afford benzo-1,3,6,2-trioxaphosphepine complexes. High-level DFT calculations provide evidence that the final product is derived from a sequence of three consecutive steps involving a ditopic van der Waals complex. PMID:27629542

  16. A New Approach to Explore the Binding Space of Polysaccharide-Based Ligands: Selectin Antagonists

    PubMed Central

    2012-01-01

    The discovery of molecules that interfere with the binding of a ligand to a receptor remains a topic of great interest in medicinal chemistry. Herein, we report that a monosaccharide unit of a polysaccharide ligand can be replaced advantageously by a conformationally locked acyclic molecular entity. A cyclic component of the selectin ligand Sialyl Lewisx, GlcNAc, is replaced by an acyclic tether, tartaric esters, which link two saccharide units. The conformational bias of this acyclic tether originates from the minimization of intramolecular dipole–dipole interaction and the gauche effect. The evaluation of the binding of these derivatives to P-selectin was measured by surface plasmon resonance spectroscopy. The results obtained in our pilot study suggest that the discovery of tunable tethers could facilitate the exploration of the carbohydrate recognition domain of various receptors. PMID:24900426

  17. Synthesis and application of a dual chiral [2.2]paracyclophane-based N-heterocyclic carbene in enantioselective β-boration of acyclic enones.

    PubMed

    Wang, Lei; Chen, Zhen; Ma, Manyuan; Duan, Wenzeng; Song, Chun; Ma, Yudao

    2015-11-21

    An enantioselective conjugate addition of boron to α,β-unsaturated ketones catalysed by either a N-heterocyclic carbene or a copper-carbene complex generated in situ from a new chiral bicyclic triazolium based on [2.2]paracyclophane is presented. The dual chiral carbene-copper catalyst has significant advantages over its carbene counterpart as an organocatalyst in asymmetric β-boration of acyclic enones, giving a variety of chiral β-boryl ketones in good yields and enantioselectivities. This is a successful example of employing the same N-heterocyclic carbene in one catalytic reaction as both an organocatalyst and a ligand for transition metal catalysis. PMID:26347490

  18. Forming Stereogenic Centers in Acyclic Systems from Alkynes.

    PubMed

    Vabre, Roxane; Island, Biana; Diehl, Claudia J; Schreiner, Peter R; Marek, Ilan

    2015-08-17

    The combined carbometalation/zinc homologation followed by reactions with α-heterosubstituted aldehydes and imines proceed through a chair-like transition structure with the substituent of the incoming aldehyde residue preferentially occupying a pseudo-axial position to avoid the two gauche interactions. The heteroatom in the axial position produces a chelated intermediate (and not a Cornforth-Evans transition structure for α-chloro aldehydes and imines) leading to a face differentiation in the allylation reaction. This method provides access to functionalized products in which three new carbon-carbon bonds and two to three stereogenic centers, including a quaternary one, were created in acyclic systems in a single-pot operation from simple alkynes. PMID:26130570

  19. Estimation of sparse directed acyclic graphs for multivariate counts data.

    PubMed

    Han, Sung Won; Zhong, Hua

    2016-09-01

    The next-generation sequencing data, called high-throughput sequencing data, are recorded as count data, which are generally far from normal distribution. Under the assumption that the count data follow the Poisson log-normal distribution, this article 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. Forming Stereogenic Centers in Acyclic Systems from Alkynes.

    PubMed

    Vabre, Roxane; Island, Biana; Diehl, Claudia J; Schreiner, Peter R; Marek, Ilan

    2015-08-17

    The combined carbometalation/zinc homologation followed by reactions with α-heterosubstituted aldehydes and imines proceed through a chair-like transition structure with the substituent of the incoming aldehyde residue preferentially occupying a pseudo-axial position to avoid the two gauche interactions. The heteroatom in the axial position produces a chelated intermediate (and not a Cornforth-Evans transition structure for α-chloro aldehydes and imines) leading to a face differentiation in the allylation reaction. This method provides access to functionalized products in which three new carbon-carbon bonds and two to three stereogenic centers, including a quaternary one, were created in acyclic systems in a single-pot operation from simple alkynes.

  1. Analyzing microarray data with transitive directed acyclic graphs.

    PubMed

    Phan, Vinhthuy; Olusegun George, E; Tran, Quynh T; Goodwin, Shirlean; Bodreddigari, Sridevi; Sutter, Thomas R

    2009-02-01

    Post hoc assignment of patterns determined by all pairwise comparisons in microarray experiments with multiple treatments has been proven to be useful in assessing treatment effects. We propose the usage of transitive directed acyclic graphs (tDAG) as the representation of these patterns and show that such representation can be useful in clustering treatment effects, annotating existing clustering methods, and analyzing sample sizes. Advantages of this approach include: (1) unique and descriptive meaning of each cluster in terms of how genes respond to all pairs of treatments; (2) insensitivity of the observed patterns to the number of genes analyzed; and (3) a combinatorial perspective to address the sample size problem by observing the rate of contractible tDAG as the number of replicates increases. The advantages and overall utility of the method in elaborating drug structure activity relationships are exemplified in a controlled study with real and simulated data. PMID:19226664

  2. The fluxional amine gold(III) complex as an excellent catalyst and precursor of biologically active acyclic carbenes.

    PubMed

    Montanel-Pérez, Sara; Herrera, Raquel P; Laguna, Antonio; Villacampa, M Dolores; Gimeno, M Concepción

    2015-05-21

    A new amine gold(III) complex [Au(C6F5)2(DPA)]ClO4 with the di-(2-picolyl)amine (DPA) ligand has been synthesised. In the solid state the complex has a chiral amine nitrogen because the ligand coordinates to the gold centre through one nitrogen atom from a pyridine and through the NH moiety, whereas in solution it shows a fluxional behaviour with a rapid exchange between the pyridine sites. This complex can be used as an excellent synton to prepare new gold(III) carbene complexes by the reaction with isocyanide CNR. The resulting gold(III) derivatives have unprecedented bidentate C^N acyclic carbene ligands. All the complexes have been spectroscopically and structurally characterized. Taking advantage of the fluxional behaviour of the amine complex, its catalytic properties have been tested in several reactions with the formation of C-C and C-N bonds. The complex showed excellent activity with total conversion, without the presence of a co-catalyst, and with a catalyst loading as low as 0.1%. These complexes also present biological properties, and cytotoxicity studies have been performed in vitro against three tumour human cell lines, Jurkat (T-cell leukaemia), MiaPaca2 (pancreatic carcinoma) and A549 (lung carcinoma). Some of them showed excellent cytotoxic activity compared with the reference cisplatin.

  3. Ferroelectric Coordination Polymers Self-Assembled from Mesogenic Zinc(II) Porphyrin and Dipolar Bridging Ligands.

    PubMed

    Hui, Joseph K-H; Kishida, Hiroyuki; Ishiba, Keita; Takemasu, Kenta; Morikawa, Masa-Aki; Kimizuka, Nobuo

    2016-09-26

    A new class of ferroelectric coordination-based polymers has been developed by the self-assembly of lipophilic zinc porphyrin (ZnP) and ditopic bridging ligands. The ligands contain dipolar benzothiadiazole or fluorobenzene units, which are axially coordinated to ZnP with the dipole moments oriented perpendicular to the coordination axes. The coordination-based polymers show ferroelectric characteristics in the liquid crystalline state, as revealed by distinctive hysteresis in the polarization-electric field (P-E) loops and inversion current peaks in current-voltage (I-V) loops. The observed ferroelectric properties are explainable by flip-flop rotation of the dipolar axle ligands induced by the applied electric field, as demonstrated by the positive-up-negative-down (PUND) measurements. The present system provides a new operating principle in supramolecular ferroelectrics.

  4. Ferroelectric Coordination Polymers Self-Assembled from Mesogenic Zinc(II) Porphyrin and Dipolar Bridging Ligands.

    PubMed

    Hui, Joseph K-H; Kishida, Hiroyuki; Ishiba, Keita; Takemasu, Kenta; Morikawa, Masa-Aki; Kimizuka, Nobuo

    2016-09-26

    A new class of ferroelectric coordination-based polymers has been developed by the self-assembly of lipophilic zinc porphyrin (ZnP) and ditopic bridging ligands. The ligands contain dipolar benzothiadiazole or fluorobenzene units, which are axially coordinated to ZnP with the dipole moments oriented perpendicular to the coordination axes. The coordination-based polymers show ferroelectric characteristics in the liquid crystalline state, as revealed by distinctive hysteresis in the polarization-electric field (P-E) loops and inversion current peaks in current-voltage (I-V) loops. The observed ferroelectric properties are explainable by flip-flop rotation of the dipolar axle ligands induced by the applied electric field, as demonstrated by the positive-up-negative-down (PUND) measurements. The present system provides a new operating principle in supramolecular ferroelectrics. PMID:27527513

  5. 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.

  6. Biphenol-based phosphoramidite ligands for the enantioselective copper-catalyzed conjugate addition of diethylzinc.

    PubMed

    Alexakis, Alexandre; Polet, Damien; Rosset, Stéphane; March, Sébastien

    2004-08-20

    Phosphoramidite ligands, based on ortho-substituted biphenols and a chiral amine, induce high enantioselectivities (ee's up to 99%) in the copper-catalyzed conjugate addition of dialkylzinc reagents to a variety of Michael acceptors. Particularly, the best reported ee's were obtained for acyclic nitroolefins. PMID:15307737

  7. 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.

  8. 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.

  9. Reproductive hormonal patterns in pregnant, pseudopregnant and acyclic captive African wild dogs (Lycaon pictus).

    PubMed

    Van der Weyde, L K; Martin, G B; Blackberry, M A; Gruen, V; Harland, A; Paris, M C J

    2015-05-01

    African wild dogs are one of the most endangered canid species, with free-living populations declining as a consequence of habitat loss, disease and human conflict. Captive breeding is considered an important conservation strategy, but is hampered by a poor overall understanding of the reproductive biology of the species. To improve our basic knowledge, we studied hormone patterns in 15 female wild dogs using non-invasive faecal collections. By comparing longitudinal hormone profiles with behavioural and anatomical changes, females could be allocated among three reproductive classes: pregnant (n=1), pseudopregnant (n=9) and acyclic (n=4). We also monitored a single female in which contraception was induced with a deslorelin implant. Comparison of pseudopregnant and acyclic females showed that, in both classes, faecal oestradiol concentrations increased from anoestrus to pro-oestrus then declined into the oestrous and dioestrous phases. Progestagen concentrations rose steadily from anoestrus to the dioestrous phase in both pseudopregnant and acyclic females and, pseudopregnant females had significantly higher concentrations of progestagens than acyclic females in all phases of the oestrous cycle. Most females classed as pseudopregnant were found in female-only groups, suggesting that wild dogs are spontaneous ovulators. Furthermore, only one adult female did not ovulate, so suppression of reproduction in subordinates is likely to be behavioural rather than physiological.

  10. Reproductive hormonal patterns in pregnant, pseudopregnant and acyclic captive African wild dogs (Lycaon pictus).

    PubMed

    Van der Weyde, L K; Martin, G B; Blackberry, M A; Gruen, V; Harland, A; Paris, M C J

    2015-05-01

    African wild dogs are one of the most endangered canid species, with free-living populations declining as a consequence of habitat loss, disease and human conflict. Captive breeding is considered an important conservation strategy, but is hampered by a poor overall understanding of the reproductive biology of the species. To improve our basic knowledge, we studied hormone patterns in 15 female wild dogs using non-invasive faecal collections. By comparing longitudinal hormone profiles with behavioural and anatomical changes, females could be allocated among three reproductive classes: pregnant (n=1), pseudopregnant (n=9) and acyclic (n=4). We also monitored a single female in which contraception was induced with a deslorelin implant. Comparison of pseudopregnant and acyclic females showed that, in both classes, faecal oestradiol concentrations increased from anoestrus to pro-oestrus then declined into the oestrous and dioestrous phases. Progestagen concentrations rose steadily from anoestrus to the dioestrous phase in both pseudopregnant and acyclic females and, pseudopregnant females had significantly higher concentrations of progestagens than acyclic females in all phases of the oestrous cycle. Most females classed as pseudopregnant were found in female-only groups, suggesting that wild dogs are spontaneous ovulators. Furthermore, only one adult female did not ovulate, so suppression of reproduction in subordinates is likely to be behavioural rather than physiological. PMID:25818522

  11. Changes in biochemical composition of follicular fluid during reproductive acyclicity in water buffalo (Bubalus bubalis).

    PubMed

    Khan, F A; Das, G K; Pande, Megha; Mir, R A; Shankar, Uma

    2011-08-01

    This study describes the changes in biochemical composition of follicular fluid during reproductive acyclicity in buffalo. A total of 73 pairs of ovaries collected from 26 reproductively acyclic and 47 reproductively cyclic buffaloes were used in the investigation. Ovarian follicles were classified into small (5.0-6.9 mm), medium (7.0-9.9 mm) and large (≥10.0 mm) sized categories depending upon their diameter. Follicular fluid was aspirated, processed and assayed for glucose, cholesterol, total protein, acid phosphatase and alkaline phosphatase. Glucose concentration was lesser in reproductively acyclic compared to cyclic buffaloes (19.3 ± 2.59 mg/dl compared to 32.6 ± 2.60 mg/dl; P<0.05), mainly due to difference in concentration between small sized follicles (12.4 ± 2.59 mg/dl compared to 28.0 ± 3.32 mg/dl; P<0.05). Cholesterol concentration was also lesser in reproductively acyclic compared to cyclic buffaloes (32.2 ± 2.14 mg/dl compared to 35.5 ± 2.16 mg/dl; P<0.05) and this was related to the lesser concentration found in large follicles (13.8 ± 3.45 mg/dl compared to 37.2 ± 4.10mg/dl; P<0.001). Total protein and acid phosphatase levels were not affected by either the reproductive cyclicity status or the follicular size (4.9 ± 1.07 g/dl to 6.0 ± 0.28 g/dl and 1.2 ± 0.17 U/dl to 2.5 ± 1.22 U/dl, respectively). An increased alkaline phosphatase activity was, however, observed in reproductively acyclic compared to cyclic buffaloes (27.5 ± 3.08 U/dl compared to 14.0 ± 1.09 U/dl; P<0.0001). In conclusion, results of the present study indicate an alteration in the biochemical composition of follicular fluid during reproductive acyclicity in buffalo. The findings provide further support to the notion that poor nutrition is an important factor triggering reproductive acyclicity in buffalo.

  12. 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.

  13. Controlling polymer properties through dynamic metal-ligand interactions: supramolecular cruciforms made easy.

    PubMed

    Gerhardt, Warren W; Zucchero, Anthony J; South, Clinton R; Bunz, Uwe H F; Weck, Marcus

    2007-01-01

    A straightforward methodology towards the supramolecular synthesis of novel organometallic polymers with attractive optical properties is presented. By coordinating bifunctional fluorescent cruciform molecules through ditopic metalated pincer complexes (Pd or Pt), we have synthesized a new class of well-defined coordination polymers that have controllable and tunable physical and photophysical properties. The formation of these new materials by employing metal coordination was monitored by (1)H NMR spectroscopy, the association strength of the metal-ligand interaction was measured by isothermal titration calorimetry, the solution polymeric properties were evaluated by viscometry, and the optical properties were measured and observed by fluorescence spectroscopy. The fast and quantitative synthesis of a wide range of prefabricated monomeric cruciform and metalated-pincer-complex components will allow for the rapid generation, growth, and optimization of this new class of functional polymers, which have potential electronic and optical applications.

  14. 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.

  15. Cascade Cyclizations of Acyclic and Macrocyclic Alkynones: Studies toward the Synthesis of Phomactin A

    PubMed Central

    Ciesielski, Jennifer; Gandon, Vincent; Frontier, Alison J.

    2013-01-01

    A study of the reactivity and diastereoselectivity of the Lewis acid-promoted cascade cyclizations of both acyclic and macrocyclic alkynones is described. In these reactions, a β-iodoallenolate intermediate is generated via conjugate addition of iodide to an alkynone, followed by an intramolecular aldol reaction with a tethered aldehyde to afford a cyclohexenyl alcohol. The Lewis acid magnesium iodide (MgI2) was found to promote irreversible ring closure, while cyclizations using BF3·OEt2 as promoter occurred reversibly. For both acyclic and macrocyclic ynones, high diastereoselectivity was observed in the intramolecular aldol reaction. The MgI2 protocol for cyclization was applied to the synthesis of advanced intermediates relevant to the synthesis of phomactin natural products, during which a novel transannular cation-olefin cyclization was observed. DFT calculations were conducted to analyze the mechanism of this unusual MgI2-promoted process. PMID:23724905

  16. N-Branched acyclic nucleoside phosphonates as monomers for the synthesis of modified oligonucleotides.

    PubMed

    Hocková, Dana; Rosenbergová, Šárka; Ménová, Petra; Páv, Ondřej; Pohl, Radek; Novák, Pavel; Rosenberg, Ivan

    2015-04-21

    Protected N-branched nucleoside phosphonates containing adenine and thymine bases were prepared as the monomers for the introduction of aza-acyclic nucleotide units into modified oligonucleotides. The phosphotriester and phosphoramidite methods were used for the incorporation of modified and natural units, respectively. The solid phase synthesis of a series of nonamers containing one central modified unit was successfully performed in both 3'→5' and 5'→3' directions. Hybridization properties of the prepared oligoribonucleotides and oligodeoxyribonucleotides were evaluated. The measurement of thermal characteristics of the complexes of modified nonamers with the complementary strand revealed a considerable destabilizing effect of the introduced units. We also examined the substrate/inhibitory properties of aza-acyclic nucleoside phosphono-diphosphate derivatives (analogues of nucleoside triphosphates) but neither inhibition of human and bacterial DNA polymerases nor polymerase-mediated incorporation of these triphosphate analogues into short DNA was observed. PMID:25766752

  17. Acyclic cucurbit[n]uril molecular containers selectively solubilize single-walled carbon nanotubes in water.

    PubMed

    Shen, Cai; Ma, Da; Meany, Brendan; Isaacs, Lyle; Wang, YuHuang

    2012-05-01

    Making single-walled carbon nanotubes (SWNTs) soluble in water is a challenging first step to use their remarkable electronic and optical properties in a variety of applications. We report that acyclic cucurbit[n]uril molecular containers 1 and 2 selectively solubilize small-diameter and low chiral angle SWNTs. The selectivity is tunable by increasing the concentration of the molecular containers or by adjusting the ionic strength of the solution. Even at a concentration 1000 times lower than typically required for surfactants, the molecular containers render SWNTs soluble in water. Molecular mechanics simulations suggest that these C-shaped acyclic molecules complex the SWNTs such that a large portion of nanotube sidewalls are exposed to the external environment. These "naked" nanotubes fluoresce upon patching the exposed surface with sodium dodecylbenzene sulfonate.

  18. 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. PMID:21644162

  19. 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

  20. Enantiomeric differentiation of acyclic terpenes by 13C NMR spectroscopy using a chiral lanthanide shift reagent.

    PubMed

    Blanc, Marie-Cécile; Bradesi, Pascale; Casanova, Joseph

    2005-02-01

    The 13C NMR behaviour of ten acyclic terpene alcohols was examined in the presence of a chiral lanthanide shift reagent (CLSR). For each alcohol, we measured the lanthanide-induced shift (LIS) on the signals of the carbons and the splitting of some signals, which allowed the enantiomeric differentiation. As expected, the LIS decreased with the number of bonds between the binding function and the considered carbon. The enantiomeric splitting is observed for several signals in the spectrum of each compound. The influence of the hindrance of the binding function (primary, secondary or tertiary alcohol) and that of the stereochemistry of the double bonds is discussed.

  1. A new strategy to construct acyclic nucleosides via Ag(I)-catalyzed addition of pronucleophiles to 9-allenyl-9H-purines.

    PubMed

    Wei, Tao; Xie, Ming-Sheng; Qu, Gui-Rong; Niu, Hong-Ying; Guo, Hai-Ming

    2014-02-01

    A new strategy to construct acyclic nucleosides with diverse side chains was developed. With Ag(I) salts as catalysts, the hydrocarboxylation, hydroamination, and hydrocarbonation reactions proceeded well, affording acyclic nucleosides in good yields (41 examples, 60-98% yields). Meanwhile, these reactions exhibited high chemoselectivities and E-selectivities. PMID:24437554

  2. Penalized likelihood methods for estimation of sparse high-dimensional directed acyclic graphs

    PubMed Central

    SHOJAIE, ALI; MICHAILIDIS, GEORGE

    2010-01-01

    Summary Directed acyclic graphs are commonly used to represent causal relationships among random variables in graphical models. Applications of these models arise in the study of physical and biological systems where directed edges between nodes represent the influence of components of the system on each other. Estimation of directed graphs from observational data is computationally NP-hard. In addition, directed graphs with the same structure may be indistinguishable based on observations alone. When the nodes exhibit a natural ordering, the problem of estimating directed graphs reduces to the problem of estimating the structure of the network. In this paper, we propose an efficient penalized likelihood method for estimation of the adjacency matrix of directed acyclic graphs, when variables inherit a natural ordering. We study variable selection consistency of lasso and adaptive lasso penalties in high-dimensional sparse settings, and propose an error-based choice for selecting the tuning parameter. We show that although the lasso is only variable selection consistent under stringent conditions, the adaptive lasso can consistently estimate the true graph under the usual regularity assumptions. PMID:22434937

  3. Investigation of diastereoselective acyclic α-alkoxydithioacetal substitutions involving thiacarbenium intermediates.

    PubMed

    Prévost, Michel; Dostie, Starr; Waltz, Marie-Ève; Guindon, Yvan

    2014-11-01

    Reported herein is an experimental and theoretical study that elucidates why silylated nucleobase additions to acyclic α-alkoxythiacarbenium intermediates proceed with high 1,2-syn stereocontrol (anti-Felkin-Anh), which is opposite to what would be expected with corresponding activated aldehydes. The acyclic thioaminals formed undergo intramolecular cyclizations to provide nucleoside analogues with anticancer and antiviral properties. The factors influencing the selectivity of the substitution reaction have been examined thoroughly. Halothioether species initially form, ionize in the presence (low dielectric media) or absence (higher dielectric media) of the nucleophile, and react through SN2-like transition structures (TS A and D), where the α-alkoxy group is gauche to the thioether moiety. An important, and perhaps counterintuitive, observation in this work was that calculations done in the gas phase or low dielectric media (toluene) are essential to locate the product- and rate-determining transition structures (C-N bond formation) that allow the most reasonable prediction of selectivity and isotope effects for more polar solvents (THF, MeCN). The ΔΔG(⧧) (G(TSA-TSD)) obtained in silico are consistent with the preferential formation of 1,2-syn product and with the trends of stereocontrol displayed by 2,3-anti and 2,3-syn α,β-bis-alkoxydithioacetals.

  4. A multicomponent conjugation strategy to unique N-steroidal peptides: first evidence of the steroidal nucleus as a β-turn inducer in acyclic peptides.

    PubMed

    Rivera, Daniel G; Vasco, Aldrin V; Echemendía, Radell; Concepción, Odette; Pérez, Carlos S; Gavín, José A; Wessjohann, Ludger A

    2014-10-01

    Constraining small peptides into specific secondary structures has been a major challenge in peptide ligand design. So far, the major solution for decreasing the conformational flexibility in small peptides has been cyclization. An alternative is the use of topological templates, which are able to induce and/or stabilize peptide secondary structures by means of covalent attachment to the peptide. Herein a multicomponent strategy and structural analysis of a new type of peptidosteroid architecture having the steroid as N-substituent of an internal amide bond is reported. The approach comprises the one-pot conjugation of two peptide chains (or amino acid derivatives) to aminosteroids by means of the Ugi reaction to give a unique family of N-steroidal peptides. The conjugation efficiency of a variety of peptide sequences and steroidal amines, as well as their consecutive head-to-tail cyclization to produce chimeric cyclopeptide-steroid conjugates, that is, macrocyclic lipopeptides, was assessed. Determination of the three-dimensional structure of an acyclic N-steroidal peptide in solution proved that the bulky, rigid steroidal template is capable of both increasing significantly the conformational rigidity, even in a peptide sequence as short as five amino acid residues, and inducing a β-turn secondary structure even in the all-s-trans isomer. This report provides the first evidence of the steroid skeleton as β-turn inducer in linear peptide sequences.

  5. Resistance of human immunodeficiency virus type 1 to acyclic 6-phenylselenenyl- and 6-phenylthiopyrimidines.

    PubMed Central

    Nguyen, M H; Schinazi, R F; Shi, C; Goudgaon, N M; McKenna, P M; Mellors, J W

    1994-01-01

    Acyclic 6-phenylselenenyl- and 6-phenylthiopyrimidine derivatives are potent and specific inhibitors of human immunodeficiency virus type 1 (HIV-1). The development of in vitro resistance to two derivatives, 5-ethyl-1-(ethoxymethyl)-(6-phenylthio)-uracil (E-EPU), was evaluated by serial passage of HIV-1 in increasing concentrations of inhibitor. HIV-1 variants exhibiting > 500-fold resistance to E-EPSeU and E-EPU were isolated after sequential passage in 1, 5, and 10 microM inhibitor. The resistant variants exhibited coresistance to related acyclic 6-substituted pyrimidines and the HIV-1-specific inhibitors (+)-(5S)-4,5,6,7-tetrahydro-5- pyrimidines and the HIV-1-specific inhibitors (+)-(5S)-4,5,6,7-tetrahydro-5- methyl-6-(3-methyl-2-butenyl)imidazo[4,5,1-jk]benzodiazepin-2(1H)- thione (TIBO R82150) and nevirapine, but remained susceptible to 3'-azido-3'-deoxythymidine, 2',3'-dideoxycytidine, 2',3'-dideoxyinosine, and phosphonoformic acid. DNA sequence analysis of reverse transcriptase (RT) derived from E-EPSeU-resistant virus identified a Tyr (TAT)-to-Cys (TGT) mutation at either codon 188 (Cys-188; 9 of 15 clones) or codon 181 (Cys-181; 5 of 15 clones). The same amino acid changes were found in RT from E-EPU-resistant virus, but the Cys-181 mutation was more common (9 of 10 clones) than the Cys-188 mutation (1 of 10 clones). Site-specific mutagenesis and production of mutant recombinant viruses demonstrated that both the Cys-181 and Cys-188 mutations cause resistance to E-EPSeU and E-EPU. Of the two mutations, the Cys-188 substitution produced greater E-EPSeU and E-EPU resistance. The predominance of the Cys-188 mutation in E-EPSeU-resistant variants has not been noted for other classes of HIV-1 specific RT inhibitors. HIV-1 resistance is likely to limit the therapeutic efficacy of acyclic 6-substituted pyrimidines if they are used as monotherapy. PMID:7840579

  6. Enantiopure 1,4-diols and 1,4-aminoalcohols via stereoselective acyclic sulfoxide-sulfenate rearrangement.

    PubMed

    Fernández de la Pradilla, Roberto; Colomer, Ignacio; Ureña, Mercedes; Viso, Alma

    2011-05-01

    Treatment of acyclic α-hydroxy and α-tosylamino sulfinyl dienes with amines affords enantiopure 1,4-diol or 1,4-hydroxysulfonamide derivatives in good yields and diastereoselectivities. This one-pot procedure entails a conjugate addition that triggers a diastereoselective sulfoxide-sulfenate [2,3]-sigmatropic rearrangement.

  7. Enantiopurity analysis of new types of acyclic nucleoside phosphonates by capillary electrophoresis with cyclodextrins as chiral selectors.

    PubMed

    Solínová, Veronika; Kaiser, Martin Maxmilián; Lukáč, Miloš; Janeba, Zlatko; Kašička, Václav

    2014-02-01

    CE methods have been developed for the chiral analysis of new types of six acyclic nucleoside phosphonates, nucleotide analogs bearing [(3-hydroxypropan-2-yl)-1H-1,2,3-triazol-4-yl]phosphonic acid, 2-[(diisopropoxyphosphonyl)methoxy]propanoic acid, or 2-(phosphonomethoxy)propanoic acid moieties attached to adenine, guanine, 2,6-diaminopurine, uracil, and 5-bromouracil nucleobases, using neutral and cationic cyclodextrins as chiral selectors. With the exception of the 5-bromouracil-derived acyclic nucleoside phosphonate with a 2-(phosphonomethoxy)propanoic acid side chain, the R and S enantiomers of the other five acyclic nucleoside phosphonates were successfully separated with sufficient resolutions, 1.51-2.94, within a reasonable time, 13-28 min, by CE in alkaline BGEs (50 mM sodium tetraborate adjusted with NaOH to pH 9.60, 9.85, and 10.30, respectively) containing 20 mg/mL β-cyclodextrin as the chiral selector. A baseline separation of the R and S enantiomers of the 5-bromouracil-derived acyclic nucleoside phosphonate with 2-(phosphonomethoxy)propanoic acid side chain was achieved within a short time of 7 min by CE in an acidic BGE (20:40 mM Tris/phosphate, pH 2.20) using 60 mg/mL quaternary ammonium β-cyclodextrin chiral selector. The developed methods were applied for the assessment of the enantiomeric purity of the above acyclic nucleoside phosphonates. The preparations of all these compounds were found to be synthesized in pure enantiomeric forms. Using UV absorption detection at 206 nm, their concentration detection limits were in the low micromolar range.

  8. A Directed Acyclic Graph-Large Margin Distribution Machine Model for Music Symbol Classification

    PubMed Central

    Wen, Cuihong; Zhang, Jing; Rebelo, Ana; Cheng, Fanyong

    2016-01-01

    Optical Music Recognition (OMR) has received increasing attention in recent years. In this paper, we propose a classifier based on a new method named Directed Acyclic Graph-Large margin Distribution Machine (DAG-LDM). The DAG-LDM is an improvement of the Large margin Distribution Machine (LDM), which is a binary classifier that optimizes the margin distribution by maximizing the margin mean and minimizing the margin variance simultaneously. We modify the LDM to the DAG-LDM to solve the multi-class music symbol classification problem. Tests are conducted on more than 10000 music symbol images, obtained from handwritten and printed images of music scores. The proposed method provides superior classification capability and achieves much higher classification accuracy than the state-of-the-art algorithms such as Support Vector Machines (SVMs) and Neural Networks (NNs). PMID:26985826

  9. Synthesis and broad spectrum antiviral evaluation of bis(POM) prodrugs of novel acyclic nucleosides.

    PubMed

    Hamada, Manabu; Roy, Vincent; McBrayer, Tamara R; Whitaker, Tony; Urbina-Blanco, Cesar; Nolan, Steven P; Balzarini, Jan; Snoeck, Robert; Andrei, Graciela; Schinazi, Raymond F; Agrofoglio, Luigi A

    2013-09-01

    A series of seventeen hitherto unknown ANP analogs bearing the (E)-but-2-enyl aliphatic side chain and modified heterocyclic base such as cytosine and 5-fluorocytosine, 2-pyrazinecarboxamide, 1,2,4-triazole-3-carboxamide or 4-substituted-1,2,3-triazoles were prepared in a straight approach through an olefin acyclic cross metathesis as key synthetic step. All novel compounds were evaluated for their antiviral activities against a large number of DNA and RNA viruses including herpes simplex virus type 1 and 2, varicella zoster virus, feline herpes virus, human cytomegalovirus, hepatitis C virus (HCV), HIV-1 and HIV-2. Among these molecules, only compound 31 showed activity against human cytomegalovirus in HEL cell cultures with at EC50 of ∼10 μM. Compounds 8a, 13, 14, and 24 demonstrated pronounced anti-HCV activity without significant cytotoxicity at 100 μM.

  10. Versatile synthesis of oxime-containing acyclic nucleoside phosphonates--synthetic solutions and antiviral activity.

    PubMed

    Solyev, Pavel N; Jasko, Maxim V; Kleymenova, Alla A; Kukhanova, Marina K; Kochetkov, Sergey N

    2015-11-28

    New oxime-containing acyclic nucleoside phosphonates 9-{2-[(phosphonomethyl)oximino]ethyl}adenine (1), -guanine (2) and 9-{2-[(phosphonomethyl)oximino]propyl}adenine (3) with wide spectrum activity against different types of viruses were synthesized. The key intermediate, diethyl aminooxymethylphosphonate, was obtained by the Mitsunobu reaction. Modified conditions for the by-product separation (without chromatography and distillation) allowed us to obtain 85% yield of the aminooxy intermediate. The impact of DBU and Cs2CO3 on the N(9)/N(7) product ratio for adenine and guanine alkylation was studied. A convenient procedure for aminooxy group detection was found. The synthesized phosphonates were tested and they appeared to display moderate activity against different types of viruses (HIV, herpes viruses in cell cultures, and hepatitis C virus in the replicon system) without toxicity up to 1000 μM. PMID:26383895

  11. Molecular Motion of the Junction Points in Model Networks Prepared by Acyclic Triene Metathesis.

    PubMed

    da Silva, Lucas Caire; Bowers, Clifford R; Graf, Robert; Wagener, Kenneth B

    2016-03-01

    The junction dynamics in a selectively deuterated model polymer network containing junctions on every 21st chain carbon is studied by solid state (2) H echo NMR. Polymer networks are prepared via acyclic triene metathesis of deuteron-labeled symmetric trienes with deuteron probes precisely placed at the alpha carbon relative to the junction point. The effect of decreasing the cross-link density on the junction dynamics is studied by introduction of polybutadiene chains in-between junctions. The networks are characterized by swelling, gel content, and solid state (1) H MAS NMR. Line shape analysis of the (2) H quadrupolar echo spectra reveals that the degree of motion anisotropy and the distribution of motion correlation times depend on the cross-link density and structural heterogeneity of the polymer networks. A detailed model of the junction dynamics at different temperatures is proposed and explained in terms of the intermolecular cooperativity in densely-packed systems. PMID:26787457

  12. A Directed Acyclic Graph-Large Margin Distribution Machine Model for Music Symbol Classification.

    PubMed

    Wen, Cuihong; Zhang, Jing; Rebelo, Ana; Cheng, Fanyong

    2016-01-01

    Optical Music Recognition (OMR) has received increasing attention in recent years. In this paper, we propose a classifier based on a new method named Directed Acyclic Graph-Large margin Distribution Machine (DAG-LDM). The DAG-LDM is an improvement of the Large margin Distribution Machine (LDM), which is a binary classifier that optimizes the margin distribution by maximizing the margin mean and minimizing the margin variance simultaneously. We modify the LDM to the DAG-LDM to solve the multi-class music symbol classification problem. Tests are conducted on more than 10000 music symbol images, obtained from handwritten and printed images of music scores. The proposed method provides superior classification capability and achieves much higher classification accuracy than the state-of-the-art algorithms such as Support Vector Machines (SVMs) and Neural Networks (NNs).

  13. 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.

  14. Synthesis of Phenylene Vinylene Macrocycles through Acyclic Diene Metathesis Macrocyclization and Their Aggregation Behavior.

    PubMed

    Zhang, Chenxi; Yu, Chao; Long, Hai; Denman, Ryan J; Jin, Yinghua; Zhang, Wei

    2015-11-16

    A series of phenylene vinylene macrocycles (PVMs) bearing substituents with various sizes and electronic properties have been synthesized through a one-step acyclic diene metathesis macrocyclization approach and their aggregation behaviors have been investigated. In great contrast to the aggregation of the analogous phenylene ethynylene macrocycles, which aggregate only when substituted with electron-withdrawing groups, these PVMs undergo exceptionally strong aggregation, regardless of the electron-donating or -withdrawing characters of the substituents. The unusual aggregation behavior of the PVMs is further investigated with thermodynamic and computer modeling studies, which show a good agreement with the recently proposed direct through-space interaction model, rather than the polar/π model. The high aggregation tendency of PVMs suggests the great potential of this novel class of shape-persistent macrocycles in a variety of applications, such as ion channels, host-guest recognition, and catalysis. PMID:26420443

  15. 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.

  16. 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.

  17. Bioefficacy of acyclic monoterpenes and their saturated derivatives against the West Nile vector Culex pipiens.

    PubMed

    Michaelakis, Antonios; Vidali, Veroniki P; Papachristos, Dimitrios P; Pitsinos, Emmanuel N; Koliopoulos, George; Couladouros, Elias A; Polissiou, Moschos G; Kimbaris, Athanasios C

    2014-02-01

    Twenty acyclic monoterpenes with different functional groups (acetoxy, hydroxyl, carbonyl and carboxyl) bearing a variable number of carbon double bonds were assayed as repellent and larvicidal agents against the West Nile vector Culex pipiens. Seven of them were derivatives that were synthesized through either hydrogenation or oxidation procedures. All repellent compounds were tested at the dose of 1mgcm(-2) and only neral and geranial were also tested at a 4-fold lower dose (0.25mgcm(-2)). Repellency results revealed that geranial, neral, nerol, citronellol, geranyl acetate and three more derivatives dihydrolinalool (3), dihydrocitronellol (5) and dihydrocitronellyl acetate (6) resulted in no landings. Based on the LC50 values the derivative dihydrocitronellyl acetate (6) was the most active of all, resulting in an LC50 value of 17.9mgL(-1). Linalyl acetate, citronellyl acetate, neryl acetate, geranyl acetate, dihydrocitronellol (5), dihydrocitronellal (7), citronellol, dihydrolinalyl acetate (2), citronellic acid and tetrahydrolinalyl acetate (1) were also toxic with LC50 values ranging from 23 to 45mgL(-1). Factors modulating toxicity have been identified, thus providing information on structural requirements for the selected acyclic monoterpenes. The acetoxy group enhanced toxicity, without being significantly affected by the unsaturation degree. Within esters, reduction of the vinyl group appears to decrease potency. Presence of a hydroxyl or carbonyl group resulted in increased activity but only in correlation to saturation degree. Branched alcohols proved ineffective compared to the corresponding linear isomers. Finally, as it concerns acids, data do not allow generalizations or correlations to be made. PMID:23938144

  18. Influence of Two Acyclic Homoterpenes (Tetranorterpenes) on the Foraging Behavior of Anthonomus grandis Boh.

    PubMed

    Magalhães, D M; Borges, M; Laumann, R A; Woodcock, C M; Pickett, J A; Birkett, M A; Blassioli-Moraes, Maria Carolina

    2016-04-01

    Previous studies have shown that the boll weevil, Anthonomus grandis, is attracted to constitutive and conspecific herbivore-induced cotton volatiles, preferring the blend emitted by cotton at the reproductive over the vegetative stage. Moreover, this preference was paralleled by the release of the acyclic homoterpenes (tetranorterpenes) (E)-4,8-dimethyl-1,3,7-nonatriene (DMNT) and (E,E)-4,8,12-trimethyltrideca-1,3,7,11-tetraene (TMTT) in Delta Opal cotton being higher at the vegetative than at the reproductive stage. Here, we evaluated whether this difference in release of acyclic homoterpenes also occurred in other cotton varieties, and if boll weevils could recognize these compounds as indicators of a specific cotton phenological stage. Results showed that cotton genotypes CNPA TB-90, BRS-293 and Delta Opal all produced higher levels of DMNT and TMTT at the vegetative stage than at the reproductive stage and that these homoterpenes allowed for principal component analysis separation of volatiles produced by the two phenological stages. Electroantennograms confirmed boll weevil antennal responses to DMNT and TMTT. Behavioral assays, using Y-tube olfactometers, showed that adding synthetic homoterpenes to reproductive cotton volatiles (mimicking cotton at the vegetative stage in terms of homoterpene levels) resulted in reduced attraction to boll weevils compared to that to unmodified reproductive cotton. Weevils showed no preference when given a choice between plants at the vegetative stage and the vegetative stage-mimicked plant. Altogether, the results show that DMNT and TMTT are used by boll weevils to distinguish between cotton phenological stages. PMID:27105878

  19. Bioefficacy of acyclic monoterpenes and their saturated derivatives against the West Nile vector Culex pipiens.

    PubMed

    Michaelakis, Antonios; Vidali, Veroniki P; Papachristos, Dimitrios P; Pitsinos, Emmanuel N; Koliopoulos, George; Couladouros, Elias A; Polissiou, Moschos G; Kimbaris, Athanasios C

    2014-02-01

    Twenty acyclic monoterpenes with different functional groups (acetoxy, hydroxyl, carbonyl and carboxyl) bearing a variable number of carbon double bonds were assayed as repellent and larvicidal agents against the West Nile vector Culex pipiens. Seven of them were derivatives that were synthesized through either hydrogenation or oxidation procedures. All repellent compounds were tested at the dose of 1mgcm(-2) and only neral and geranial were also tested at a 4-fold lower dose (0.25mgcm(-2)). Repellency results revealed that geranial, neral, nerol, citronellol, geranyl acetate and three more derivatives dihydrolinalool (3), dihydrocitronellol (5) and dihydrocitronellyl acetate (6) resulted in no landings. Based on the LC50 values the derivative dihydrocitronellyl acetate (6) was the most active of all, resulting in an LC50 value of 17.9mgL(-1). Linalyl acetate, citronellyl acetate, neryl acetate, geranyl acetate, dihydrocitronellol (5), dihydrocitronellal (7), citronellol, dihydrolinalyl acetate (2), citronellic acid and tetrahydrolinalyl acetate (1) were also toxic with LC50 values ranging from 23 to 45mgL(-1). Factors modulating toxicity have been identified, thus providing information on structural requirements for the selected acyclic monoterpenes. The acetoxy group enhanced toxicity, without being significantly affected by the unsaturation degree. Within esters, reduction of the vinyl group appears to decrease potency. Presence of a hydroxyl or carbonyl group resulted in increased activity but only in correlation to saturation degree. Branched alcohols proved ineffective compared to the corresponding linear isomers. Finally, as it concerns acids, data do not allow generalizations or correlations to be made.

  20. 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. PMID:27467163

  1. Uptake of Hydrocarbons in Aqueous Solution by Encapsulation in Acyclic Cucurbit[n]uril-Type Molecular Containers.

    PubMed

    Lu, Xiaoyong; Isaacs, Lyle

    2016-07-01

    The ability of two water-soluble acyclic cucurbit[n]uril (CB[n]) type containers, whose hydrophobic cavity is defined by a glycoluril tetramer backbone and terminal aromatic (benzene, naphthalene) sidewalls, to act as solubilizing agents for hydrocarbons in water is described. (1) H NMR spectroscopy studies and phase-solubility diagrams establish that the naphthalene-walled container performs as well as, or better than, CB[7] and CB[8] in promoting the uptake of poorly soluble hydrocarbons into aqueous solution through formation of host-hydrocarbon complexes. The naphthalene-walled acyclic CB[n] container is able to extract large hydrocarbons from crude oil into aqueous solution. PMID:27169688

  2. Investigating temporary acyclicity in a captive group of Asian elephants (Elephas maximus): Relationship between management, adrenal activity and social factors.

    PubMed

    Edwards, Katie L; Trotter, Jessica; Jones, Martin; Brown, Janine L; Steinmetz, Hanspeter W; Walker, Susan L

    2016-01-01

    Routine faecal steroid monitoring has been used to aid the management of five captive Asian elephant (Elephas maximus) females at Chester Zoo, UK, since 2007. Progestagen analysis initially revealed synchronised oestrous cycles among all females. However, a 14- to 20-week period of temporary acyclicity subsequently occurred in three females, following several management changes (increased training, foot-care and intermittent matriarch removal for health reasons) and the initiation of pregnancy in another female. The aim of this study was to retrospectively investigate whether these management changes were related to increased adrenal activity and disruption of ovarian activity, or whether social factors may have been involved in the temporary cessation of cyclicity. Faecal samples collected every other day were analysed to investigate whether glucocorticoid metabolites were related to reproductive status (pregnant, cycling, acyclic) or management (training, foot-care, matriarch presence). Routine training and foot-care were not associated with adrenal activity; however, intensive foot-care to treat an abscess in one female was associated with increased glucocorticoid concentration. Matriarch presence influenced adrenal activity in three females, being lower when the matriarch was separated from the group at night compared to being always present. However, in the females that exhibited temporary acyclicity, there was no consistent relationship between glucocorticoids and cyclicity state. Although the results of this study do not fully explain this occurrence, the highly synchronised nature of oestrous cycles within this group, and the concurrent acyclicity in three females, raises the question of whether social factors could have been involved in the temporary disruption of ovarian activity.

  3. Investigating temporary acyclicity in a captive group of Asian elephants (Elephas maximus): Relationship between management, adrenal activity and social factors.

    PubMed

    Edwards, Katie L; Trotter, Jessica; Jones, Martin; Brown, Janine L; Steinmetz, Hanspeter W; Walker, Susan L

    2016-01-01

    Routine faecal steroid monitoring has been used to aid the management of five captive Asian elephant (Elephas maximus) females at Chester Zoo, UK, since 2007. Progestagen analysis initially revealed synchronised oestrous cycles among all females. However, a 14- to 20-week period of temporary acyclicity subsequently occurred in three females, following several management changes (increased training, foot-care and intermittent matriarch removal for health reasons) and the initiation of pregnancy in another female. The aim of this study was to retrospectively investigate whether these management changes were related to increased adrenal activity and disruption of ovarian activity, or whether social factors may have been involved in the temporary cessation of cyclicity. Faecal samples collected every other day were analysed to investigate whether glucocorticoid metabolites were related to reproductive status (pregnant, cycling, acyclic) or management (training, foot-care, matriarch presence). Routine training and foot-care were not associated with adrenal activity; however, intensive foot-care to treat an abscess in one female was associated with increased glucocorticoid concentration. Matriarch presence influenced adrenal activity in three females, being lower when the matriarch was separated from the group at night compared to being always present. However, in the females that exhibited temporary acyclicity, there was no consistent relationship between glucocorticoids and cyclicity state. Although the results of this study do not fully explain this occurrence, the highly synchronised nature of oestrous cycles within this group, and the concurrent acyclicity in three females, raises the question of whether social factors could have been involved in the temporary disruption of ovarian activity. PMID:26393308

  4. Dual Catalysis Using Boronic Acid and Chiral Amine: Acyclic Quaternary Carbons via Enantioselective Alkylation of Branched Aldehydes with Allylic Alcohols.

    PubMed

    Mo, Xiaobin; Hall, Dennis G

    2016-08-31

    A ferrocenium boronic acid salt activates allylic alcohols to generate transient carbocations that react with in situ-generated chiral enamines from branched aldehydes. The optimized conditions afford the desired acyclic products embedding a methyl-aryl quaternary carbon center with up to 90% yield and 97:3 enantiomeric ratio, with only water as the byproduct. This noble-metal-free method complements alternative methods that are incompatible with carbon-halogen bonds and other sensitive functional groups. PMID:27518200

  5. Transition state analogue inhibitors of human methylthioadenosine phosphorylase and bacterial methylthioadenosine/S-adenosylhomocysteine nucleosidase incorporating acyclic ribooxacarbenium ion mimics

    PubMed Central

    Clinch, Keith; Evans, Gary B.; Fröhlich, Richard F. G.; Gulab, Shivali A.; Gutierrez, Jemy A.; Mason, Jennifer M.; Schramm, Vern L.; Tyler, Peter C.; Woolhouse, Anthony D.

    2012-01-01

    Several acyclic hydroxy-methylthio-amines with 3 to 5 carbon atoms were prepared and coupled via a methylene link to 9-deazaadenine. The products were tested for inhibition against human MTAP and E. coli and N. meningitidis MTANs and gave Ki values as low as 0.23 nM. These results were compared to those obtained with 1st and 2nd generation inhibitors (1S)-1-(9-deazaadenin-9-yl)-1,4-dideoxy-1,4-imino-5-methylthio-d-ribitol (MT-Immucillin-A, 3) and (3R,4S)-1-[9-deazaadenin-9-yl)methyl]3-hydroxy-4-methylthiomethylpyrrolidine (MT-DADMe-Immucillin-A, 4). The best inhibitors were found to exhibit binding affinities of approximately 2- to 4-fold those of 3 but were significantly weaker than 4. Cleavage of the 2,3 carbon–carbon bond in MT-Immucillin-A (3) gave an acyclic product (79) with a 21,500 fold loss of activity against E. coli MTAN. In another case, N-methylation of a side chain secondary amine resulted in a 250-fold loss of activity against the same enzyme [(±)-65 vs (±)-68]. The inhibition results were also contrasted with those acyclic derivatives previously prepared as inhibitors for a related enzyme, purine nucleoside phosphorylase (PNP), where some inhibitors in the latter case were found to be more potent than their cyclic counterparts. PMID:22854195

  6. Analytic Bounds on Causal Risk Differences in Directed Acyclic Graphs Involving Three Observed Binary Variables

    PubMed Central

    Kaufman, Sol; Kaufman, Jay S.; MacLehose, Richard F.

    2009-01-01

    We apply a linear programming approach which uses the causal risk difference (RDC) as the objective function and provides minimum and maximum values that RDC can achieve under any set of linear constraints on the potential response type distribution. We consider two scenarios involving binary exposure X, covariate Z and outcome Y. In the first, Z is not affected by X, and is a potential confounder of the causal effect of X on Y. In the second, Z is affected by X and intermediate in the causal pathway between X and Y. For each scenario we consider various linear constraints corresponding to the presence or absence of arcs in the associated directed acyclic graph (DAG), monotonicity assumptions, and presence or absence of additive-scale interactions. We also estimate Z-stratum-specific bounds when Z is a potential effect measure modifier and bounds for both controlled and natural direct effects when Z is affected by X. In the absence of any additional constraints deriving from background knowledge, the well-known bounds on RDc are duplicated: −Pr(Y≠X) ≤ RDC ≤ Pr(Y=X). These bounds have unit width, but can be narrowed by background knowledge-based assumptions. We provide and compare bounds and bound widths for various combinations of assumptions in the two scenarios and apply these bounds to real data from two studies. PMID:20161106

  7. Synthesis of modified cyclic and acyclic dextrins and comparison of their complexation ability

    PubMed Central

    Jicsinszky, László; Sohajda, Tamás; Puskás, István; Fenyvesi, Éva

    2014-01-01

    Summary We compared the complex forming ability of α-, β- and γ-cyclodextrins (α-CD, β-CD and γ-CD) with their open ring analogs. In addition to the native cyclodextrins also modified cyclodextrins and the corresponding maltooligomers, functionalized with neutral 2-hydroxypropyl moieties, were synthesized. A new synthetic route was worked out via bromination, benzylation, deacetylation and debenzylation to obtain the 2-hydroxypropyl maltooligomer counterparts. The complexation properties of non-modified and modified cyclic and acyclic dextrins were studied and compared by photon correlation spectroscopy (PCS) and capillary electrophoresis (CE) using model guest compounds. In some cases cyclodextrins and their open-ring analogs (acyclodextrins) show similar complexation abilities, while with other guests considerably different behavior was observed depending on the molecular dimensions and chemical characteristics of the guests. This was explained by the enhanced flexibility of the non-closed rings. Even the signs of enantiorecognition were observed for the chloropheniramine/hydroxypropyl maltohexaose system. Further studies are planned to help the deeper understanding of the interactions. PMID:25550750

  8. Directed acyclic graph-based technology mapping of genetic circuit models.

    PubMed

    Roehner, Nicholas; Myers, Chris J

    2014-08-15

    As engineering foundations such as standards and abstraction begin to mature within synthetic biology, it is vital that genetic design automation (GDA) tools be developed to enable synthetic biologists to automatically select standardized DNA components from a library to meet the behavioral specification for a genetic circuit. To this end, we have developed a genetic technology mapping algorithm that builds on the directed acyclic graph (DAG) based mapping techniques originally used to select parts for digital electronic circuit designs and implemented it in our GDA tool, iBioSim. It is among the first genetic technology mapping algorithms to adapt techniques from electronic circuit design, in particular the use of a cost function to guide the search for an optimal solution, and perhaps that which makes the greatest use of standards for describing genetic function and structure to represent design specifications and component libraries. This paper demonstrates the use of our algorithm to map the specifications for three different genetic circuits against four randomly generated libraries of increasing size to evaluate its performance against both exhaustive search and greedy variants for finding optimal and near-optimal solutions.

  9. 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.

  10. New in vitro method for evaluating antiviral activity of acyclic nucleoside phosphonates against plant viruses.

    PubMed

    Spak, J; Holý, A; Pavingerová, D; Votruba, I; Spaková, V; Petrzik, K

    2010-12-01

    A new method was developed for testing antiviral compounds against plant viruses based on rapidly growing brassicas in vitro on liquid medium. This method enables exchange of media containing tested chemicals in various concentrations and simultaneous evaluation of their phytotoxicity and antiviral activity. While using ribavirin as a standard for comparison, phytotoxicity and ability of the acyclic nucleotide analogues (R)-PMPA, PMEA, PMEDAP, and (S)-HPMPC to eliminate ssRNA Turnip yellow mosaic virus (TYMV) were evaluated by this method. Double antibody sandwich ELISA and real-time PCR were used for relative quantification of viral protein and nucleic acid in plants. Ribavirin had the most powerful antiviral effect against TYMV. On the other hand, (R)-PMPA and PMEA had no antiviral effect and almost no phytotoxicity compared to the control. (S)-HPMPC and PMEDAP showed moderate antiviral effect, accompanied by higher phytotoxicity. The tested compounds can be screened within 6-9 weeks in contrast to the 6 months for traditionally used explants on solid medium. The method enables large-scale screening of potential antivirals for in vitro elimination of viruses from vegetatively propagated crops and ornamentals.

  11. In vitro susceptibility of fungi to acyclic inhibitors of 2,3-oxidosqualene cyclases.

    PubMed

    Airaudi, D; Ceruti, M; Bianco, C; Filipello Marchisio, V

    1996-01-01

    In the present study we determine the antifungal properties of two acyclic inhibitors of 2,3-oxidosqualene cyclases: 22,23-epoxy-2-aza-2,3-dihydrosqualene (EAS) and azasqualene alcohol (ASA). Fungistatic and fungicidal activity towards dermatophytes and other fungi involved in cutaneous and systemic infections was tested (48 isolates from 10 species). The tests were carried out by inoculating 10 microliters of mycelial homogenate in 1 ml of Sabouraud glucose liquid medium containing serial dilutions of 100 to 0.25 micrograms ml-1 of the substance. For each isolate, the minimum inhibitory concentration (MIC) and the minimum fungicidal concentration (MFC) of both compounds were determined. EAS was more active (MIC range 1.5-25 micrograms ml-1) than ASA (MIC range 3-50 micrograms ml-1). At the highest concentration tested, EAS also showed fungicidal action towards some isolates of Trichophyton mentagrophytes, T. terrestre, Epidermophyton floccosum, Microsporum canis and Scopulariopsis brumptii. The most sensitive species was T. mentagrophytes, the most resistant T. rubrum. PMID:8786759

  12. Solution-Phase Parallel Synthesis of Acyclic Nucleoside Libraries of Purine, Pyrimidine, and Triazole Acetamides

    PubMed Central

    2015-01-01

    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. PMID:24933643

  13. 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.

  14. Source diagnostic and weathering indicators of tar balls utilizing acyclic, polycyclic and S-heterocyclic components.

    PubMed

    Hegazi, A H; Andersson, J T; Abu-Elgheit, M A; El-Gayar, M Sh

    2004-05-01

    This study represents a forensic chemical analysis to define the liability for the coastal bitumens polluting the beaches of the Mediterranean city of Alexandria. Six tar balls collected from several locations along the coast of the city were analyzed for their acyclic and polycyclic hydrocarbons as well as sulfur heterocycles using GC/FID, GC/AED and gas chromatography/mass spectrometry techniques. The analysis of one Egyptian crude oil is also included as a possible source oil. The tar ball samples were at early stages of weathering. Based on the GC traces and biomarker signatures, the tar balls could be genetically different. One sample collected from the Eastern Harbor region appears to be a Bunker C type fuel produced from Egyptian crudes. The refining process has removed the low molecular weight components. On the other hand, the wide n-alkane distribution together with the absence of an unresolved complex mixture suggests that crude oils probably from tank washings, ballast discharges or accident spills from tankers could have contributed significantly to the other tar ball samples. The distribution of source specific hopane and sterane markers revealed that the tar samples probably originate from different oil fields.

  15. 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.

  16. Ester prodrugs of acyclic nucleoside thiophosphonates compared to phosphonates: synthesis, antiviral activity and decomposition study.

    PubMed

    Roux, Loïc; Priet, Stéphane; Payrot, Nadine; Weck, Clément; Fournier, Maëlenn; Zoulim, Fabien; Balzarini, Jan; Canard, Bruno; Alvarez, Karine

    2013-05-01

    9-[2-(Thiophosphonomethoxy)ethyl]adenine [S-PMEA, 8] and (R)-9-[2-(Thiophosphonomethoxy)propyl]adenine [S-PMPA, 9] are acyclic nucleoside thiophosphonates we described recently that display the same antiviral spectrum (DNA viruses) as approved and potent phosphonates PMEA and (R)-PMPA. Here, we describe the synthesis, antiviral activities in infected cell cultures and decomposition study of bis(pivaloyloxymethoxy)-S-PMEA [Bis-POM-S-PMEA, 13] and bis(isopropyloxymethylcarbonyl)-S-PMPA [Bis-POC-S-PMPA, 14] as orally bioavailable prodrugs of the S-PMEA 8 and S-PMPA 9, in comparison to the equivalent "non-thio" derivatives [Bis-POM-PMEA, 11] and [Bis-POC-PMPA, 12]. Compounds 11, 12, 13 and 14 were evaluated for their in vitro antiviral activity against HIV-1-, HIV-2-, HBV- and a broad panel of DNA viruses, and found to exhibit moderate to potent antiviral activity. In order to determine the decomposition pathway of the prodrugs 11, 12, 13 and 14 into parent compounds PMEA, PMPA, 8 and 9, kinetic data and decomposition pathways in several media are presented. As expected, bis-POM-S-PMEA 13 and bis-POC-S-PMPA 14 behaved as prodrugs of S-PMEA 8 and S-PMPA 9. However, thiophosphonates 8 and 9 were released very smoothly in cell extracts, in contrast to the release of PMEA and PMPA from "non-thio" prodrugs 11 and 12. PMID:23603046

  17. Hippolides A-H, acyclic manoalide derivatives from the marine sponge Hippospongia lachne.

    PubMed

    Piao, Shu-Juan; Zhang, Hong-Jun; Lu, Hai-Yan; Yang, Fan; Jiao, Wei-Hua; Yi, Yang-Hua; Chen, Wan-Sheng; Lin, Hou-Wen

    2011-05-27

    Eight new acyclic manoalide-related sesterterpenes, hippolides A-H (1-8), together with two known manoalide derivatives, (6E)-neomanoalide (9) and (6Z)-neomanoalide (10), were isolated from the South China Sea sponge Hippospongia lachne. The absolute configurations of 1-8 were established by the modified Mosher's method and CD data. Compound 1 exhibited cytotoxicity against A549, HeLa, and HCT-116 cell lines with IC50 values of 5.22×10(-2), 4.80×10(-2), and 9.78 μM, respectively. Compound 1 also showed moderate PTP1B inhibitory activitiy with an IC50 value of 23.81 μM, and compound 2 showed moderate cytotoxicity against the HCT-116 cell line and PTP1B inhibitory activity with IC50 values of 35.13 and 39.67 μM, respectively. In addition, compounds 1 and 5 showed weak anti-inflammatory activity, with IC50 values of 61.97 and 40.35 μM for PKCγ and PKCα, respectively.

  18. Cadmium(II) and mercury(II) complexes of an NO2S2-donor macrocycle and its ditopic xylyl-bridged analogue.

    PubMed

    Jin, Yongri; Yoon, Il; Seo, Joobeom; Lee, Ji-Eun; Moon, Seok-Tae; Kim, Jineun; Han, Sang Woo; Park, Ki-Min; Lindoy, Leonard F; Lee, Shim Sung

    2005-02-21

    The NO2S2-donor macrocycle (L1) was synthesised from the ring closure reaction between Boc-N-protected 2,2'-iminobis(ethanethiol) (3) and 2,2'-(ethylenedioxy)bis(benzyl chloride) (4) followed by deprotection of the Boc-group. alpha,alpha'-Dibromo-p-xylene was employed as a dialkylating agent to bridge two L1 to yield the corresponding N-linked product (L2). The X-ray structure of L2 (as its HBr salt) is described. A range of Cd(II) and Hg(II) complexes of L1 (6-9) and L2 (10-12) were prepared and characterised. Reaction of HgX2 (X = Br or I) with L1 afforded [Hg(L1)Br]2[Hg2Br6].2CH2Cl2 6 and [Hg(L1)I(2)] 7, respectively. For 6, the Hg(II) ion in the complex cation has a distorted tetrahedral coordination environment composed of S2N donor atoms from L1 and a bromo ligand. In 7 the coordination geometry is highly distorted tetrahedral, with the macrocycle coordinating in an exodentate manner via one S and one N atom. The remaining two coordination sites are occupied by iodide ions. [Hg(L1)(ClO4)]ClO4 8 was isolated from the reaction of Hg(ClO4)2 and L1. The X-ray structure reveals that all macrocyclic ring donors bind to the central mercury ion in this case, with the latter exhibiting a highly distorted octahedral coordination geometry. The O2S2-donors from the macrocyclic ring define the equatorial plane while the axial positions are occupied by the ring nitrogen as well as by an oxygen from a monodentate perchlorato ion. Reaction of Cd(NO3)(2).4H2O with L1 afforded [Cd(L1)(NO3)2](.)0.5CH2Cl2 9 in which L1 acts as a tridentate ligand, binding exo-fashion via its S2N donors. The remaining coordination positions are filled by two bidentate nitrate ions such that, overall, the cadmium is seven-coordinate. Reactions of HgX2(X = Br or I) with L2 yielded the isostructural 2 : 1 (metal : ligand) complexes, [Hg2(L2)Br4] 10 and [Hg2(L2)I(4)] 11. Each mercury ion has a distorted tetrahedral environment made up of S and N donors from an exodentate L2 and two coordinated

  19. 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.

  20. Potent inhibition of hemangioma formation in rats by the acyclic nucleoside phosphonate analogue cidofovir.

    PubMed

    Liekens, S; Andrei, G; Vandeputte, M; De Clercq, E; Neyts, J

    1998-06-15

    The acyclic nucleoside phosphonate analogue cidofovir elicited a marked protection against hemangioma growth in newborn rats that had been infected i.p. with a high titer of murine polyomavirus. Untreated, infected rats developed cutaneous, i.m., and cerebral hemangiomas associated with severe hemorrhage and anemia leading to death within 3 weeks postinfection (p.i.). s.c. treatment with cidofovir at 25 mg/kg, once a week, resulted in a complete suppression of hemangioma development and associated mortality when treatment was initiated at 3 days p.i. (100% survival compared with 0% for the untreated animals). Cidofovir still afforded 40% survival and a significant delay in tumor-associated mortality when treatment was started at a time at which cerebral hemangiomas were already macroscopically visible (i.e., 9 days p.i.). Infectious virus or viral DNA was undetectable in the brain at different times p.i. as assessed by means of (a) a DNA-DNA hybridization assay and (b) titration of the brain for infectious virus content, indicating that there was no viral replication in murine polyomavirus-infected rats. Moreover, a semiquantitative PCR for viral protein 1 DNA revealed that the amount of viral protein 1 DNA declined with time after infection to become virtually undetectable at 18 days p.i. Therefore, an antitumor or antiangiogenic effect, rather than inhibition of viral replication, may be the reason for the inhibitory activity of cidofovir in this model. Cidofovir may thus be further explored for the treatment of vascular tumors and, in particular, life-threatening juvenile hemangiomas.

  1. 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. PMID:25280628

  2. Cell Tracking Accuracy Measurement Based on Comparison of Acyclic Oriented Graphs

    PubMed Central

    Sorokin, Dmitry V.; Matula, Petr; Ortiz-de-Solórzano, Carlos; Kozubek, Michal

    2015-01-01

    Tracking motile cells in time-lapse series is challenging and is required in many biomedical applications. Cell tracks can be mathematically represented as acyclic oriented graphs. Their vertices describe the spatio-temporal locations of individual cells, whereas the edges represent temporal relationships between them. Such a representation maintains the knowledge of all important cellular events within a captured field of view, such as migration, division, death, and transit through the field of view. The increasing number of cell tracking algorithms calls for comparison of their performance. However, the lack of a standardized cell tracking accuracy measure makes the comparison impracticable. This paper defines and evaluates an accuracy measure for objective and systematic benchmarking of cell tracking algorithms. The measure assumes the existence of a ground-truth reference, and assesses how difficult it is to transform a computed graph into the reference one. The difficulty is measured as a weighted sum of the lowest number of graph operations, such as split, delete, and add a vertex and delete, add, and alter the semantics of an edge, needed to make the graphs identical. The measure behavior is extensively analyzed based on the tracking results provided by the participants of the first Cell Tracking Challenge hosted by the 2013 IEEE International Symposium on Biomedical Imaging. We demonstrate the robustness and stability of the measure against small changes in the choice of weights for diverse cell tracking algorithms and fluorescence microscopy datasets. As the measure penalizes all possible errors in the tracking results and is easy to compute, it may especially help developers and analysts to tune their algorithms according to their needs. PMID:26683608

  3. Acyclic CB[n]-Type Molecular Containers: Effect of Solubilizing Group on their Function as Solubilizing Excipients

    PubMed Central

    Zhang, Ben; Zavalij, Peter Y.; Isaacs, Lyle

    2014-01-01

    We report the synthesis and x-ray crystal structures of three acyclic CB[n]-type molecular containers (2a, 2h, 2f) that differ in the charge on their solubilizing groups (SO3−, OH, NH3+). The x-ray crystal structures of compounds 2h and 2f reveal a self-folding of the ArOCH2CH2X wall into the cavity driven by π–π interactions, H-bonds and ion-dipole interactions. The need to reverse this self-folding phenomenon upon guest binding decreases the affinity of 2h and 2f toward cationic guests in water relative to 2a as revealed by direct 1H NMR and UV/Vis titrations as well as UV/Vis competition experiments. We determined the pKa of 6-aminocoumarin 7 (pKa = 3.6) on its own and in the presence anionic, neutral, and cationic hosts (2a: pKa = 4.9; 2h: pKa = 4.1; 2f, pKa = 3.4) which reflect in part the relevance of direct ion-ion interactions between the arms of the host and the guest toward the recognition properties of acyclic CB[n]-type containers. Finally, we showed that the weaker binding affinities measured for neutral and positively charged hosts 2h and 2f compared to anionic 2a results in a decreased ability to act as solubilizing agents for either cationic (tamoxifen), neutral (17α–ethynylestradiol), or anionic (indomethacin) drugs in water. The results establish that acyclic CB[n] compounds that bear anionic solubilizing groups are most suitable for development as general purpose solubilizing excipients for insoluble pharmaceutical agents. PMID:24595500

  4. Modulating adsorption and stability properties in pillared metal-organic frameworks: a model system for understanding ligand effects.

    PubMed

    Burtch, Nicholas C; Walton, Krista S

    2015-11-17

    Metal-organic frameworks (MOFs) are nanoporous materials with highly tunable properties that make them ideal for a wide array of adsorption applications. Through careful choice of metal and ligand precursors, one can target the specific functionality and pore characteristics desired for the application of interest. However, among the wide array of MOFs reported in the literature, there are varying trends in the effects that ligand identity has on the adsorption, chemical stability, and intrinsic framework dynamics of the material. This is largely due to ligand effects being strongly coupled with structural properties arising from the differing topologies among frameworks. Given the important role such properties play in dictating adsorbent performance, understanding these effects will be critical for the design of next generation functional materials. Pillared MOFs are ideal platforms for understanding how ligand properties can affect the adsorption, stability, and framework dynamics in MOFs. In this Account, we highlight our recent work demonstrating how experiment and simulation can be used to understand the important role ligand identity plays in governing the properties of isostructural MOFs containing interconnected layers pillared by bridging ligands. Changing the identity of the linear, ditopic ligand in either the 2-D layer or the pillaring third dimension allows targeted modulation of the chemical functionality, porosity, and interpenetration of the framework. We will discuss how these characteristics can have important consequences on the adsorption, chemical stability, and dynamic properties of pillared MOFs. The structures discussed in this Account comprise the greatest diversity of isostructural MOFs whose stability properties have been studied, allowing valuable insight into how ligand properties dictate the chemical stability of isostructural frameworks. We also discuss how functional groups can affect adsorbate energetics at their most favorable

  5. The atu and liu clusters are involved in the catabolic pathways for acyclic monoterpenes and leucine in Pseudomonas aeruginosa.

    PubMed

    Aguilar, J A; Zavala, A N; Díaz-Pérez, C; Cervantes, C; Díaz-Pérez, A L; Campos-García, J

    2006-03-01

    Evidence suggests that the Pseudomonas aeruginosa PAO1 gnyRDBHAL cluster, which is involved in acyclic isoprenoid degradation (A. L. Díaz-Pérez, N. A. Zavala-Hernández, C. Cervantes, and J. Campos-García, Appl. Environ. Microbiol. 70:5102-5110, 2004), corresponds to the liuRABCDE cluster (B. Hoschle, V. Gnau, and D. Jendrossek, Microbiology 151:3649-3656, 2005). A liu (leucine and isovalerate utilization) homolog cluster was found in the PAO1 genome and is related to the catabolism of acyclic monoterpenes of the citronellol family (AMTC); it was named the atu cluster (acyclic terpene utilization), consisting of the atuCDEF genes and lacking the hydroxymethyl-glutaryl-coenzyme A (CoA) lyase (HMG-CoA lyase) homolog. Mutagenesis of the atu and liu clusters showed that both are involved in AMTC and leucine catabolism by encoding the enzymes related to the geranyl-CoA and the 3-methylcrotonyl-CoA pathways, respectively. Intermediary metabolites of the acyclic monoterpene pathway, citronellic and geranic acids, were accumulated, and leucine degradation rates were affected in both atuF and liuD mutants. The alpha subunit of geranyl-CoA carboxylase and the alpha subunit of 3-methylcrotonyl-CoA carboxylase (alpha-MCCase), encoded by the atuF and liuD genes, respectively, were both induced by citronellol, whereas only the alpha-MCCase subunit was induced by leucine. Both citronellol and leucine also induced a LacZ transcriptional fusion at the liuB gene. The liuE gene encodes a probable hydroxy-acyl-CoA lyase (probably HMG-CoA lyase), an enzyme with bifunctional activity that is essential for both AMTC and leucine degradation. P. aeruginosa PAO1 products encoded by the liuABCD cluster showed a higher sequence similarity (77.2 to 79.5%) with the probable products of liu clusters from several Pseudomonas species than with the atuCDEF cluster from PAO1 (41.5%). Phylogenetic studies suggest that the atu cluster from P. aeruginosa could be the result of horizontal transfer

  6. Development of Catalysts and Ligands for Enantioselective Gold Catalysis

    PubMed Central

    Wang, Yi-Ming; Lackner, Aaron D.; Toste, F. Dean

    2014-01-01

    CONSPECTUS The use of Au(I) complexes for the catalytic activation of C-C π-bonds has been the subject of intense investigation in the last decade or so. The facile formation of carbon-carbon and carbon-heteroatom bonds facilitated by gold naturally led to efforts to render these transformations enantioselective. Early examples of enantioselective gold-catalyzed transformations have focused on bis(phosphinegold) complexes derived from axially chiral scaffolds. Although these complexes were highly successful in some reactions like cyclopropanation, careful choice of the weakly coordinating ligand (or counterion) was needed 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 order to expand the scope of reactions amenable to enantioselective gold catalysis to cycloadditions and other carbocyclization processes, a new class of mononuclear phosphite and phosphoramidite ligands was developed to supplement the previously widely utilized phosphines. Finally carbene ligands, in particular, the acyclic diaminocarbenes, have also been successfully applied to enantioselective transformations. PMID:24228794

  7. The Effect of Acyclic Retinoid on the Metabolomic Profiles of Hepatocytes and Hepatocellular Carcinoma Cells

    PubMed Central

    Qin, Xian-Yang; Wei, Feifei; Tanokura, Masaru; Ishibashi, Naoto; Shimizu, Masahito; Moriwaki, Hisataka; Kojima, Soichi

    2013-01-01

    Background/Purpose Acyclic retinoid (ACR) is a promising chemopreventive agent for hepatocellular carcinoma (HCC) that selectively inhibits the growth of HCC cells (JHH7) but not normal hepatic cells (Hc). To better understand the molecular basis of the selective anti-cancer effect of ACR, we performed nuclear magnetic resonance (NMR)-based and capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS)-based metabolome analyses in JHH7 and Hc cells after treatment with ACR. Methodology/Principal Findings NMR-based metabolomics revealed a distinct metabolomic profile of JHH7 cells at 18 h after ACR treatment but not at 4 h after ACR treatment. CE-TOFMS analysis identified 88 principal metabolites in JHH7 and Hc cells after 24 h of treatment with ethanol (EtOH) or ACR. The abundance of 71 of these metabolites was significantly different between EtOH-treated control JHH7 and Hc cells, and 49 of these metabolites were significantly down-regulated in the ACR-treated JHH7 cells compared to the EtOH-treated JHH7 cells. Of particular interest, the increase in adenosine-5′-triphosphate (ATP), the main cellular energy source, that was observed in the EtOH-treated control JHH7 cells was almost completely suppressed in the ACR-treated JHH7 cells; treatment with ACR restored ATP to the basal levels observed in both EtOH-control and ACR-treated Hc cells (0.72-fold compared to the EtOH control-treated JHH7 cells). Moreover, real-time PCR analyses revealed that ACR significantly increased the expression of pyruvate dehydrogenase kinases 4 (PDK4), a key regulator of ATP production, in JHH7 cells but not in Hc cells (3.06-fold and 1.20-fold compared to the EtOH control, respectively). Conclusions/Significance The results of the present study suggest that ACR may suppress the enhanced energy metabolism of JHH7 cells but not Hc cells; this occurs at least in part via the cancer-selective enhancement of PDK4 expression. The cancer-selective metabolic pathways identified in

  8. 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.

  9. 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.

  10. 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

  11. 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.

  12. 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.

  13. The Pseudomonas aeruginosa liuE gene encodes the 3-hydroxy-3-methylglutaryl coenzyme A lyase, involved in leucine and acyclic terpene catabolism.

    PubMed

    Chávez-Avilés, Mauricio; Díaz-Pérez, Alma Laura; Reyes-de la Cruz, Homero; Campos-García, Jesús

    2009-07-01

    The enzymes involved in the catabolism of leucine are encoded by the liu gene cluster in Pseudomonas aeruginosa PAO1. A mutant in the liuE gene (ORF PA2011) of P. aeruginosa was unable to utilize both leucine/isovalerate and acyclic terpenes as the carbon source. The liuE mutant grown in culture medium with citronellol accumulated metabolites of the acyclic terpene pathway, suggesting an involvement of liuE in both leucine/isovalerate and acyclic terpene catabolic pathways. The LiuE protein was expressed as a His-tagged recombinant polypeptide purified by affinity chromatography in Escherichia coli. LiuE showed a mass of 33 kDa under denaturing and 79 kDa under nondenaturing conditions. Protein sequence alignment and fingerprint sequencing suggested that liuE encodes 3-hydroxy-3-methylglutaryl-coenzyme A lyase (HMG-CoA lyase), which catalyzes the cleavage of HMG-CoA to acetyl-CoA and acetoacetate. LiuE showed HMG-CoA lyase optimal activity at a pH of 7.0 and 37 degrees C, an apparent K(m) of 100 microM for HMG-CoA and a V(max) of 21 micromol min(-1) mg(-1). These results demonstrate that the liuE gene of P. aeruginosa encodes for the HMG-CoA lyase, an essential enzyme for growth in both leucine and acyclic terpenes.

  14. Heterologous expression, purification, and enzymatic characterization of the acyclic carotenoid 1,2-hydratase from Rubrivivax gelatinosus.

    PubMed

    Steiger, Sabine; Mazet, Andreas; Sandmann, Gerhard

    2003-06-01

    The carotenoid 1,2-hydratase CrtC from Rubrivivax gelatinosus has been expressed in Escherichia coli in an active form and purified by affinity chromatography. The enzyme catalyzes the conversion of various acyclic carotenes including 1-hydroxy derivatives. This broad substrate specificity reflects the participation of CrtC in 1'-HO-spheroidene and in spirilloxanthin biosynthesis. Enzyme kinetic studies including the determination of substrate specificity constants indicate that among the alternative biosynthetic routes to 1'-HO-spheroidene the one via spheroidene is the dominating pathway. In contrast to CrtC from Rvi. gelatinosus, the equivalent enzyme from Rhodobacter capsulatus, a closely related bacterium which lacks the biosynthetic branch to spirilloxanthin and accumulates spheroidene instead of substantial amounts of 1'-HO-spheroidene, is extremely poor in converting 1-HO-carotenoids. The individual catalytic properties of both carotenoid 1,2-hydratases reflect the in situ carotenogenic pathways in both purple photosynthetic bacteria.

  15. 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

  16. Handling ligands with Coot

    PubMed Central

    Debreczeni, Judit É.; Emsley, Paul

    2012-01-01

    Coot is a molecular-graphics application primarily aimed to assist in model building and validation of biological macromolecules. Recently, tools have been added to work with small molecules. The newly incorporated tools for the manipulation and validation of ligands include interaction with PRODRG, subgraph isomorphism-based tools, representation of ligand chemistry, ligand fitting and analysis, and are described here. PMID:22505262

  17. One- and two-dimensional divalent copper coordination polymers based on kinked organodiimine and long flexible aliphatic dicarboxylate ligands

    NASA Astrophysics Data System (ADS)

    Mallika Krishnan, Subhashree; Supkowski, Ronald M.; LaDuca, Robert L.

    2008-11-01

    Hydrothermal synthesis under acidic conditions has afforded a pair of divalent copper coordination polymers containing the kinked dipodal tethering organodiimine 4,4'-dipyridylamine (dpa) and flexible long-chain aliphatic dicarboxylate ligands. The new materials were characterized by single crystal X-ray structure determination, infrared spectroscopy, and thermogravimetric analysis. [CuCl(suberate) 0.5(dpa)] ( 1) manifests 1-D ladder-like motifs aggregated into 3-D through hydrogen bonding and copper-mediated supramolecular interactions. Extension of the aliphatic chain within the dicarboxylate ligand by one methylene unit resulted in {[Cu(azelate)(dpa)(H 2O)] · 3H 2O} ( 2), a (4,4) rhomboid grid 2-D coordination polymer encapsulating acyclic water molecule trimers.

  18. Gas chromatographic-mass spectrometric characterization of all acyclic C5-C7 alkenes from fluid catalytic cracked gasoline using polydimethylsiloxane and squalane stationary phases.

    PubMed

    Soják, Ladislav; Addová, Gabriela; Kubinec, Róbert; Kraus, Angelika; Hu, Gengyuan

    2002-02-15

    Published retention indices of acyclic alkenes C5-C7 on squalane and polydimethylsiloxane as stationary phases were investigated, and reliable retention indices of alkenes from various sources were converted to separation systems used in a laboratory. Retention indices measured on available authentic commercial alkenes and on alkenic fraction of gasoline, published retention indices as well as means of GC-MS were used for verification of calculated retention indices. Retention of some gas chromatographic unseparated isomer pairs was obtained by mass spectrometric deconvolution using a specific single-ion monitoring. On the basis of these retention data, C5-C7 alkenes were identified and analyzed in the gasoline from fluid catalytic cracking. In the gasoline all 59 acyclic C5-C7 isomeric alkenes were determined at significantly different concentration levels.

  19. 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.

  20. 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.

  1. Phenylalanine Ammonia-Lyase-Catalyzed Deamination of an Acyclic Amino Acid: Enzyme Mechanistic Studies Aided by a Novel Microreactor Filled with Magnetic Nanoparticles.

    PubMed

    Weiser, Diána; Bencze, László Csaba; Bánóczi, Gergely; Ender, Ferenc; Kiss, Róbert; Kókai, Eszter; Szilágyi, András; Vértessy, Beáta G; Farkas, Ödön; Paizs, Csaba; Poppe, László

    2015-11-01

    Phenylalanine ammonia-lyase (PAL), found in many organisms, catalyzes the deamination of l-phenylalanine (Phe) to (E)-cinnamate by the aid of its MIO prosthetic group. By using PAL immobilized on magnetic nanoparticles and fixed in a microfluidic reactor with an in-line UV detector, we demonstrated that PAL can catalyze ammonia elimination from the acyclic propargylglycine (PG) to yield (E)-pent-2-ene-4-ynoate. This highlights new opportunities to extend MIO enzymes towards acyclic substrates. As PG is acyclic, its deamination cannot involve a Friedel-Crafts-type attack at an aromatic ring. The reversibility of the PAL reaction, demonstrated by the ammonia addition to (E)-pent-2-ene-4-ynoate yielding enantiopure l-PG, contradicts the proposed highly exothermic single-step mechanism. Computations with the QM/MM models of the N-MIO intermediates from L-PG and L-Phe in PAL show similar arrangements within the active site, thus supporting a mechanism via the N-MIO intermediate.

  2. Acyclic monoterpene primary alcohol:NADP+ oxidoreductase of Rauwolfia serpentina cells: the key enzyme in biosynthesis of monoterpene alcohols.

    PubMed

    Ikeda, H; Esaki, N; Nakai, S; Hashimoto, K; Uesato, S; Soda, K; Fujita, T

    1991-02-01

    Acyclic monoterpene primary alcohol:NADP+ oxidoreductase, a key enzyme in the biosynthesis of monoterpene alcohols in plants, is unstable and has been only poorly characterized. However we have established conditions which stabilize the enzyme from Rauwolfia serpentina cells, and then purified it to homogeneity. It is a monomer with a molecular weight of about 44,000 and contains zinc ions. Various branched-chain allylic primary alcohols such as nerol, geraniol, and 10-hydroxygeraniol were substrates, but ethanol was inert. The enzyme exclusively requires NADP+ or NADPH as the cofactor. Steady-state kinetic studies showed that the nerol dehydrogenation proceeds by an ordered Bi-Bi mechanism. NADP+ binds the enzyme first and then NADPH is the second product released from it. Gas chromatography-mass spectrometric analysis of the reaction products showed that 10-hydroxygeraniol undergoes a reversible dehydrogenation to produce 10-oxogeraniol or 10-hydroxygeranial, which are oxidized further to give 10-oxogeranial, the direct precursor of iridodial. The enzyme has been found to exclusively transfer the pro-R hydrogen of NADPH to neral. The N-terminal sequence of the first 21 amino acids revealed no significant homology with those of various other proteins including the NAD(P)(+)-dependent alcohol dehydrogenases registered in a protein data bank. PMID:1864846

  3. Hydroxamate based inhibitors of adenylyl cyclase. Part 1: the effect of acyclic linkers on P-site binding.

    PubMed

    Levy, Daniel; Marlowe, Charles; Kane-Maguire, Kim; Bao, Ming; Cherbavaz, Diana; Tomlinson, James; Sedlock, David; Scarborough, Robert

    2002-11-01

    The adenylyl cyclases (ACs) are a family of enzymes that are key elements of signal transduction by virtue of their ability to convert ATP to cAMP. The catalytic mechanism of this transformation proceeds through initial binding of ATP to the purine binding site (P-site) followed by metal mediated cyclization with loss of pyrophosphate. Crystallographic analysis of ACs with known inhibitors reveals the presence of two metals in the active site. Presently, nine isoforms of adenylyl cyclase are known and unique isoform combinations are expressed in a tissue specific manner. The development of isoform specific inhibitors of adenylyl cyclase may prove to be a useful strategy toward the design of novel therapeutic agents. In order to develop novel AC inhibitors, we have chosen a design approach utilizing molecules with the adenine ring system joined to a metal-coordinating hydroxamic acid via flexible acyclic linkers. The designed inhibitors were assayed against type V AC with the size and heteroatom content of the linkers varied to probe the interaction of the nucleotide and metal binding sites within the enzyme. PMID:12372507

  4. 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

  5. Activities of acyclic nucleoside phosphonates against Orf virus in human and ovine cell monolayers and organotypic ovine raft cultures.

    PubMed

    Dal Pozzo, F; Andrei, G; Holy, A; Van Den Oord, J; Scagliarini, A; De Clercq, E; Snoeck, R

    2005-12-01

    Orf virus, a member of the Parapoxvirus genus, causes a contagious pustular dermatitis in sheep, goats, and humans. Previous studies have demonstrated the activity of (S)-1-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine (HPMPC; cidofovir; Vistide) against orf virus in cell culture and humans. We have evaluated a broad range of acyclic nucleoside phosphonates (ANPs) against several orf virus strains in primary lamb keratinocytes (PLKs) and human embryonic lung (HEL) monolayers. HPMPC, (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]-2,6- diaminopurine (HPMPDAP), and (R)-9-[3-hydroxy-2-(phosphonomethoxy)propoxy]-2,4-diaminopyrimidine (HPMPO-DAPy) were three of the most active compounds that were subsequently tested in a virus yield assay with PLK and HEL cells by virus titration and DNA quantification. HPMPC, HPMPDAP, and HPMPO-DAPy were evaluated for their activities against orf virus replication in organotypic epithelial raft cultures from differentiated PLK cells. At the highest concentrations (50 and 20 microg/ml), full protection was provided by the three drugs, while at 5 microg/ml, only HPMPDAP and HPMPC offered partial protection. The activities of the three compounds in the raft culture system were confirmed by quantification of infectious virus and viral DNA. These findings provide a rationale for the use of HPMPC and other ANPs in the treatment of orf (contagious ecthyma) in humans and animals.

  6. Intramolecular OH⋅⋅⋅Fluorine Hydrogen Bonding in Saturated, Acyclic Fluorohydrins: The γ-Fluoropropanol Motif

    PubMed Central

    Linclau, Bruno; Peron, Florent; Bogdan, Elena; Wells, Neil; Wang, Zhong; Compain, Guillaume; Fontenelle, Clement Q; Galland, Nicolas; LeQuestel, Jean-Yves; Graton, Jérôme

    2015-01-01

    Fluorination is commonly exercised in compound property optimization. However, the influence of fluorination on hydrogen-bond (HB) properties of adjacent functional groups, as well as the HB-accepting capacity of fluorine itself, is still not completely understood. Although the formation of OH⋅⋅⋅F intramolecular HBs (IMHBs) has been established for conformationally restricted fluorohydrins, such interaction in flexible compounds remained questionable. Herein is demonstrated for the first time—and in contrast to earlier reports—the occurrence of OH⋅⋅⋅F IMHBs in acyclic saturated γ-fluorohydrins, even for the parent 3-fluoropropan-1-ol. The relative stereochemistry is shown to have a crucial influence on the corresponding h1JOH⋅⋅⋅F values, as illustrated by syn- and anti-4-fluoropentan-2-ol (6.6 and 1.9Hz). The magnitude of OH⋅⋅⋅F IMHBs and their strong dependence on the overall molecular conformational profile, fluorination motif, and alkyl substitution level, is rationalized by quantum chemical calculations. For a given alkyl chain, the “rule of shielding” applies to OH⋅⋅⋅F IMHB energies. Surprisingly, the predicted OH⋅⋅⋅F IMHB energies are only moderately weaker than these of the corresponding OH⋅⋅⋅OMe. These results provide new insights of the impact of fluorination of aliphatic alcohols, with attractive perspectives for rational drug design. PMID:26494542

  7. Assessing causal relationships in genomics: From Bradford-Hill criteria to complex gene-environment interactions and directed acyclic graphs

    PubMed Central

    2011-01-01

    Observational studies of human health and disease (basic, clinical and epidemiological) are vulnerable to methodological problems -such as selection bias and confounding- that make causal inferences problematic. Gene-disease associations are no exception, as they are commonly investigated using observational designs. A rich body of knowledge exists in medicine and epidemiology on the assessment of causal relationships involving personal and environmental causes of disease; it includes seminal causal criteria developed by Austin Bradford Hill and more recently applied directed acyclic graphs (DAGs). However, such knowledge has seldom been applied to assess causal relationships in clinical genetics and genomics, even in studies aimed at making inferences relevant for human health. Conversely, incorporating genetic causal knowledge into clinical and epidemiological causal reasoning is still a largely unexplored area. As the contribution of genetics to the understanding of disease aetiology becomes more important, causal assessment of genetic and genomic evidence becomes fundamental. The method we develop in this paper provides a simple and rigorous first step towards this goal. The present paper is an example of integrative research, i.e., research that integrates knowledge, data, methods, techniques, and reasoning from multiple disciplines, approaches and levels of analysis to generate knowledge that no discipline alone may achieve. PMID:21658235

  8. Acyclic forms of aldohexoses and ketohexoses in aqueous and DMSO solutions: conformational features studied using molecular dynamics simulations.

    PubMed

    Plazinski, Wojciech; Plazinska, Anita; Drach, Mateusz

    2016-04-14

    The molecular properties of aldohexoses and ketohexoses are usually studied in the context of their cyclic, furanose or pyranose structures which is due to the abundance of related tautomeric forms in aqueous solution. We studied the conformational features of a complete series of D-aldohexoses (D-allose, D-altrose, D-glucose, D-mannose, D-gulose, d-idose, D-galactose and D-talose) and D-ketohexoses (D-psicose, D-fructose, D-sorbose and D-tagatose) as well as of L-psicose by using microsecond-timescale molecular dynamics in explicit water and DMSO with the use of enhanced sampling methods. In each of the studied cases the preferred conformation corresponded to an extended chain structure; the less populated conformers included the quasi-cyclic structures, close to furanose rings and common for both aldo- and ketohexoses. The orientational preferences of the aldehyde or ketone groups are correlated with the relative populations of anomers characteristic of cyclic aldo- and ketohexoses, respectively, thus indicating that basic features of anomeric equilibria are preserved even if hexose molecules are not in their cyclic forms. No analogous relationship is observed in the case of other structural characteristics, such as the preferences of acyclic molecules to form either the furanose-or pyranose-like structures or maintaining the chair-like geometry of pseudo-pyranose rings.

  9. Enzymatic synthesis of acyclic nucleoside thiophosphonate diphosphates: effect of the α-phosphorus configuration on HIV-1 RT activity.

    PubMed

    Priet, Stéphane; Roux, Loic; Saez-Ayala, Magali; Ferron, François; Canard, Bruno; Alvarez, Karine

    2015-05-01

    The acyclic nucleosides thiophosphonates (9-[2-(thiophosphonomethoxy)ethyl]adenine (S-PMEA) and (R)-9-[2-(thiophosphonomethoxy)propyl]adenine (S-PMPA), exhibit antiviral activity against HIV-1, -2 and HBV. Their diphosphate forms S-PMEApp and S-PMPApp, synthesized as stereoisomeric mixture, are potent inhibitors of wild-type (WT) HIV-1 RT. Understanding HIV-1 RT stereoselectivity, however, awaits resolution of the diphosphate forms into defined stereoisomers. To this aim, thiophosphonate monophosphates S-PMEAp and S-PMPAp were synthesized and used in a stereocontrolled enzyme-catalyzed phosphoryl transfer reaction involving either nucleoside diphosphate kinase (NDPK) or creatine kinase (CK) to obtain thiophosphonate diphosphates as separated isomers. We then quantified substrate preference of recombinant WT HIV-1 RT toward pure stereoisomers using in vitro steady-state kinetic analyses. The crystal structure of a complex between Dictyostelium NDPK and S-PMPApp at 2.32Å allowed to determine the absolute configuration at the α-phosphorus atom in relation to the stereo-preference of studied enzymes. The RP isomer of S-PMPApp and S-PMEApp are the preferred substrate over SP for both NDPK and HIV-1 RT. PMID:25766862

  10. From an Isolable Acyclic Phosphinosilylene Adduct to Donor-Stabilized Si=E Compounds (E=O, S, Se).

    PubMed

    Hansen, Kerstin; Szilvási, Tibor; Blom, Burgert; Irran, Elisabeth; Driess, Matthias

    2015-12-21

    Reaction of the arylchlorosilylene-NHC adduct ArSi(NHC)Cl [Ar=2,6-Trip2C6H3; NHC=(MeC)2(NMe)2C:] 1 with one molar equiv of lithium diphenylphosphanide affords the first stable NHC-stabilized acyclic phosphinosilylene adduct 2 (ArSi(NHC)PPh2), which could be structurally characterized. Compound 2, when reacted with one molar equiv selenium and sulfur, affords the silanechalcogenones 4 a and 4 b (ArSi(NHC)(=E)PPh2, 4 a: E=Se, 4 b: E=S), respectively. Conversion of 2 with an excess of Se and S, through additional insertion of one chalcogen atom into the Si=P bond, leads to 3 a and 3 b (ArSi(NHC)(=E)-E-P(=E)Ph2, 3 a: E=Se, 3 b: E=S), respectively. Additionally, the exposure of 2 to N2O or CO2 yielded the isolable NHC-stabilized silanone 4 c, Ar(NHC)(Ph2P)Si=O. PMID:26592863

  11. 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.

  12. 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).

  13. Acyclic Cucurbit[n]uril-Type Molecular Containers: Influence of Linker Length on Their Function as Solubilizing Agents.

    PubMed

    Sigwalt, David; Moncelet, Damien; Falcinelli, Shane; Mandadapu, Vijaybabu; Zavalij, Peter Y; Day, Anthony; Briken, Volker; Isaacs, Lyle

    2016-05-01

    Two acyclic cucurbit[n]uril (CB[n])-type molecular containers that differ in the length of the (CH2 )n linker (M2C2: n=2, M2C4: n=4) between their aromatic sidewalls and sulfonate solubilizing groups were prepared and studied. The inherent solubilities of M2C2 (68 mm) and M2C4 (196 mm) are higher than the analogue with a (CH2 )3 linker (M2, 14 mm) studied previously. (1) H NMR dilution experiments show that M2C2 and M2C4 do not self-associate in water, which enables their use as solubilizing excipients. We used phase solubility diagrams (PSDs) to compare the solubilizing capacities of M2, M2C2, M2C4, hydroxypropyl-β-cyclodextrin (HP-β-CD), and sulfobutylether-β-cyclodextrin (SBE-β-CD) toward 15 insoluble drugs. We found that M2C2 and M2C4-as gauged by the slope of their PSDs-are less potent solubilizing agents than M2. However, the higher inherent solubility of M2C2 allows higher concentrations of drug to be formulated using M2C2 than with M2 in several cases. The solubilizing ability of M2C2 and SBE-β-CD were similar in many cases, with Krel values averaging 23 and 12, respectively, relative to HP-β-CD. In vitro cytotoxicity and in vivo maximum tolerated dose studies document the biocompatibility of M2C2. PMID:26990780

  14. 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. PMID:26426398

  15. 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).

  16. 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

  17. 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). PMID:26920294

  18. Selective electrochemical discrimination between dopamine and phenethylamine-derived psychotropic drugs using electrodes modified with an acyclic receptor containing two terminal 3-alkoxy-5-nitroindazole rings.

    PubMed

    Doménech, Antonio; Navarro, Pilar; Arán, Vicente J; Muro, Beatriz; Montoya, Noemí; García-España, Enrique

    2010-06-01

    Electrochemical discrimination between dopamine and psychotropic drugs which have in common a skeletal structure of phenethylamine, can be obtained using acyclic receptors L(1) and L(2), containing two terminal 3-alkoxy-5-nitroindazole rings. Upon attachment to graphite electrodes, L(1) and L(2) exhibit a well-defined, essentially reversible solid state electrochemistry in contact with aqueous media, based on electrolyte-assisted reduction processes involving successive cation and anion insertion/binding. As a result, a distinctive, essentially Nernstian electrochemical response is obtained for phenethylammonium ions of methamphetamine (METH), p-methoxyamphetamine (PMA), amphetamine (AMPH), mescaline (MES), homoveratrylamine (HOM), phenethylamine (PEA) and dopamine (DA) in aqueous media.

  19. 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.

  20. Ovarian acyclicity in zoo African elephants (Loxodonta africana) is associated with high body condition scores and elevated serum insulin and leptin.

    PubMed

    Morfeld, Kari A; Brown, Janine L

    2016-04-01

    The purpose of the present study was to determine whether excessive body fat and altered metabolic hormone concentrations in the circulation were associated with ovarian acyclicity in the world's largest land mammal, the African elephant. We compared body condition, glucose, insulin and leptin concentrations and the glucose-to-insulin ratio (G:I) between cycling (n=23; normal 14-16 week cycles based on serum progestagens for at least 2 years) and non-cycling (n=23; consistent baseline progestagen concentrations for at least 2 years) females. A validated body condition score (BCS) index (five-point scale; 1=thinnest, 5=fattest) was used to assess the degree of fatness of the study elephants. The mean BCS of non-cycling elephants was higher than that of their cycling counterparts. There were differences in concentrations of serum metabolic biomarkers, with non-cycling elephants in the BCS 5 category having higher leptin and insulin concentrations and a lower G:I ratio than cycling BCS 5 females. Using 'non-cycling' as the outcome variable in regression models, high BCS was a strong predictor of a non-cycling status. This study provides the first evidence that ovarian acyclicity in zoo African elephants is associated with body condition indicative of obesity, as well as elevated, perturbed biomarkers of metabolic status.

  1. 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

  2. Conformational analysis of an acyclic tetrapeptide: ab-initio structure determination from X-ray powder diffraction, Hirshfeld surface analysis and electronic structure.

    PubMed

    Das, Uday; Naskar, Jishu; Mukherjee, Alok Kumar

    2015-12-01

    A terminally protected acyclic tetrapeptide has been synthesized, and the crystal structure of its hydrated form, Boc-Tyr-Aib-Tyr-Ile-OMe·2H2O (1), has been determined directly from powder X-ray diffraction data. The backbone conformation of tetrapeptide (1) exhibiting two consecutive β-turns is stabilized by two 4 → 1 intramolecular N-H · · · O hydrogen bonds. In the crystalline state, the tetrapeptide molecules are assembled through water-mediated O-H · · · O hydrogen bonds to form two-dimensional molecular sheets, which are further linked by intermolecular C-H · · · O hydrogen bonds into a three-dimensional supramolecular framework. The molecular electrostatic potential (MEP) surface of (1) has been used to supplement the crystallographic observations. The nature of intermolecular interactions in (1) has been analyzed quantitatively through the Hirshfeld surface and two-dimensional fingerprint plot. The DFT optimized molecular geometry of (1) agrees closely with that obtained from the X-ray structure analysis. The present structure analysis of Boc-Tyr-Aib-Tyr-Ile-OMe·2H2 O (1) represents a case where ab-initio crystal structure of an acyclic tetrapeptide with considerable molecular flexibility has been accomplished from laboratory X-ray powder diffraction data.

  3. 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.

  4. Carbodiphosphoranes and Related Ligands

    NASA Astrophysics Data System (ADS)

    Petz, Wolfgang; Frenking, Gernot

    The theoretical and experimental research on carbodiphosphoranes C(PR3)2 and related compounds CL2, both as free molecules and as ligands in transition metal complexes, is reviewed. Carbodiphosphoranes are examples of divalent carbon(0) compounds CL2 which have peculiar donor properties that are due to the fact that the central carbon atom has two lone electron pairs. The bonding situation is best described in terms of L→C←L donor acceptor interactions which distinguishes CL2 compounds (carbones) from divalent carbon(II) compounds (carbenes) through the number of lone electron pairs. The structures and stabilities of transition metal complexes with ligands CL2 can be understood and predictions can be made considering the double donor ability of the carbone compounds.

  5. Ligand exclusion on acetylcholinesterase.

    PubMed

    Berman, H A; Leonard, K

    1990-11-27

    This paper examines covalent reactivity of AchE with respect to cationic and uncharged methylphosphonates and substrates in the absence and presence of cationic ligands selective for the active center and the peripheral anionic site. The organophosphorus inhibitors are enantiomeric alkyl methylphosphonothioates (1-5) containing cycloheptyl and isopropyl phosphono ester groups and S-methyl, S-n-pentyl, and S-[beta-(trimethylammonio)ethyl] leaving groups; these agents differ in their configuration about phosphorus and their steric, hydrophobic, and electrostatic characteristics. The synthetic substrates examined are acetylthiocholine, p-nitrophenyl acetate, and 7-acetoxy-4-methylcoumarin (7AMC). Antagonism of the methylphosphonothioate reaction by cationic ligands is strongly dependent on the nature of both the cation and the methylphosphonate but independent of the configuration about phosphorus. While all cations cause linear mixed inhibition of acetylthiocholine hydrolysis, there are observed a variety of inhibition patterns of 7AMC and p-nitrophenyl acetate hydrolysis that are distinctly nonlinear, as well as patterns in which the reciprocal plots intersect in the upper right quadrant. Strong antagonism of cationic (methylphosphonyl)thiocholines correlates very well with linear inhibition of acetylthiocholine. Ligands that cause only negligible antagonism of the uncharged methylphosphonates display nonlinear inhibition of uncharged substrates. These relationships, since they are most pronounced for peripheral site ligands and are strongly dependent on the charge carried by the reactant, suggest that the peripheral anionic site alters enzyme reactivity through an electrostatic interaction with the net negative active center. Such behavior indicates a potential role for the peripheral anionic site in conserving AchE catalytic efficiency within a narrow range of values. PMID:2271673

  6. 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.

  7. EGF receptor ligands: recent advances.

    PubMed

    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

  8. 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

  9. Rescoring ligand docking poses.

    PubMed

    Zhong, Shijun; Zhang, Youping; Xiu, Zhilong

    2010-05-01

    The ranking of ligand docking poses according to certain scoring systems to identify the best fit is the most important step in virtual database screening for drug discovery. By focusing on method development strategy, this review provides possibilities for constructing rescoring approaches based on an overview of recent developments in the field. These developments can be classified into three categories. The first category involves a scaling approach that employs a factor to scale the primary scoring function. These scaling factors are defined with respect to the geometrical match between the location of a ligand and the target binding site, or defined according to a molecular weight distribution consistent with the empirical range of molecular weights of drug-like compounds. The second category involves consensus scoring approaches that use multiple scoring functions to rank the ligand poses retained in a docking procedure, based on the preliminary ranking according to a primary scoring function. The final category involves the addition of selected accuracy-oriented energy terms, such as the solvent effect and quantum mechanics/molecular mechanics treatments. PMID:20443166

  10. 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.

  11. 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.

  12. Thermodynamic and Structural Effects of Macrocyclic Constraints in Protein−Ligand Interactions

    PubMed Central

    2010-01-01

    The thermodynamic and structural effects of macrocyclization as a tactic for stabilizing the biologically active conformation of Grb2 SH2 binding peptides were investigated using isothermal titration calorimetry and X-ray crystallography. 23-Membered macrocycles containing the sequence pYVN were slightly more potent than their linear controls; however, preorganization did not necessarily eventuate in a more favorable binding entropy. Structures of complexes of macrocycle 7 and its acyclic control 8 are similar except for differences in relative orientations of corresponding atoms in the linking moieties of 7 and 8. There are no differences in the number of direct or water-mediated protein−ligand contacts that might account for the less favorable binding enthalpy of 7; however, an intramolecular hydrogen bond between the pY and the pY+3 residues in 8 that is absent in 7 may be a factor. These studies highlight the difficulties associated with correlating energetics and structure in protein−ligand interactions. PMID:21116482

  13. Bexarotene ligand pharmaceuticals.

    PubMed

    Hurst, R E

    2000-12-01

    Bexarotene (LGD-1069), from Ligand, was the first retinoid X receptor (RXR)-selective, antitumor retinoid to enter clinical trials. The company launched the drug for the treatment of cutaneous T-cell lymphoma (CTCL), as Targretin capsules, in the US in January 2000 [359023]. The company filed an NDA for Targretin capsules in June 1999, and for topical gel in December 1999 [329011], [349982] specifically for once-daily oral administration for the treatment of patients with early-stage CTCL who have not tolerated other therapies, patients with refractory or persistent early stage CTCL and patients with refractory advanced stage CTCL. The FDA approved Targretin capsules at the end of December 1999 for once-daily oral treatment of all stages of CTCL in patients refractory to at least one prior systemic therapy, at an initial dose of 300 mg/m2/day. After an NDA was submitted in December 1999 for Targretin gel, the drug received Priority Review status for use as a treatment of cutaneous lesions in patients with stage IA, IB or IIA CTCL [354836]. The FDA issued an approvable letter in June 2000, and granted marketing clearance for CTCL in the same month [370687], [372768], [372769], [373279]. Ligand had received Orphan Drug designation for this indication [329011]. At the request of the FDA, Ligand agreed to carry out certain post-approval phase IV and pharmacokinetic studies [351604]. The company filed an MAA with the EMEA for Targretin Capsules to treat lymphoma in November 1999 [348944]. The NDA for Targretin gel is based on a multicenter phase III trial that was conducted in the US, Canada, Europe and Australia involving 50 patients and a multicenter phase I/II clinical program involving 67 patients. Targretin gel was evaluated for the treatment of patients with early stage CTCL (IA-IIA) who were refractory to, intolerant to, or reached a response plateau for at least 6 months on at least two prior therapies. Efficacy results exceeded the protocol-defined response

  14. Three-dimensional topographic index applied to the prediction of acyclic C5-C8 alkenes Kováts retention indices on polydimethylsiloxane and squalane columns.

    PubMed

    Ren, Yueying; Liu, Huanxiang; Yao, Xiaojun; Liu, Mancang

    2007-06-29

    A novel approach is described for the prediction of gas chromatographic Kováts retention indices of 150 acyclic C5-C8 alkenes on two stationary phases (polydimethylsiloxane, PDMS, and squalane, SQ). The heuristic method was used to build multiple linear regression models using descriptors calculated by MODLESLAB software and CODESSA program. The resulting quantitative structure-retention relationship (QSRR) models were well-correlated, with predictive R2 values of 0.970 and 0.958 for retention indices on PDMS and SQ columns, respectively. 1Omegap, a three-dimensional (3D) topographic index, was found to play the most important role in the description of the chromatographic retention behavior of the alkenes in these two stationary phases. Moreover, this index could completely distinguish different isomers of alkene. Therefore, it can also be extended to distinguish different isomers of other compounds so that can well describe their quantitative structure-retention relationships.

  15. Synthesis and olfactory characterization of silicon-containing derivatives of the acyclic lily-of-the-valley odorant 5,7,7-trimethyl-4-methylideneoctanal.

    PubMed

    Dörrich, Steffen; Mahler, Christoph; Tacke, Reinhold; Kraft, Philip

    2014-11-01

    5-Methyl-4-methylidene-6-(trimethylsilyl)hexanal (1b), a sila analog of the acyclic lily-of-the-valley odorant 5,7,7-trimethyl-4-methylideneoctanal (1a), and the Si-containing derivatives 2-6 were prepared in multistep syntheses, starting from Cl3 SiH and Cl2 SiMe2 , respectively. Compounds 1b, 2-6, and their new precursors were characterized by elemental analyses (C, H, N) and NMR spectroscopic studies ((1) H, (13) C, (15) N, and (29) Si). To gain more information about the structureodor correlation in the family of lily-of-the-valley or 'muguet' odorants, C/Si analogs 1a/1b and derivatives 2-6 were evaluated for their olfactory properties. PMID:25408317

  16. Synthesis and olfactory characterization of silicon-containing derivatives of the acyclic lily-of-the-valley odorant 5,7,7-trimethyl-4-methylideneoctanal.

    PubMed

    Dörrich, Steffen; Mahler, Christoph; Tacke, Reinhold; Kraft, Philip

    2014-11-01

    5-Methyl-4-methylidene-6-(trimethylsilyl)hexanal (1b), a sila analog of the acyclic lily-of-the-valley odorant 5,7,7-trimethyl-4-methylideneoctanal (1a), and the Si-containing derivatives 2-6 were prepared in multistep syntheses, starting from Cl3 SiH and Cl2 SiMe2 , respectively. Compounds 1b, 2-6, and their new precursors were characterized by elemental analyses (C, H, N) and NMR spectroscopic studies ((1) H, (13) C, (15) N, and (29) Si). To gain more information about the structureodor correlation in the family of lily-of-the-valley or 'muguet' odorants, C/Si analogs 1a/1b and derivatives 2-6 were evaluated for their olfactory properties.

  17. 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.

  18. Reaction of soluble penicillin-binding protein 2a of methicillin-resistant Staphylococcus aureus with beta-lactams and acyclic substrates: kinetics in homogeneous solution.

    PubMed Central

    Graves-Woodward, K; Pratt, R F

    1998-01-01

    The kinetics of reaction of solubilized penicillin-binding protein 2a (sPBP2a) of methicillin-resistant Staphylococcus aureus with a variety of beta-lactams and acyclic species was studied in homogeneous aqueous solution at 37 degreesC in 25 mM Hepes buffer, pH7.0, containing 1 M NaCl. Under these conditions, but not at lower salt concentrations, protein precipitation did not occur either during or after the reaction. The reactions of beta-lactams in general could be monitored by competition with a chromophoric beta-lactam, nitrocefin, or directly in certain cases by protein fluorescence. Rate constants for reaction of a wide variety of beta-lactams are reported. The interactions are characterized by a slow second-order acylation reaction followed by a slower deacylation. For example, the rate constants for benzylpenicillin were 12 M-1.s-1 and 3x10(-5) s-1 respectively. The acylation is slow in comparison with those of normal non-resistant high-molecular-mass penicillin-binding proteins. sPBP2a also seemed to catalyse the slow hydrolysis of a variety of acyclic depsipeptides but not that of a d-Ala-d-Ala peptide. The reactions with certain depsipeptides also led to protein precipitation. These reactions were, however, not affected by prior blockage of the beta-lactam-binding site by benzylpenicillin and thus might take place elsewhere on the enzyme. Two classes of potential transition- state analogue inhibitors, phosphonate monoesters and boronates, seemed to have little effect on the rate of reaction of sPBP2a with nitrocefin and therefore seem to have little affinity for the beta-lactam-binding/D,D-peptidase site. PMID:9620879

  19. 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.

  20. The maximal affinity of ligands

    PubMed Central

    Kuntz, I. D.; Chen, K.; Sharp, K. A.; Kollman, P. A.

    1999-01-01

    We explore the question of what are the best ligands for macromolecular targets. A survey of experimental data on a large number of the strongest-binding ligands indicates that the free energy of binding increases with the number of nonhydrogen atoms with an initial slope of ≈−1.5 kcal/mol (1 cal = 4.18 J) per atom. For ligands that contain more than 15 nonhydrogen atoms, the free energy of binding increases very little with relative molecular mass. This nonlinearity is largely ascribed to nonthermodynamic factors. An analysis of the dominant interactions suggests that van der Waals interactions and hydrophobic effects provide a reasonable basis for understanding binding affinities across the entire set of ligands. Interesting outliers that bind unusually strongly on a per atom basis include metal ions, covalently attached ligands, and a few well known complexes such as biotin–avidin. PMID:10468550

  1. 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.

  2. Reductive metalation of cyclic and acyclic pseudopeptidic bis-disulfides and back conversion of the resulting diamidato/dithiolato complexes to bis-disulfides.

    PubMed

    Desbenoît, Nicolas; Galardon, Erwan; Frapart, Yves; Tomas, Alain; Artaud, Isabelle

    2010-09-20

    Cyclic and acyclic pseudopeptidic bis-disulfides built on an o-phenylene diamine scaffold were prepared: (N(2)H(2)S(2))(2), 1a, N(2)H(2)(S-SCH(3))(2), 1b, and N(2)H(2)(S-StBu)(2), 1c. Reductive metalation of these disulfides with (PF(6))[Cu(CH(3)CN)(4)] in the presence of Et(4)NOH as a base, or with (Et(4)N)[Fe(SEt)(4)] and Et(4)NCl, yields the corresponding diamidato/dithiolato copper(III) or iron(III) complex, (Et(4)N)[Cu(N(2)S(2))], 2, or (Et(4)N)(2)[Fe(N(2)S(2))Cl], 5. These complexes display characteristics similar to those previously described in the literature. The mechanism of the metalation with copper has been investigated by X-band electron paramagnetic resonance (EPR) spectroscopy at 10 K. After metalation of the bis-disulfide 1c and deprotonation of the amide nitrogens, the reductive cleavage of the S-S bonds occurs by two one-electron transfers leading to the intermediate formation of a copper(II) complex and a thyil radical. Complexes 2 and 5 can be converted back to the cyclic bis-disulfide 1a with iodine in an 80% yield. Reaction of 5 with iodine in the presence of CH(3)S-SCH(3) affords a 1/1 mixture of the acyclic N(2)H(2)(S-SCH(3))(2) disulfide 1b and cyclic bis-disulfide 1a. From 2, the reaction was monitored by (1)H NMR and gives 1b as major product. While there is no reaction of 2 or 5 with tBuS-StBu and iodine, reaction with an excess of tBuSI affords quantitatively the di-tert-butyl disulfide 1c. To assess the role of the Cu(III) oxidation state, control experiments were carried out under strictly anaerobic conditions with the copper(II) complex, (Et(4)N)(2)[Cu(N(2)S(2))], 6. Complex 6 is oxidized to 2 by iodine, and it reacts with an excess of tBuSI, yielding 1c as final product, through the intermediate formation of complex 2. PMID:20718487

  3. 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.

  4. 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

  5. 2,3,22,23-tetrahydroxyl-2,6,10,15,19,23-hexamethyl-6,10,14,18-tetracosatetraene, an acyclic triterpenoid isolated from the seeds of Alpinia katsumadai, Inhibits acyl-CoA : cholesterol acyltransferase activity.

    PubMed

    Choi, Soon-Yong; Lee, Moon Hee; Choi, Jung Ho; Kim, Young Kook

    2012-01-01

    In order to isolate a cholesterol-lowering compound from Alpinia katsumadai, an inhibitor for acyl-CoA : cholesterol acyltransferase (ACAT), an enzyme responsible for the cholesterol ester formation in liver, was purified, its chemical structure was determined, and in vivo and in vitro inhibition activities were performed. In a high fat diet mouse model, we discovered that the ethanol extract of Alpinia katsumadai reduced plasma cholesterol, triglyceride, and low density lipoprotein (LDL) levels. An acyclic triterpenoid showing ACAT inhibitory activity was isolated from the extract of seeds of A. katsumadai. By NMR spectroscopic analysis of its (1)H-NMR, (13)C-NMR, (1)H-(1)H correlation spectroscopy, heteronuclear multiple bond connectivity (HMBC), hetero multiquantum coherence (HMQC) and nuclear Overhauser effect, chemical structure of 2,3,22,23-tetrahydroxyl-2,6,10,15,19,23-hexamethyl-6,10,14,18-tetracosatetraene (1), were elucidated. The acyclic triterpenoid was found to be responsible for the ACAT inhibition activities of rat liver microsomes with IC(50) values of 47.9 µM. It also decreased cholesteryl ester formation with IC(50) values of 26 µM in human hepatocyte HepG2 cell. The experimental study revealed that the ethanol extract of A. katsumadai has a hypolipemic effect in high fat diet mice, and the isolated acyclic triterpenoid has ACAT inhibition activity, showing a potential novel therapeutic approach for the treatment of hyperlipidemia and atherosclerosis.

  6. Insights into the mechanism of action of cidofovir and other acyclic nucleoside phosphonates against polyoma- and papillomaviruses and non-viral induced neoplasia.

    PubMed

    Andrei, G; Topalis, D; De Schutter, T; Snoeck, R

    2015-02-01

    Acyclic nucleoside phosphonates (ANPs) are well-known for their antiviral properties, three of them being approved for the treatment of human immunodeficiency virus infection (tenofovir), chronic hepatitis B (tenofovir and adefovir) or human cytomegalovirus retinitis (cidofovir). In addition, cidofovir is mostly used off-label for the treatment of infections caused by several DNA viruses other than cytomegalovirus, including papilloma- and polyomaviruses, which do not encode their own DNA polymerases. There is considerable interest in understanding why cidofovir is effective against these small DNA tumor viruses. Considering that papilloma- and polyomaviruses cause diseases associated either with productive infection (characterized by high production of infectious virus) or transformation (where only a limited number of viral proteins are expressed without synthesis of viral particles), it can be envisaged that cidofovir may act as antiviral and/or antiproliferative agent. The aim of this review is to discuss the advances in recent years in understanding the mode of action of ANPs as antiproliferative agents, given the fact that current data suggest that their use can be extended to the treatment of non-viral related malignancies.

  7. 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.

  8. Spider mite-induced (3S)-(E)-nerolidol synthase activity in cucumber and lima bean. The first dedicated step in acyclic C11-homoterpene biosynthesis.

    PubMed

    Bouwmeester, H J; Verstappen, F W; Posthumus, M A; Dicke, M

    1999-09-01

    Many plant species respond to herbivory with de novo production of a mixture of volatiles that attracts carnivorous enemies of the herbivores. One of the major components in the blend of volatiles produced by many different plant species in response to herbivory by insects and spider mites is the homoterpene 4,8-dimethyl-1,3(E), 7-nonatriene. One study (J. Donath, W. Boland [1995] Phytochemistry 39: 785-790) demonstrated that a number of plant species can convert the acyclic sesquiterpene alcohol (3S)-(E)-nerolidol to this homoterpene. Cucumber (Cucumis sativus L.) and lima bean (Phaseolus lunatus L.) both produce 4,8-dimethyl-1,3(E),7-nonatriene in response to herbivory. We report the presence in cucumber and lima bean of a sesquiterpene synthase catalyzing the formation of (3S)-(E)-nerolidol from farnesyl diphosphate. The enzyme is inactive in uninfested cucumber leaves, slightly active in uninfested lima bean leaves, and strongly induced by feeding of the two-spotted spider mite (Tetranychus urticae Koch) on both plant species, but not by mechanical wounding. The activities of the (3S)-(E)-nerolidol synthase correlated well with the levels of release of 4, 8-dimethyl-1,3(E),7-nonatriene from the leaves of the different treatments. Thus, (3S)-(E)-nerolidol synthase is a good candidate for a regulatory role in the release of the important signaling molecule 4,8-dimethyl-1,3(E),7-nonatriene. PMID:10482672

  9. Spider Mite-Induced (3S)-(E)-Nerolidol Synthase Activity in Cucumber and Lima Bean. The First Dedicated Step in Acyclic C11-Homoterpene Biosynthesis1

    PubMed Central

    Bouwmeester, Harro J.; Verstappen, Francel W.A.; Posthumus, Maarten A.; Dicke, Marcel

    1999-01-01

    Many plant species respond to herbivory with de novo production of a mixture of volatiles that attracts carnivorous enemies of the herbivores. One of the major components in the blend of volatiles produced by many different plant species in response to herbivory by insects and spider mites is the homoterpene 4,8-dimethyl-1,3(E),7-nonatriene. One study (J. Donath, W. Boland [1995] Phytochemistry 39: 785–790) demonstrated that a number of plant species can convert the acyclic sesquiterpene alcohol (3S)-(E)-nerolidol to this homoterpene. Cucumber (Cucumis sativus L.) and lima bean (Phaseolus lunatus L.) both produce 4,8-dimethyl-1,3(E),7-nonatriene in response to herbivory. We report the presence in cucumber and lima bean of a sesquiterpene synthase catalyzing the formation of (3S)-(E)-nerolidol from farnesyl diphosphate. The enzyme is inactive in uninfested cucumber leaves, slightly active in uninfested lima bean leaves, and strongly induced by feeding of the two-spotted spider mite (Tetranychus urticae Koch) on both plant species, but not by mechanical wounding. The activities of the (3S)-(E)-nerolidol synthase correlated well with the levels of release of 4,8-dimethyl-1,3(E),7-nonatriene from the leaves of the different treatments. Thus, (3S)-(E)-nerolidol synthase is a good candidate for a regulatory role in the release of the important signaling molecule 4,8-dimethyl-1,3(E),7-nonatriene. PMID:10482672

  10. Designing ligands to bind proteins.

    PubMed

    Whitesides, George M; Krishnamurthy, Vijay M

    2005-11-01

    The ability to design drugs (so-called 'rational drug design') has been one of the long-term objectives of chemistry for 50 years. It is an exceptionally difficult problem, and many of its parts lie outside the expertise of chemistry. The much more limited problem - how to design tight-binding ligands (rational ligand design) - would seem to be one that chemistry could solve, but has also proved remarkably recalcitrant. The question is 'Why is it so difficult?' and the answer is 'We still don't entirely know'. This perspective discusses some of the technical issues - potential functions, protein plasticity, enthalpy/entropy compensation, and others - that contribute, and suggests areas where fundamental understanding of protein-ligand interactions falls short of what is needed. It surveys recent technological developments (in particular, isothermal titration calorimetry) that will, hopefully, make now the time for serious progress in this area. It concludes with the calorimetric examination of the association of a series of systematically varied ligands with a model protein. The counterintuitive thermodynamic results observed serve to illustrate that, even in relatively simple systems, understanding protein-ligand association is challenging.

  11. 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.

  12. 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

  13. Fluorescent ligands for adenosine receptors.

    PubMed

    Kozma, Eszter; Jayasekara, P Suresh; Squarcialupi, Lucia; Paoletta, Silvia; Moro, Stefano; Federico, Stephanie; Spalluto, Giampiero; Jacobson, Kenneth A

    2013-01-01

    Interest is increasing in developing fluorescent ligands for characterization of adenosine receptors (ARs), which hold a promise of usefulness in the drug discovery process. The size of a strategically labeled AR ligand can be greatly increased after the attachment of a fluorophore. The choice of dye moiety (e.g. Alexa Fluor 488), attachment point and linker length can alter the selectivity and potency of the parent molecule. Fluorescent derivatives of adenosine agonists and antagonists (e.g. XAC and other heterocyclic antagonist scaffolds) have been synthesized and characterized pharmacologically. Some are useful AR probes for flow cytometry, fluorescence correlation spectroscopy, fluorescence microscopy, fluorescence polarization, fluorescence resonance energy transfer, and scanning confocal microscopy. Thus, the approach of fluorescent labeled GPCR ligands, including those for ARs, is a growing dynamic research field.

  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. The many facets of Notch ligands

    PubMed Central

    D'souza, Brendan; Miyamoto, Alison; Weinmaster, Gerry

    2009-01-01

    The Notch signaling pathway regulates a diverse array of cell types and cellular processes and is tightly regulated by ligand binding. Both canonical and noncanonical Notch ligands have been identified that may account for some of the pleiotropic nature associated with Notch signaling. This review focuses on the molecular mechanisms by which Notch ligands function as signaling agonists and antagonists, and discusses different modes of activating ligands as well as findings that support intrinsic ligand signaling activity independent of Notch. Post-translational modification, proteolytic processing, endocytosis and membrane trafficking, as well as interactions with the actin cytoskeleton may contribute to the recently appreciated multi-functionality of Notch ligands. The regulation of Notch ligand expression by other signaling pathways provides a mechanism to coordinate Notch signaling with multiple cellular and developmental cues. The association of Notch ligands with inherited human disorders and cancer highlights the importance of understanding the molecular nature and activities intrinsic to Notch ligands. PMID:18758484

  16. 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.

  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. Rosetta Ligand docking with flexible XML protocols.

    PubMed

    Lemmon, Gordon; Meiler, Jens

    2012-01-01

    RosettaLigand is premiere software for predicting how a protein and a small molecule interact. Benchmark studies demonstrate that 70% of the top scoring RosettaLigand predicted interfaces are within 2Å RMSD from the crystal structure [1]. The latest release of Rosetta ligand software includes many new features, such as (1) docking of multiple ligands simultaneously, (2) representing ligands as fragments for greater flexibility, (3) redesign of the interface during docking, and (4) an XML script based interface that gives the user full control of the ligand docking protocol. PMID:22183535

  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. In Vitro selectivity of an acyclic cucurbit[n]uril molecular container towards neuromuscular blocking agents relative to commonly used drugs.

    PubMed

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

    2016-01-28

    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

  1. In Vitro selectivity of an acyclic cucurbit[n]uril molecular container towards neuromuscular blocking agents relative to commonly used drugs.

    PubMed

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

    2016-01-28

    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.

  2. 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

    2016-03-01

    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.

  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

    2016-03-01

    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. PMID:26756920

  4. 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. PMID:2500596

  5. Polypharmacology of dopamine receptor ligands.

    PubMed

    Butini, S; Nikolic, K; Kassel, S; Brückmann, H; Filipic, S; Agbaba, D; Gemma, S; Brogi, S; Brindisi, M; Campiani, G; Stark, H

    2016-07-01

    Most neurological diseases have a multifactorial nature and the number of molecular mechanisms discovered as underpinning these diseases is continuously evolving. The old concept of developing selective agents for a single target does not fit with the medical need of most neurological diseases. The development of designed multiple ligands holds great promises and appears as the next step in drug development for the treatment of these multifactorial diseases. Dopamine and its five receptor subtypes are intimately involved in numerous neurological disorders. Dopamine receptor ligands display a high degree of cross interactions with many other targets including G-protein coupled receptors, transporters, enzymes and ion channels. For brain disorders like Parkinsońs disease, schizophrenia and depression the dopaminergic system, being intertwined with many other signaling systems, plays a key role in pathogenesis and therapy. The concept of designed multiple ligands and polypharmacology, which perfectly meets the therapeutic needs for these brain disorders, is herein discussed as a general ligand-based concept while focusing on dopaminergic agents and receptor subtypes in particular. PMID:27234980

  6. A race for RAGE ligands.

    PubMed

    Schleicher, Erwin D

    2010-08-01

    In experimental animals a causal involvement of the multiligand receptor for advanced glycation end products (RAGE) in the development of diabetic vascular complications has been demonstrated. However, the nature of RAGE ligands present in patients with diabetic nephropathy has not yet been defined; this leaves open the relevance of the RAGE system to the human disease.

  7. Alkene to carbyne: tandem Lewis acid activation and dehydrogenation of a molybdenum ethylene complex.

    PubMed

    Stennett, Tom E; Haddow, Mairi F; Wass, Duncan F

    2013-10-18

    Carbyne formation: Treatment of a molybdenum ethylene complex with B(C6 F5 )3 induces ditopic activation of an ethylene ligand and acceptor-assisted ethane elimination to generate a novel type of zwitterionic carbyne complex. PMID:24038792

  8. Expansion of the Ligand Knowledge Base for Chelating P,P-Donor Ligands (LKB-PP).

    PubMed

    Jover, Jesús; Fey, Natalie; Harvey, Jeremy N; Lloyd-Jones, Guy C; Orpen, A Guy; Owen-Smith, Gareth J J; Murray, Paul; Hose, David R J; Osborne, Robert; Purdie, Mark

    2012-08-13

    We have expanded the ligand knowledge base for bidentate P,P- and P,N-donor ligands (LKB-PP, Organometallics2008, 31, 1372-1383) by 208 ligands and introduced an additional steric descriptor (nHe8). This expanded knowledge base now captures information on 334 bidentate ligands and has been processed with principal component analysis (PCA) of the descriptors to produce a detailed map of bidentate ligand space, which better captures ligand variation and has been used for the analysis of ligand properties. PMID:24882917

  9. Controlled-deactivation cannabinergic ligands.

    PubMed

    Sharma, Rishi; Nikas, Spyros P; Paronis, Carol A; Wood, Jodianne T; Halikhedkar, Aneetha; Guo, Jason Jianxin; Thakur, Ganesh A; Kulkarni, Shashank; Benchama, Othman; Raghav, Jimit Girish; Gifford, Roger S; Järbe, Torbjörn U C; Bergman, Jack; Makriyannis, Alexandros

    2013-12-27

    We report an approach for obtaining novel cannabinoid analogues with controllable deactivation and improved druggability. Our design involves the incorporation of a metabolically labile ester group at the 2'-position on a series of (-)-Δ(8)-THC analogues. We have sought to introduce benzylic substituents α to the ester group which affect the half-lives of deactivation through enzymatic activity while enhancing the affinities and efficacies of individual ligands for the CB1 and CB2 receptors. The 1'-(S)-methyl, 1'-gem-dimethyl, and 1'-cyclobutyl analogues exhibit remarkably high affinities for both CB receptors. The novel ligands are susceptible to enzymatic hydrolysis by plasma esterases in a controllable manner, while their metabolites are inactive at the CB receptors. In further in vitro and in vivo experiments key analogues were shown to be potent CB1 receptor agonists and to exhibit CB1-mediated hypothermic and analgesic effects.

  10. 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.

  11. Unusual ligand coordination for cesium

    SciTech Connect

    Bryan, J.C.; Kavallieratos, K.; Sachleben, R.A.

    2000-04-03

    When complexed by tetrabenzo-24-crown-8, the cesium ion can accommodate unprecedented ligation. The structures of the complexes are presented. These structures are the first reported examples of linear {eta}{sup 2}-acetonitrile coordination to any metal ion and the first structures illustrating {eta}{sup 2}-acetonitrile and dichloromethane ligation to an alkali metal ion. Possible steric and electronic origins of these unusual metal-ligand interactions are discussed.

  12. Absolute Ligand Discrimination by Dimeric Signaling Receptors.

    PubMed

    Fathi, Sepehr; Nayak, Chitra R; Feld, Jordan J; Zilman, Anton G

    2016-09-01

    Many signaling pathways act through shared components, where different ligand molecules bind the same receptors or activate overlapping sets of response regulators downstream. Nevertheless, different ligands acting through cross-wired pathways often lead to different outcomes in terms of the target cell behavior and function. Although a number of mechanisms have been proposed, it still largely remains unclear how cells can reliably discriminate different molecular ligands under such circumstances. Here we show that signaling via ligand-induced receptor dimerization-a very common motif in cellular signaling-naturally incorporates a mechanism for the discrimination of ligands acting through the same receptor. PMID:27602720

  13. 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

  14. 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.

  15. Design, Synthesis, Protein−Ligand X-ray Structure, and Biological Evaluation of a Series of Novel Macrocyclic Human Immunodeficiency Virus-1 Protease Inhibitors to Combat Drug Resistance

    SciTech Connect

    Ghosh, Arun K.; Kulkarni, Sarang; Anderson, David D.; Hong, Lin; Baldridge, Abigail; Wang, Yuan-Fang; Chumanevich, Alexander A.; Kovalevsky, Andrey Y.; Tojo, Yasushi; Amano, Masayuki; Koh, Yasuhiro; Tang, Jordan; Weber, Irene T.; Mitsuya, Hiroaki

    2010-04-05

    The structure-based design, synthesis, and biological evaluation of a series of nonpeptidic macrocyclic HIV protease inhibitors are described. The inhibitors are designed to effectively fill in the hydrophobic pocket in the S1'-S2' subsites and retain all major hydrogen bonding interactions with the protein backbone similar to darunavir (1) or inhibitor 2. The ring size, the effect of methyl substitution, and unsaturation within the macrocyclic ring structure were assessed. In general, cyclic inhibitors were significantly more potent than their acyclic homologues, saturated rings were less active than their unsaturated analogues and a preference for 10- and 13-membered macrocylic rings was revealed. The addition of methyl substituents resulted in a reduction of potency. Both inhibitors 14b and 14c exhibited marked enzyme inhibitory and antiviral activity, and they exerted potent activity against multidrug-resistant HIV-1 variants. Protein-ligand X-ray structures of inhibitors 2 and 14c provided critical molecular insights into the ligand-binding site interactions.

  16. 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.

  17. Design and synthesis of novel antimicrobial acyclic and heterocyclic dyes and their precursors for dyeing and/or textile finishing based on 2-N-acylamino-4,5,6,7-tetrahydro-benzo[b]thiophene systems.

    PubMed

    Shams, Hoda Zaki; Mohareb, Rafat Milad; Helal, Maher Helmy; Mahmoud, Amira El-Sayed

    2011-07-26

    A series of novel polyfunctionalized acyclic and heterocyclic dye precursors and their respective azo (hydrazone) counterpart dyes and dye precursors based on conjugate enaminones and/or enaminonitrile moieties were synthesized. The dyes and their precursors are based on 2-cyano-N-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-acetamide, 2-ethoxycarbonyl-N-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-acetamide or 2-phenylcarbamoyl-N-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-acetamide systems as precursors. The latter compounds were used to synthesize polyfunctional thiophene-, thiazole-, pyrazole, pyridine-, pyrimidine-, oxazine-, as well as acyclic moieties. The dyes and dye precursors were characterized by elemental analysis and spectral methods. All dyes and their precursors were screened in vitro and evaluated for both their antibacterial and antifungal activities. MIC data of the novel dye systems and their respective precursors showed significant antimicrobial activity against most tested organisms. Some compounds exhibited comparable or even higher efficiency than selected standards. Dyes were applied at 5% depth for disperse dyeing of nylon, acetate and polyester fabrics. Their spectral characteristics and fastness properties were measured and evaluated.

  18. 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.

  19. Conformational readout of RNA by small ligands

    PubMed Central

    Kligun, Efrat; Mandel-Gutfreund, Yael

    2013-01-01

    RNA molecules have highly versatile structures that can fold into myriad conformations, providing many potential pockets for binding small molecules. The increasing number of available RNA structures, in complex with proteins, small ligands and in free form, enables the design of new therapeutically useful RNA-binding ligands. Here we studied RNA ligand complexes from 10 RNA groups extracted from the protein data bank (PDB), including adaptive and non-adaptive complexes. We analyzed the chemical, physical, structural and conformational properties of binding pockets around the ligand. Comparing the properties of ligand-binding pockets to the properties of computed pockets extracted from all available RNA structures and RNA-protein interfaces, revealed that ligand-binding pockets, mainly the adaptive pockets, are characterized by unique properties, specifically enriched in rare conformations of the nucleobase and the sugar pucker. Further, we demonstrate that nucleotides possessing the rare conformations are preferentially involved in direct interactions with the ligand. Overall, based on our comprehensive analysis of RNA-ligand complexes, we suggest that the unique conformations adopted by RNA nucleotides play an important role in RNA recognition by small ligands. We term the recognition of a binding site by a ligand via the unique RNA conformations “RNA conformational readout.” We propose that “conformational readout” is a general way by which RNA binding pockets are recognized and selected from an ensemble of different RNA states. PMID:23618839

  20. Canonical and non-canonical Notch ligands

    PubMed Central

    D’SOUZA, BRENDAN; MELOTY-KAPELLA, LAURENCE; WEINMASTER, GERRY

    2015-01-01

    Notch signaling induced by canonical Notch ligands is critical for normal embryonic development and tissue homeostasis through the regulation of a variety of cell fate decisions and cellular processes. Activation of Notch signaling is normally tightly controlled by direct interactions with ligand-expressing cells and dysregulated Notch signaling is associated with developmental abnormalities and cancer. While canonical Notch ligands are responsible for the majority of Notch signaling, a diverse group of structurally unrelated non-canonical ligands has also been identified that activate Notch and likely contribute to the pleiotropic effects of Notch signaling. Soluble forms of both canonical and non-canonical ligands have been isolated, some of which block Notch signaling and could serve as natural inhibitors of this pathway. Ligand activity can also be indirectly regulated by other signaling pathways at the level of ligand expression, serving to spatio-temporally compartmentalize Notch signaling activity and integrate Notch signaling into a molecular network that orchestrates developmental events. Here, we review the molecular mechanisms underlying the dual role of Notch ligands as activators and inhibitors of Notch signaling. Additionally, evidence that Notch ligands function independent of Notch are presented. We also discuss how ligand post-translational modification, endocytosis, proteolysis and spatio-temporal expression regulate their signaling activity. PMID:20816393

  1. 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

  2. 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.

  3. 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

  4. Fragment-based ligand discovery.

    PubMed

    Fischer, Marcus; Hubbard, Roderick E

    2009-02-01

    From home building and decor to mass production, modular design is a standard feature of the modern age. The concept also promises to define drug discovery efforts in the near future, as a wide range of methodologies, from NMR to X-ray crystallography, are being adapted to high-throughput platforms. In particular, "fragment-based ligand discovery" describes the laboratory-driven evolution of drugs from libraries of chemical building blocks. "Evolution" is an apt word for the process, as a wide array of methods are used to define how compound fragments can be best fit into the binding sites of medically relevant target biomolecules. A number of compounds that evolved from fragments have entered the clinic, and the approach is increasingly accepted as an additional route to identifying new hit compounds in pharmaceutical discovery and inhibitor design. PMID:19299661

  5. 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. PMID:27161975

  6. Utilizing target-ligand interaction information in fingerprint searching for ligands of related targets.

    PubMed

    Tan, Lu; Bajorath, Jürgen

    2009-07-01

    Protein-ligand interaction information is captured by determination of interacting fragments (IF) of ligands available in complex X-ray structures. From IF, fingerprints (IF-FP) are calculated for similarity searching. Previously, we have shown that IF-FP often produce higher search performance than general structural fragment- or key-type fingerprints. In this study, we introduce the transfer of target-ligand interaction information from one target to a related one for which no structural information is available. Thus, IFs from a crystallographic target B-ligand complex are incorporated into structural key fingerprints of known ligands for target A. Similarity searching using these IF transfer fingerprints (IF-TFP) is shown to further increase the search performance of conventional ligand fingerprints. Thus, interaction information can be transferred between related targets in order to support ligand-based fingerprint search calculations for targets for which no structural information is currently available.

  7. NMR studies of protein-ligand interactions.

    PubMed

    Maurer, Till

    2005-01-01

    Interaction between biological macromolecules or of macromolecules with low-molecular-weight ligands is a central paradigm in the understanding of function in biological systems. It is also the major goal in pharmaceutical research to find and optimize ligands that modulate the function of biological macromolecules. Both technological advances and new methods in the field of nuclear magnetic resonance (NMR) have led to the development of several tools by which the interaction of proteins or DNA and low molecular weight-ligands can be characterized at an atomic level. Information can be gained quickly and easily with ligand-based techniques. These need only small amounts of nonisotope labeled, and thus readily available target macromolecules. As the focus is on the signals stemming only from the ligand, no further NMR information regarding the target is needed. Techniques based on the observation of isotopically labeled biological macromolecules open the possibility to observe interactions of proteins with low-molecular-weight ligands, DNA or other proteins. With these techniques, the structure of high-molecular-weight complexes can be determined. Here, the resonance signals of the macromolecule must be identified beforehand, which can be time consuming but with the benefit of obtaining more information with respect to the target ligand complex.

  8. 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.

  9. 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.

  10. 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

  11. 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

  12. 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.

  13. Flexible ligand docking using conformational ensembles.

    PubMed Central

    Lorber, D. M.; Shoichet, B. K.

    1998-01-01

    Molecular docking algorithms suggest possible structures for molecular complexes. They are used to model biological function and to discover potential ligands. A present challenge for docking algorithms is the treatment of molecular flexibility. Here, the rigid body program, DOCK, is modified to allow it to rapidly fit multiple conformations of ligands. Conformations of a given molecule are pre-calculated in the same frame of reference, so that each conformer shares a common rigid fragment with all other conformations. The ligand conformers are then docked together, as an ensemble, into a receptor binding site. This takes advantage of the redundancy present in differing conformers of the same molecule. The algorithm was tested using three organic ligand protein systems and two protein-protein systems. Both the bound and unbound conformations of the receptors were used. The ligand ensemble method found conformations that resembled those determined in X-ray crystal structures (RMS values typically less than 1.5 A). To test the method's usefulness for inhibitor discovery, multi-compound and multi-conformer databases were screened for compounds known to bind to dihydrofolate reductase and compounds known to bind to thymidylate synthase. In both cases, known inhibitors and substrates were identified in conformations resembling those observed experimentally. The ligand ensemble method was 100-fold faster than docking a single conformation at a time and was able to screen a database of over 34 million conformations from 117,000 molecules in one to four CPU days on a workstation. PMID:9568900

  14. 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…

  15. 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.

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

    NASA Astrophysics Data System (ADS)

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

    2015-09-01

    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.

  17. 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

  18. 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

  19. Ligand-responsive RNA mechanical switches.

    PubMed

    Boerneke, Mark A; Hermann, Thomas

    2015-01-01

    Ligand-responsive RNA mechanical switches represent a new class of simple switching modules that adopt well-defined ligand-free and bound conformational states, distinguishing them from metabolite-sensing riboswitches. Initially discovered in the internal ribosome entry site (IRES) of hepatitis C virus (HCV), these RNA switch motifs were found in the genome of diverse other viruses. Although large variations are seen in sequence and local secondary structure of the switches, their function in viral translation initiation that requires selective ligand recognition is conserved. We recently determined the crystal structure of an RNA switch from Seneca Valley virus (SVV) which is able to functionally replace the switch of HCV. The switches from both viruses recognize identical cognate ligands despite their sequence dissimilarity. Here, we describe the discovery of 7 new switches in addition to the previously established 5 examples. We highlight structural and functional features unique to this class of ligand-responsive RNA mechanical switches and discuss implications for therapeutic development and the construction of RNA nanostructures. PMID:26158858

  20. 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.

  1. 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.

  2. Determining ligand specificity of Ly49 receptors.

    PubMed

    Lavender, Kerry J; Kane, Kevin P

    2010-01-01

    Ly49 receptors in rodents, like KIR in humans, play an integral role in the regulation of NK cell activity. Some inhibitory Ly49 are known to interact with specific MHC I alleles to maintain tolerance to self tissues, and NK activation is triggered upon the loss of inhibitory signals due to pathological downregulation of self MHC I. Although a virally encoded ligand has been identified that can trigger NK cytotoxicity through an activating Ly49, some activating Ly49 also recognize MHC I and the role of most activating receptors in NK effector function remains poorly defined. As many Ly49 remain orphan receptors, we describe methods to unambiguously discern receptor-ligand pairs. Additionally, we describe a method for the mutagenesis of Ly49 and MHC ligands that can be used to define the motifs conferring receptor specificity for their ligands. Further elucidation of Ly49 ligands is required to continue to define the role of Ly49 in regulating NK cell effector function and may give vital clues to the role of KIR in human health and disease. PMID:20033649

  3. 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.

  4. Ligand identification using electron-density map correlations

    SciTech Connect

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

    2007-01-01

    An automated ligand-fitting procedure is applied to (F{sub o} − F{sub c})exp(iϕ{sub c}) difference density for 200 commonly found ligands from macromolecular structures in the Protein Data Bank to identify ligands from density maps. A procedure for the identification of ligands bound in crystal structures of macromolecules is described. Two characteristics of the density corresponding to a ligand are used in the identification procedure. One is the correlation of the ligand density with each of a set of test ligands after optimization of the fit of that ligand to the density. The other is the correlation of a fingerprint of the density with the fingerprint of model density for each possible ligand. The fingerprints consist of an ordered list of correlations of each the test ligands with the density. The two characteristics are scored using a Z-score approach in which the correlations are normalized to the mean and standard deviation of correlations found for a variety of mismatched ligand-density pairs, so that the Z scores are related to the probability of observing a particular value of the correlation by chance. The procedure was tested with a set of 200 of the most commonly found ligands in the Protein Data Bank, collectively representing 57% of all ligands in the Protein Data Bank. Using a combination of these two characteristics of ligand density, ranked lists of ligand identifications were made for representative (F{sub o} − F{sub c})exp(iϕ{sub c}) difference density from entries in the Protein Data Bank. In 48% of the 200 cases, the correct ligand was at the top of the ranked list of ligands. This approach may be useful in identification of unknown ligands in new macromolecular structures as well as in the identification of which ligands in a mixture have bound to a macromolecule.

  5. 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.

  6. The first scorpionate ligand based on diazaphosphole.

    PubMed

    Mlateček, Martin; Dostál, Libor; Růžičková, Zdeňka; Honzíček, Jan; Holubová, Jana; Erben, Milan

    2015-12-14

    The reaction of PhBCl2 with 1H-1,2,4-λ(3)-diazaphosphole in the presence of NEt3 gives a new scorpionate ligand, phenyl-tris(1,2,4-diazaphospholyl)borate (PhTdap). The coordination behaviour of this ligand toward transition and non-transition metals has been comprehensively studied. In the thallium(I) complex, Tl(PhTdap), κ(2)-N,N bonding supported with intramolecular η(3)-phenyl coordination has been observed in the solid state. Tl(PhTdap) also shows unusual intermolecular π-interactions between five-membered diazaphosphole rings and the thallium atom giving infinite molecular chains in the crystal. In the square planar complex [Pd(C,N-C6H4CH2NMe2)(PhTdap)], κ(2)-bonded scorpionate has been detected in both solution and in the solid state. For other studied compounds with the central metal ion Ti(IV), Mo(II), Mn(I), Fe(II), Ru(II), Co(II), Co(III), Ni(II) and Cd(II), the κ(3)-N,N,N coordination pattern was observed. Electronic properties of PhTdap and its ligand-field strength were elucidated from UV-Vis spectra of transition-metal species. The CH/P replacement on going from tris(pyrazolyl)borate to the ligand PhTdap causes a slight increase in electronic density rendered to the central metal atom. The following order of ligand-field strength has been established: HB(3,5-Me2pz)3 < PhB(pz)3 < HB(1,2,4-triazolyl) < HB(pz)3 < PhB(1,2,4-triazolyl) < PhTdap. The crystal structures of ten metal complexes bearing the new ligand are reported. The possibility of PhTdap coordination through the phosphorus atom is also briefly discussed. PMID:26537349

  7. 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

  8. Multifunctional Ligands in Transition Metal Catalysis (invited 'Focus' article),

    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.

  9. 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.

  10. 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.

  11. The selective cytotoxic activity in breast cancer cells by an anthranilic alcohol-derived acyclic 5-fluorouracil O,N-acetal is mediated by endoplasmic reticulum stress-induced apoptosis.

    PubMed

    Caba, Octavio; Rodríguez-Serrano, Fernando; Díaz-Gavilán, Mónica; Conejo-García, Ana; Ortiz, Raúl; Martínez-Amat, Antonio; Alvarez, Pablo; Gallo, Miguel A; Campos, Joaquín M; Marchal, Juan A; Aránega, Antonia

    2012-04-01

    Advance in the knowledge of molecular biology has thrown light on many aspects of apoptosis regulation mechanisms. This has allowed a change in anti-cancer therapy trends, from classic cytotoxic strategies to the development of new non-harmful therapies which target the apoptosis response selectively only in tumour cells. We have selected an anthranilic alcohol-derived acyclic 5-fluorouracil O,N-acetal (5) to carry out the anti-cancer studies. This compound shows activity as a potent growth inhibitor of the tumour cell line MCF-7 at a very low concentration. Moreover, when this compound was administered to the non-neoplastic cell line, MCF-10A displayed less toxicity resulting in lower rates of apoptosis. Further studies by microarray hybridization, real-time PCR and western blot showed that when administered to human breast cancer cells, MCF-7, 5 had no activity against classic pro-apoptotic genes such as p53, and even induced the down-regulation of anti-apoptotic genes such as Bcl-2. In contrast, several pro-apoptotic genes related with the endoplasmic reticulum (ER)-stress-induced apoptosis, such as BBC3 and Noxa, appeared up-regulated. These results seem to show that the mechanism of action and selectivity of 5 was via the activation of the ER stress-induced apoptosis. The selective activity of this compound against tumour cells via the ER stress-induced apoptosis supposes a great advantage for future therapeutic use. PMID:22373735

  12. Strong Ligand-Protein Interactions Derived from Diffuse Ligand Interactions with Loose Binding Sites.

    PubMed

    Marsh, Lorraine

    2015-01-01

    Many systems in biology rely on binding of ligands to target proteins in a single high-affinity conformation with a favorable ΔG. Alternatively, interactions of ligands with protein regions that allow diffuse binding, distributed over multiple sites and conformations, can exhibit favorable ΔG because of their higher entropy. Diffuse binding may be biologically important for multidrug transporters and carrier proteins. A fine-grained computational method for numerical integration of total binding ΔG arising from diffuse regional interaction of a ligand in multiple conformations using a Markov Chain Monte Carlo (MCMC) approach is presented. This method yields a metric that quantifies the influence on overall ligand affinity of ligand binding to multiple, distinct sites within a protein binding region. This metric is essentially a measure of dispersion in equilibrium ligand binding and depends on both the number of potential sites of interaction and the distribution of their individual predicted affinities. Analysis of test cases indicates that, for some ligand/protein pairs involving transporters and carrier proteins, diffuse binding contributes greatly to total affinity, whereas in other cases the influence is modest. This approach may be useful for studying situations where "nonspecific" interactions contribute to biological function. PMID:26064949

  13. Strong Ligand-Protein Interactions Derived from Diffuse Ligand Interactions with Loose Binding Sites

    PubMed Central

    2015-01-01

    Many systems in biology rely on binding of ligands to target proteins in a single high-affinity conformation with a favorable ΔG. Alternatively, interactions of ligands with protein regions that allow diffuse binding, distributed over multiple sites and conformations, can exhibit favorable ΔG because of their higher entropy. Diffuse binding may be biologically important for multidrug transporters and carrier proteins. A fine-grained computational method for numerical integration of total binding ΔG arising from diffuse regional interaction of a ligand in multiple conformations using a Markov Chain Monte Carlo (MCMC) approach is presented. This method yields a metric that quantifies the influence on overall ligand affinity of ligand binding to multiple, distinct sites within a protein binding region. This metric is essentially a measure of dispersion in equilibrium ligand binding and depends on both the number of potential sites of interaction and the distribution of their individual predicted affinities. Analysis of test cases indicates that, for some ligand/protein pairs involving transporters and carrier proteins, diffuse binding contributes greatly to total affinity, whereas in other cases the influence is modest. This approach may be useful for studying situations where “nonspecific” interactions contribute to biological function. PMID:26064949

  14. Rosetta and the Design of Ligand Binding Sites.

    PubMed

    Moretti, Rocco; Bender, Brian J; Allison, Brittany; Meiler, Jens

    2016-01-01

    Proteins that bind small molecules (ligands) can be used as biosensors, signal modulators, and sequestering agents. When naturally occurring proteins for a particular target ligand are not available, artificial proteins can be computationally designed. We present a protocol based on RosettaLigand to redesign an existing protein pocket to bind a target ligand. Starting with a protein structure and the structure of the ligand, Rosetta can optimize both the placement of the ligand in the pocket and the identity and conformation of the surrounding sidechains, yielding proteins that bind the target compound.

  15. Rosetta and the Design of Ligand Binding Sites.

    PubMed

    Moretti, Rocco; Bender, Brian J; Allison, Brittany; Meiler, Jens

    2016-01-01

    Proteins that bind small molecules (ligands) can be used as biosensors, signal modulators, and sequestering agents. When naturally occurring proteins for a particular target ligand are not available, artificial proteins can be computationally designed. We present a protocol based on RosettaLigand to redesign an existing protein pocket to bind a target ligand. Starting with a protein structure and the structure of the ligand, Rosetta can optimize both the placement of the ligand in the pocket and the identity and conformation of the surrounding sidechains, yielding proteins that bind the target compound. PMID:27094285

  16. Physical Limit to Concentration Sensing Amid Spurious Ligands

    NASA Astrophysics Data System (ADS)

    Mora, Thierry

    2015-07-01

    To adapt their behavior in changing environments, cells sense concentrations by binding external ligands to their receptors. However, incorrect ligands may bind nonspecifically to receptors, and when their concentration is large, this binding activity may interfere with the sensing of the ligand of interest. Here, I derive analytically the physical limit to the accuracy of concentration sensing amid a large number of interfering ligands. A scaling transition is found when the mean bound time of correct ligands is twice that of incorrect ligands. I discuss how the physical bound can be approached by a cascade of receptor states generalizing kinetic proofreading schemes.

  17. 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.

  18. Nanoparticle ligand presentation for targeting solid tumors.

    PubMed

    Duskey, Jason T; Rice, Kevin G

    2014-10-01

    Among the many scientific advances to come from the study of nanoscience, the development of ligand-targeted nanoparticles to eliminate solid tumors is predicted to have a major impact on human health. There are many reports describing novel designs and testing of targeted nanoparticles to treat cancer. While the principles of the technology are well demonstrated in controlled lab experiments, there are still many hurdles to overcome for the science to mature into truly efficacious targeted nanoparticles that join the arsenal of agents currently used to treat cancer in humans. One of these hurdles is overcoming unwanted biodistribution to the liver while maximizing delivery to the tumor. This almost certainly requires advances in both nanoparticle stealth technology and targeting. Currently, it continues to be a challenge to control the loading of ligands onto polyethylene glycol (PEG) to achieve maximal targeting. Nanoparticle cellular uptake and subcellular targeting of genes and siRNA also remain a challenge. This review examines the types of ligands that have been most often used to target nanoparticles to solid tumors. As the science matures over the coming decade, careful control over ligand presentation on nanoparticles of precise size, shape, and charge will likely play a major role in achieving success.

  19. Micropatterned Surfaces with Controlled Ligand Tethering

    PubMed Central

    Petrie, Timothy A.; Stanley, Brandon T.; García, Andrés J.

    2008-01-01

    Microcontact printing (μ-CP) is a facile, cost-effective, and versatile soft-lithography technique to create 2-dimensional patterns of domains with distinct functionalities that provides a robust platform to generate micropatterned biotechnological arrays and cell culture substrates. Current μ-CP approaches rely on non-specific immobilization of biological ligands, either by direct printing or adsorption from solution, onto micropatterned domains surrounded by a non-fouling background. This technique is limited by insufficient control over ligand density. We present a modified μ-CP protocol involving stamping mixed ratios of carboxyl- and tri(ethylene glycol)-terminated alkanethiols that provides for precise covalent tethering of single or multiple ligands to prescribed micropatterns via standard peptide chemistry. Processing parameters were optimized to identify conditions that control relevant endpoint pattern characteristics. This technique provides a facile method to generate micropatterned arrays with tailorable and controlled presentation of biological ligands for biotechnological applications and analyses of cell-material interactions. PMID:18570314

  20. Nanoparticle ligand presentation for targeting solid tumors.

    PubMed

    Duskey, Jason T; Rice, Kevin G

    2014-10-01

    Among the many scientific advances to come from the study of nanoscience, the development of ligand-targeted nanoparticles to eliminate solid tumors is predicted to have a major impact on human health. There are many reports describing novel designs and testing of targeted nanoparticles to treat cancer. While the principles of the technology are well demonstrated in controlled lab experiments, there are still many hurdles to overcome for the science to mature into truly efficacious targeted nanoparticles that join the arsenal of agents currently used to treat cancer in humans. One of these hurdles is overcoming unwanted biodistribution to the liver while maximizing delivery to the tumor. This almost certainly requires advances in both nanoparticle stealth technology and targeting. Currently, it continues to be a challenge to control the loading of ligands onto polyethylene glycol (PEG) to achieve maximal targeting. Nanoparticle cellular uptake and subcellular targeting of genes and siRNA also remain a challenge. This review examines the types of ligands that have been most often used to target nanoparticles to solid tumors. As the science matures over the coming decade, careful control over ligand presentation on nanoparticles of precise size, shape, and charge will likely play a major role in achieving success. PMID:24927668

  1. 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.

  2. 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.

  3. 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

  4. Metal-ion-ligand interactions in thermotropic liquid crystals

    NASA Astrophysics Data System (ADS)

    Diehl, P.; Wasser, H. R.; Gowda, G. A. Nagana; Suryaprakash, N.; Khetrapal, C. L.

    1989-07-01

    The interactions of lithium perchlorate with ligands such as dimethyl sulphoxide, acetonitrile, pyridine and the Schiff base liquid crystals are investigated. The experiments open a new field for the study of metal-ion-ligand interactions in thermotropic liquid crystals.

  5. 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

    2016-03-01

    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.

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

    DOE PAGESBeta

    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 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

  7. 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.

  8. 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.

  9. 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. PMID:22669908

  10. Role of ligand-ligand vs. core-core interactions in gold nanoclusters.

    PubMed

    Milowska, Karolina Z; Stolarczyk, Jacek K

    2016-05-14

    The controlled assembly of ligand-coated gold nanoclusters (NCs) into larger structures paves the way for new applications ranging from electronics to nanomedicine. Here, we demonstrate through rigorous density functional theory (DFT) calculations employing novel functionals accounting for van der Waals forces that the ligand-ligand interactions determine whether stable assemblies can be formed. The study of NCs with different core sizes, symmetry forms, ligand lengths, mutual crystal orientations, and in the presence of a solvent suggests that core-to-core van der Waals interactions play a lesser role in the assembly. The dominant interactions originate from combination of steric effects, augmented by ligand bundling on NC facets, and related to them changes in electronic properties induced by neighbouring NCs. We also show that, in contrast to standard colloidal theory approach, DFT correctly reproduces the surprising experimental trends in the strength of the inter-particle interaction observed when varying the length of the ligands. The results underpin the importance of understanding NC interactions in designing gold NCs for a specific function. PMID:27097887

  11. Ligand identification using electron-density map correlations.

    PubMed

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

    2007-01-01

    A procedure for the identification of ligands bound in crystal structures of macromolecules is described. Two characteristics of the density corresponding to a ligand are used in the identification procedure. One is the correlation of the ligand density with each of a set of test ligands after optimization of the fit of that ligand to the density. The other is the correlation of a fingerprint of the density with the fingerprint of model density for each possible ligand. The fingerprints consist of an ordered list of correlations of each the test ligands with the density. The two characteristics are scored using a Z-score approach in which the correlations are normalized to the mean and standard deviation of correlations found for a variety of mismatched ligand-density pairs, so that the Z scores are related to the probability of observing a particular value of the correlation by chance. The procedure was tested with a set of 200 of the most commonly found ligands in the Protein Data Bank, collectively representing 57% of all ligands in the Protein Data Bank. Using a combination of these two characteristics of ligand density, ranked lists of ligand identifications were made for representative (F(o) - F(c))exp(i(phi)c) difference density from entries in the Protein Data Bank. In 48% of the 200 cases, the correct ligand was at the top of the ranked list of ligands. This approach may be useful in identification of unknown ligands in new macromolecular structures as well as in the identification of which ligands in a mixture have bound to a macromolecule.

  12. Gas-phase ligand loss and ligand substitution reactions of platinum(II) complexes of tridentate nitrogen donor ligands.

    PubMed

    Wee, Sheena; O'Hair, Richard A J; McFadyen, W David

    2004-01-01

    The source of protons associated with the ligand loss channel of HX((n - 1)+) from [Pt(II)(dien)X](n+) (X = Cl, Br and I for n = 1 and X = NC(5)H(5) for n = 2) in the gas phase was investigated by deuterium-labelling studies. The results of these studies indicate that these protons originate from both the amino groups and the carbon backbone of the dien ligand. In some instances (e.g. X = Br and I), the protons lost from the carbon backbone can be even more abundant than the protons lost from the amino groups. The gas-phase substitution reactions of coordinatively saturated [Pt(II)(L(3))L(a)](2+) complexes (L(3) = tpy or dien) were also examined using ion-molecule reactions. The outcome of the ion-molecule reactions depends on both the ancillary ligand (L(3)) as well as the leaving group (L(a)). [Pt(II)(tpy)L(a)](2+) complexes undergo substitution reactions, with a faster rate when L(a) is a good leaving group, while the [Pt(II)(dien)L(a)](2+) complex undergoes a proton transfer reaction. PMID:15164352

  13. Heterologous production of two unusual acyclic carotenoids, 1,1'-dihydroxy-3,4-didehydrolycopene and 1-hydroxy-3,4,3',4'-tetradehydrolycopene by combination of the crtC and crtD genes from Rhodobacter and Rubrivivax.

    PubMed

    Steiger, Sabine; Takaichi, Shinichi; Sandmann, Gerhard

    2002-07-17

    Acyclic hydroxy carotenoids were produced from lycopene and 3,4-didehydrolycopene in Escherichia coli by combining different carotenogenic genes including the carotene hydratase gene crtC and the carotene 3,4-desaturase gene crtD. The genes originated either from Rhodobacter species or Rubrivivax gelatinosus. It was shown that the product of crtD from Rubrivivax unlike the one from Rhodobacter is able to convert 1-HO-3,4-didehydrolycopene to 1-HO-3,4,3',4'-tetradehydrolycopene (=3,4,3',4'-tetradehydro-1,2-dihydro-psi,psi-caroten-1-ol). Thus, only when the desaturase from Rubrivivax is expressed can this novel carotenoid be obtained. In the presence of crtC from Rubrivivax, another carotenoid 1,1'-(HO)(2)-3,4-didehydrolycopene (=3,4-didehydrolycopene-1,2,1',2'-tetrahydro-psi,psi-caroten-1,1'-diol) not found in a non-transgenic organism before is formed in E. coli. Its accumulation under these conditions and its absence when crtC from Rubrivivax is replaced by the corresponding gene from Rhodobacter is discussed. The function of the different crtC and crtD genes in the pathway leading to the individual carotenoids is outlined. Since 1,1'-(HO)(2)-3,4-didehydrolycopene could not be produced in substantial amounts and 1-HO-3,4,3',4'-tetradehydrolycopene has not been described before, their structural characteristics were determined for the definite assignment of their identity. This included spectral properties, determination of relative molecular mass as well as the number of hydroxy groups by mass spectroscopy and NMR spectroscopy for 1,1'-(HO)(2)-3,4-didehydrolycopene.

  14. Glycomimetic ligands for the human asialoglycoprotein receptor.

    PubMed

    Mamidyala, Sreeman K; Dutta, Sanjay; Chrunyk, Boris A; Préville, Cathy; Wang, Hong; Withka, Jane M; McColl, Alexander; Subashi, Timothy A; Hawrylik, Steven J; Griffor, Matthew C; Kim, Sung; Pfefferkorn, Jeffrey A; Price, David A; Menhaji-Klotz, Elnaz; Mascitti, Vincent; Finn, M G

    2012-02-01

    The asialoglycoprotein receptor (ASGPR) is a high-capacity galactose-binding receptor expressed on hepatocytes that binds its native substrates with low affinity. More potent ligands are of interest for hepatic delivery of therapeutic agents. We report several classes of galactosyl analogues with varied substitution at the anomeric, C2-, C5-, and C6-positions. Significant increases in binding affinity were noted for several trifluoromethylacetamide derivatives without covalent attachment to the protein. A variety of new ligands were obtained with affinity for ASGPR as good as or better than that of the parent N-acetylgalactosamine, showing that modification on either side of the key C3,C4-diol moiety is well tolerated, consistent with previous models of a shallow binding pocket. The galactosyl pyranose motif therefore offers many opportunities for the attachment of other functional units or payloads while retaining low-micromolar or better affinity for the ASGPR.

  15. Targeting mitochondrial energy metabolism with TSPO ligands.

    PubMed

    Gut, Philipp

    2015-08-01

    The translocator protein (18 kDa) (TSPO) resides on the outer mitochondrial membrane where it is believed to participate in cholesterol transport and steroid hormone synthesis. Although it is almost ubiquitously expressed, what TSPO does in non-steroidogenic tissues is largely unexplored. Recent studies report changes in glucose homoeostasis and cellular energy production when TSPO function is modulated by selective ligands or by genetic loss-of-function. This review summarizes findings that connect TSPO function with the regulation of mitochondrial energy metabolism. The juxtaposition of TSPO at the cytosolic/mitochondrial interface and the existence of endogenous ligands that are regulated by metabolism suggest that TSPO functions to adapt mitochondrial to cellular metabolism. From a pharmacological perspective the specific up-regulation of TSPO in neuro-inflammatory and injury-induced conditions make TSPO an interesting, druggable target of mitochondrial metabolism.

  16. Receptor-ligand interactions: Advanced biomedical applications.

    PubMed

    Guryanov, Ivan; Fiorucci, Stefano; Tennikova, Tatiana

    2016-11-01

    Receptor-ligand interactions (RLIs) are at the base of all biological events occurring in living cells. The understanding of interactions between complementary macromolecules in biological systems represents a high-priority research area in bionanotechnology to design the artificial systems mimicking natural processes. This review summarizes and analyzes RLIs in some cutting-edge biomedical fields, in particular, for the preparation of novel stationary phases to separate complex biological mixtures in medical diagnostics, for the design of ultrasensitive biosensors for identification of biomarkers of various diseases at early stages, as well as in the development of innovative biomaterials and approaches for regenerative medicine. All these biotechnological fields are closely related, because their success depends on a proper choice, combination and spatial disposition of the single components of ligand-receptor pairs on the surface of appropriately designed support.

  17. Receptor-ligand interactions: Advanced biomedical applications.

    PubMed

    Guryanov, Ivan; Fiorucci, Stefano; Tennikova, Tatiana

    2016-11-01

    Receptor-ligand interactions (RLIs) are at the base of all biological events occurring in living cells. The understanding of interactions between complementary macromolecules in biological systems represents a high-priority research area in bionanotechnology to design the artificial systems mimicking natural processes. This review summarizes and analyzes RLIs in some cutting-edge biomedical fields, in particular, for the preparation of novel stationary phases to separate complex biological mixtures in medical diagnostics, for the design of ultrasensitive biosensors for identification of biomarkers of various diseases at early stages, as well as in the development of innovative biomaterials and approaches for regenerative medicine. All these biotechnological fields are closely related, because their success depends on a proper choice, combination and spatial disposition of the single components of ligand-receptor pairs on the surface of appropriately designed support. PMID:27524092

  18. 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.

  19. 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.

  20. Targeting Selectins and Their Ligands in Cancer

    PubMed Central

    Natoni, Alessandro; Macauley, Matthew S.; O’Dwyer, Michael E.

    2016-01-01

    Aberrant glycosylation is a hallmark of cancer cells with increased evidence pointing to a role in tumor progression. In particular, aberrant sialylation of glycoproteins and glycolipids has been linked to increased immune cell evasion, drug evasion, drug resistance, tumor invasiveness, and vascular dissemination, leading to metastases. Hypersialylation of cancer cells is largely the result of overexpression of sialyltransferases (STs). Differentially, humans express twenty different STs in a tissue-specific manner, each of which catalyzes the attachment of sialic acids via different glycosidic linkages (α2-3, α2-6, or α2-8) to the underlying glycan chain. One important mechanism whereby overexpression of STs contributes to an enhanced metastatic phenotype is via the generation of selectin ligands. Selectin ligand function requires the expression of sialyl-Lewis X and its structural isomer sialyl-Lewis A, which are synthesized by the combined action of alpha α1-3-fucosyltransferases, α2-3-sialyltransferases, β1-4-galactosyltranferases, and N-acetyl-β-glucosaminyltransferases. The α2-3-sialyltransferases ST3Gal4 and ST3Gal6 are critical to the generation of functional E- and P-selectin ligands and overexpression of these STs have been linked to increased risk of metastatic disease in solid tumors and poor outcome in multiple myeloma. Thus, targeting selectins and their ligands as well as the enzymes involved in their generation, in particular STs, could be beneficial to many cancer patients. Potential strategies include ST inhibition and the use of selectin antagonists, such as glycomimetic drugs and antibodies. Here, we review ongoing efforts to optimize the potency and selectivity of ST inhibitors, including the potential for targeted delivery approaches, as well as evaluate the potential utility of selectin inhibitors, which are now in early clinical development. PMID:27148485

  1. 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

  2. Synthetic ligands discovered by in vitro selection.

    PubMed

    Wrenn, S Jarrett; Weisinger, Rebecca M; Halpin, David R; Harbury, Pehr B

    2007-10-31

    The recognition and catalytic properties of biopolymers derive from an elegant evolutionary mechanism, whereby the genetic material encoding molecules with superior functional attributes survives a selective pressure and is propagated to subsequent generations. This process is routinely mimicked in vitro to generate nucleic-acid or peptide ligands and catalysts. Recent advances in DNA-programmed organic synthesis have raised the possibility that evolutionary strategies could also be used for small-molecule discovery, but the idea remains unproven. Here, using DNA-programmed combinatorial chemistry, a collection of 100 million distinct compounds is synthesized and subjected to selection for binding to the N-terminal SH3 domain of the proto-oncogene Crk. Over six generations, the molecular population converges to a small number of novel SH3 domain ligands. Remarkably, the hits bind with affinities similar to those of peptide SH3 ligands isolated from phage libraries of comparable complexity. The evolutionary approach has the potential to drastically simplify and accelerate small-molecule discovery.

  3. The Recognition of Identical Ligands by Unrelated Proteins.

    PubMed

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

    2015-12-18

    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.

  4. Time, the forgotten dimension of ligand binding teaching.

    PubMed

    Corzo, Javier

    2006-11-01

    Ligand binding is generally explained in terms of the equilibrium constant K(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 protein-ligand complexes may be unable to trigger further biological processes as signal transduction or internalization if such processes are relatively slow with respect to dissociation of the complex that initiated them. Protein-ligand complex life span depends on the first-order rate constant for the dissociation of the complex, K(off) , but this constant and its implications are generally not treated in textbooks. This report presents a brief discussion and some examples useful for teaching the importance of time in ligand binding by macromolecules in the context of a general biochemistry course.

  5. Separation of tryptophan enantiomers by ligand-exchange chromatography with novel chiral ionic liquids ligand.

    PubMed

    Qing, Haiqun; Jiang, Xinyu; Yu, Jingang

    2014-03-01

    Chiral ionic liquids (CILs) with amino acids as cations have been applied as novel chiral ligands coordinated with Cu(2+) to separate tryptophan enantiomers in ligand exchange chromatography. Four kinds of amino acid ionic liquids, including [L-Pro][CF3COO], [L-Pro][NO3], [L-Pro]2[SO4], and [L-Phe][CF3COO] were successfully synthesized and used for separation of tryptophan enantiomers. To optimize the separation conditions, [L-Pro][CF3COO] was selected as the model ligand. Some factors influencing the efficiency of chiral separation, such as copper ion concentration, CILs concentration, methanol ratio (methanol/H2O, v/v), and pH, were investigated. The obtained optimal separation conditions were as follows: 8.0 mmol/L Cu(OAc)2, 4.0 mmol/L [L-Pro][CF3COO], and 20% (v/v) methanol at pH 3.6. Under the optimum conditions, acceptable enantioseparation of tryptophan enantiomers could be observed with a resolution of 1.89. The results demonstrate the good applicability of CILs with amino acids as cations for chiral separation. Furthermore, a comparative study was also conducted for exploring the mechanism of the CILs as new ligands in ligand exchange chromatography.

  6. ProBiS-ligands: a web server for prediction of ligands by examination of protein binding sites

    PubMed Central

    Konc, Janez; Janežič, Dušanka

    2014-01-01

    The ProBiS-ligands web server predicts binding of ligands to a protein structure. Starting with a protein structure or binding site, ProBiS-ligands first identifies template proteins in the Protein Data Bank that share similar binding sites. Based on the superimpositions of the query protein and the similar binding sites found, the server then transposes the ligand structures from those sites to the query protein. Such ligand prediction supports many activities, e.g. drug repurposing. The ProBiS-ligands web server, an extension of the ProBiS web server, is open and free to all users at http://probis.cmm.ki.si/ligands. PMID:24861616

  7. Low symmetry pyrazole-based tripodal tetraamine ligands: metal complexes and ligand decomposition reactions.

    PubMed

    Cubanski, John R; Cameron, Scott A; Crowley, James D; Blackman, Allan G

    2013-02-14

    The new low symmetry pyrazole-based tripodal tetraamine ligands 2-(1H-pyrazol-1-yl)-N,N-bis(1H-pyrazol-1-ylmethyl)ethanamine (bmpz) and 2-(1H-pyrazol-1-yl)-N-[2-(1H-pyrazol-1-yl)ethyl]-N-(1H-pyrazol-1-ylmethyl)ethanamine (bepz) have been prepared and characterised, as have metal complexes containing these ligands. X-ray crystal structures of [Co(bmpz)Cl](2)[CoCl(4)]·H(2)O, [Co(bmpz)MeCN](ClO(4))(2)·0.13H(2)O, [Zn(bmpz)MeCN](ClO(4))(2)·0.15H(2)O, [Zn(bepz)OH(2)](ClO(4))(2)·0.5H(2)O and [(Co(bepz)Cl)(2)]Cl(2)·6H(2)O confirm coordination of the intact tripodal ligands to the metal ions through all four N atoms. However, attempts to make Cu(2+) complexes containing bmpz and bepz gave, respectively, [Cu(7)Cl(2)]·0.2H(2)O and [Cu(8)Cl(2)] (7 = 1-(1H-pyrazol-1-yl)-N-(1H-pyrazol-1-ylmethyl)ethanamine, 8 = 2-(1H-pyrazol-1-yl)-N-[2-(1H-pyrazol-1-yl)ethyl]ethanamine), complexes containing the tridentate ligands 7 and 8 which are formed by loss of a pyrazolylmethyl arm from the appropriate tripodal ligand. This decomposition reaction occurs in protic solvents both in the presence and absence of metal ions, and is ascribed to the presence of an aminal functionality in the tripodal ligands. A possible mechanism for the decomposition, based on NMR and ESMS data, is suggested.

  8. Defining the property space for chromatographic ligands from a homologous series of mixed-mode ligands.

    PubMed

    Woo, James A; Chen, Hong; Snyder, Mark A; Chai, Yiming; Frost, Russell G; Cramer, Steven M

    2015-08-14

    A homologous ligand library based on the commercially-available Nuvia cPrime ligand was generated to systematically explore various features of a multimodal cation-exchange ligand and to identify structural variants that had significantly altered chromatographic selectivity. Substitution of the polar amide bond with more hydrophobic chemistries was found to enhance retention while remaining hydrophobically-selective for aromatic residues. In contrast, increasing the solvent exposure of the aromatic ring was observed to strengthen the ligand affinity for both types of hydrophobic residues. An optimal linker length between the charged and hydrophobic moieties was also observed to enhance retention, balancing the steric accessibility of the hydrophobic moiety with its ability to interact independently of the charged group. The weak pKa of the carboxylate charge group was found to have a notable impact on protein retention on Nuvia cPrime at lower pH, increasing hydrophobic interactions with the protein. Substituting the charged group with a sulfonic acid allowed this strong MM ligand to retain its electrostatic-dominant character in this lower pH range. pH gradient experiments were also carried out to further elucidate this pH dependent behavior. A single QSAR model was generated using this accumulated experimental data to predict protein retention across a range of multimodal and ion exchange systems. This model could correctly predict the retention of proteins on resins that were not included in the original model and could prove quite powerful as an in silico approach toward designing more effective and differentiated multimodal ligands. PMID:26162668

  9. Landscape of protein-small ligand binding modes.

    PubMed

    Kasahara, Kota; Kinoshita, Kengo

    2016-09-01

    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

  10. Landscape of protein-small ligand binding modes.

    PubMed

    Kasahara, Kota; Kinoshita, Kengo

    2016-09-01

    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.

  11. 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.

  12. Integrin receptors and ligand-gated channels.

    PubMed

    Morini, Raffaella; Becchetti, Andrea

    2010-01-01

    Plastic expression of different integrin subunits controls the different stages of neural development, whereas in the adult integrins regulate synaptic stability. Evidence of integrin-channel crosstalk exists for ionotropic glutamate receptors. As is often the case in other tissues, integrin engagement regulates channel activity through complex signaling pathways that often include tyrosine phosphorylation cascades. The specific pathways recruited by integrin activation depend on cerebral region and cell type. In turn, ion channels control integrin expression onto the plasma membrane and their ligand binding affinity. The most extensive studies concern the hippocampus and suggest implications for neuronal circuit plasticity. The physiological relevance of these findings depends on whether adhesion molecules, aside from determining tissue stability, contribute to synaptogenesis and the responsiveness of mature synapses, thus contributing to long-term circuit consolidation. Little evidence is available for other ligand-gated channels, with the exception of nicotinic receptors. These exert a variety of functions in neurons and non neural tissue, both in development and in the adult, by regulating cell cycle, synaptogenesis and synaptic circuit refinement. Detailed studies in epidermal keratinocytes have shed some light on the possible mechanisms through which ACh can regulate cell motility, which may be of general relevance for morphogenetic processes. As to the control of mature synapses, most results concern the integrinic control of nicotinic receptors in the neuromuscular junction. Following this lead, a few studies have addressed similar topics in adult cerebral synapses. However, pursuing and interpreting these results in the brain is especially difficult because of the complexity of the nicotinic roles and the widespread contribution of nonsynaptic, paracrine transmission. From a pathological point of view, considering the well-known contribution of both

  13. Computer-aided design of GPCR ligands.

    PubMed

    Gutiérrez-de-Terán, Hugo; Keränen, Henrik; Azuaje, Jhonny; Rodríguez, David; Åqvist, Johan; Sotelo, Eddy

    2015-01-01

    The recent availability of several GPCR crystal structures now contributes decisively to the perspective of structure-based ligand design. In this context, computational approaches are extremely helpful, particularly if properly integrated in drug design projects with cooperation between computational and medicinal chemistry teams. Here, we present the pipelines used in one such project, devoted to the design of novel potent and selective antagonists for the different adenosine receptors. The details of the computational strategies are described, and particular attention is given to explain how these procedures can effectively guide the synthesis of novel chemical entities.

  14. Oncolytic measles virus retargeting by ligand display.

    PubMed

    Msaouel, Pavlos; Iankov, Ianko D; Allen, Cory; Russell, Stephen J; Galanis, Evanthia

    2012-01-01

    Despite significant advances in recent years, treatment of metastatic malignancies remains a significant challenge. There is an urgent need for development of novel therapeutic approaches. Virotherapy approaches have considerable potential, and among them measles virus (MV) vaccine strains have emerged as a promising oncolytic platform. Retargeted MV strains deriving from the Edmonston vaccine lineage (MV-Edm) have shown comparable antitumor efficacy to unmodified strains against receptor expressing tumor cells with improved therapeutic index. Here, we describe the construction, rescue, amplification, and titration of fully retargeted MV-Edm derivatives displaying tumor specific receptor binding ligands on the viral surface in combination with H protein CD46 and SLAM entry ablating mutations.

  15. 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.

  16. The Ligand Gated Ion Channel Database.

    PubMed

    Le Novère, N; Changeux, J P

    1999-01-01

    The ligand gated ion channels (LGICs) are ionotropic receptors to neurotransmitters. Their physiological effect is carried out by the opening of an ionic channel upon binding of a particular neurotransmitter. These LGICs constitute superfamilies of receptors formed by homologous subunits. A database has been developed to handle the growing wealth of cloned subunits. This database contains nucleic acid sequences, protein sequences, as well as multiple sequence alignments and phylogenetic studies. This database is accessible via the worldwide web (http://www.pasteur.fr/units/neubiomol/LGIC.h tml), where it is continuously updated. A downloadable version is also available [currently v0.1 (98.06)].

  17. Architectural repertoire of ligand-binding pockets on protein surfaces.

    PubMed

    Weisel, Martin; Kriegl, Jan M; Schneider, Gisbert

    2010-03-01

    Knowledge of the three-dimensional structure of ligand binding sites in proteins provides valuable information for computer-assisted drug design. We present a method for the automated extraction and classification of ligand binding site topologies, in which protein surface cavities are represented as branched frameworks. The procedure employs a growing neural gas approach for pocket topology assignment and pocket framework generation. We assessed the structural diversity of 623 known ligand binding site topologies based on framework cluster analysis. At a resolution of 5 A only 23 structurally distinct topology groups were formed; this suggests an overall limited structural diversity of ligand-accommodating protein cavities. Higher resolution allowed for identification of protein-family specific pocket features. Pocket frameworks highlight potentially preferred modes of ligand-receptor interactions and will help facilitate the identification of druggable subpockets suitable for ligand affinity and selectivity optimization. PMID:20069621

  18. 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

  19. Weak Ligand-Field Effect from Ancillary Ligands on Enhancing Single-Ion Magnet Performance.

    PubMed

    Meng, Yin-Shan; Zhang, Yi-Quan; Wang, Zhe-Ming; Wang, Bing-Wu; Gao, Song

    2016-08-26

    A series of bis-pentamethylcyclopentadienyl-supported Dy complexes containing different ancillary ligands were synthesized and characterized. Magnetic studies showed that 1 Dy [Cp*2 DyCl(THF)], 1 Dy' [Cp*2 DyCl2 K(THF)]n , 2 Dy [Cp*2 DyBr(THF)], 3 Dy [Cp*2 DyI(THF)] and 4 Dy [Cp*2 DyTp] (Tp=hydrotris(1-pyrazolyl)borate) were single-ion magnets (SIMs). The 1D dysprosium chain 1 Dy' exhibited a hysteresis at up to 5 K. Furthermore, 3 Dy featured the highest energy barrier (419 cm(-1) ) among the complexes. The effects of ancillary ligands on single-ion magnetic properties were studied by experimental, ab initio calculations and electrostatic analysis methods in detail. These results demonstrated that the QTM rate was strongly dependent on the ancillary ligands and that a weak equatorial ligand field could be beneficial for constructing Dy-SIMs. PMID:27417884

  20. Ligand binding by the tandem glycine riboswitch depends on aptamer dimerization but not double ligand occupancy

    PubMed Central

    Ruff, Karen M.

    2014-01-01

    The glycine riboswitch predominantly exists as a tandem structure, with two adjacent, homologous ligand-binding domains (aptamers), followed by a single expression platform. The recent identification of a leader helix, the inclusion of which eliminates cooperativity between the aptamers, has reopened the debate over the purpose of the tandem structure of the glycine riboswitch. An equilibrium dialysis-based assay was combined with binding-site mutations to monitor glycine binding in each ligand-binding site independently to understand the role of each aptamer in glycine binding and riboswitch tertiary interactions. A series of mutations disrupting the dimer interface was used to probe how dimerization impacts ligand binding by the tandem glycine riboswitch. While the wild-type tandem riboswitch binds two glycine equivalents, one for each aptamer, both individual aptamers are capable of binding glycine when the other aptamer is unoccupied. Intriguingly, glycine binding by aptamer-1 is more sensitive to dimerization than glycine binding by aptamer-2 in the context of the tandem riboswitch. However, monomeric aptamer-2 shows dramatically weakened glycine-binding affinity. In addition, dimerization of the two aptamers in trans is dependent on glycine binding in at least one aptamer. We propose a revised model for tandem riboswitch function that is consistent with these results, wherein ligand binding in aptamer-1 is linked to aptamer dimerization and stabilizes the P1 stem of aptamer-2, which controls the expression platform. PMID:25246650

  1. LASSO-ligand activity by surface similarity order: a new tool for ligand based virtual screening.

    PubMed

    Reid, Darryl; Sadjad, Bashir S; Zsoldos, Zsolt; Simon, Aniko

    2008-01-01

    Virtual Ligand Screening (VLS) has become an integral part of the drug discovery process for many pharmaceutical companies. Ligand similarity searches provide a very powerful method of screening large databases of ligands to identify possible hits. If these hits belong to new chemotypes the method is deemed even more successful. eHiTS LASSO uses a new interacting surface point types (ISPT) molecular descriptor that is generated from the 3D structure of the ligand, but unlike most 3D descriptors it is conformation independent. Combined with a neural network machine learning technique, LASSO screens molecular databases at an ultra fast speed of 1 million structures in under 1 min on a standard PC. The results obtained from eHiTS LASSO trained on relatively small training sets of just 2, 4 or 8 actives are presented using the diverse directory of useful decoys (DUD) dataset. It is shown that over a wide range of receptor families, eHiTS LASSO is consistently able to enrich screened databases and provides scaffold hopping ability.

  2. 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.

  3. 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.

  4. 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.

  5. The reactivity of cytochrome c with soft ligands.

    PubMed

    Schejter, A; Plotkin, B; Vig, I

    1991-03-25

    The spectral changes caused by binding soft ligands to the cytochrome c iron and their correlation to ligand affinities support the hypothesis that the iron-methionine sulfur bond of this heme protein is enhanced by delocalization of the metal t2g electrons into the empty 3d orbitals of the ligand atom. These findings also explain the unique spectrum of cytochrome c in the far red.

  6. Structural insight into PPARgamma ligands binding.

    PubMed

    Farce, A; Renault, N; Chavatte, P

    2009-01-01

    Peroxisome Proliferator Activated Receptors (PPARs) are a family of three related nuclear receptors first cloned in 1990. Their involvement in glucidic and lipidic homeostasis quickly made them an attractive target for the treatment of metabolic syndrome, the most prevalent mortality factor in developed countries. They therefore attracted much synthetic efforts, more particularly PPARgamma. Supported by a large number of crystallographic studies, data derived from these compounds lead to a fairly clear view of the agonist binding mode into the Ligand Binding Domain (LBD). Nearly all the compounds conform to a three-module structure, with a binder group involved in a series of hydrogen bonds in front of the ligand-dependent Activation Function (AF2), a linker mostly arranged around a phenoxyethyl and an effector end occupying the large cavity of the binding site. Following the marketing of the glitazones and the observation of the hepatotoxicity of troglitazone, variations in the binder led to the glitazars, and then pharmacomodulations have been undertaken on the two other modules, leading to a large family of highly related chemical structures. Some compounds, while still adhering to the three-module structure, diverge from the mainstream, such as the phthalates. Curiously, these plasticizers were known to elicit biological effects that led to the discovery of PPARs but were not actively studied as PPARs agonists. As the biological effects of PPARs became clearer, new compounds were also found to exert at least a part of their actions by the activation of PPARgamma. PMID:19442144

  7. 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.

  8. Continuous microfluidic assortment of interactive ligands (CMAIL).

    PubMed

    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 10(5) CFU (colony forming unit) antigen-interacting phages were isolated with ~100% specificity from a phage library containing 3 × 10(9) 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

  9. Continuous microfluidic assortment of interactive ligands (CMAIL).

    PubMed

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

    2016-08-31

    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 10(5) CFU (colony forming unit) antigen-interacting phages were isolated with ~100% specificity from a phage library containing 3 × 10(9) 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.

  10. 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.

  11. 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

  12. The dynamics of ligands binding to proteins

    NASA Astrophysics Data System (ADS)

    Callender, Robert

    2001-03-01

    The static structures of many proteins have been solved, and this has revealed much about how they function. On the other hand, although the importance of atomic motion to how proteins function has been conjectured for several decades, the characterization of protein dynamics on multiple time scales is scant. This is because of severe experimental and theoretical difficulties, particularly characterizing the nanosecond to millisecond time scales. Recently, several new techniques have been introduced that make it possible to initiate chemical reactions on fast time scales. We have applied advanced laser induced temperature jump relaxation spectroscopy with nanosecond resolution to examine the binding kinetics of ligands to several enzymes. The observed kinetics take place over multiple time scales. The results reveal the dynamical nature of the binding process and show that there are substantial populations of many structures that are in a constant dynamic equilibrium in some cases. Some of these structures lie quite far from the static structure defined in crystallographic studies, which suggest that the conventional thermodynamical picture of binding (an equilibrium between ligand free in solution and bound) is far off the mark. Moreover, the results suggest that the dynamics can certainly play a crucial role in kinetic control of protein function as in, for example, affecting the rates of enzymatic catalysis. This work is a collaborative project with Hong Deng and Nick Zhadin, also at Albert Einstein. Work supported by the NSF and NIH.

  13. Assisted assignment of ligands corresponding to unknown electron density.

    SciTech Connect

    Binkowski, T. A.; Cuff, M.; Nocek, B.; Chang, C.; Joachimiak, A.; Biosciences Division

    2010-01-03

    A semi-automated computational procedure to assist in the identification of bound ligands from unknown electron density has been developed. The atomic surface surrounding the density blob is compared to a library of three-dimensional ligand binding surfaces extracted from the Protein Data Bank (PDB). Ligands corresponding to surfaces which share physicochemical texture and geometric shape similarities are considered for assignment. The method is benchmarked against a set of well represented ligands from the PDB, in which we show that we can identify the correct ligand based on the corresponding binding surface. Finally, we apply the method during model building and refinement stages from structural genomics targets in which unknown density blobs were discovered. A semi-automated computational method is described which aims to assist crystallographers with assigning the identity of a ligand corresponding to unknown electron density. Using shape and physicochemical similarity assessments between the protein surface surrounding the density and a database of known ligand binding surfaces, a plausible list of candidate ligands are identified for consideration. The method is validated against highly observed ligands from the Protein Data Bank and results are shown from its use in a high-throughput structural genomics pipeline.

  14. Melanoma cell galectin-1 ligands functionally correlate with malignant potential*

    PubMed Central

    Yazawa, Erika M.; Geddes-Sweeney, Jenna E.; Cedeno-Laurent, Filiberto; Walley, Kempland C.; Barthel, Steven R.; Opperman, Matthew J.; Liang, Jennifer; Lin, Jennifer Y.; Schatton, Tobias; Laga, Alvaro C.; Mihm, Martin C.; Qureshi, Abrar A.; Widlund, Hans R.; Murphy, George F.; Dimitroff, Charles J.

    2015-01-01

    Galectin-1 (Gal-1)-binding to Gal-1 ligands on immune and endothelial cells can influence melanoma development through dampening anti-tumor immune responses and promoting angiogenesis. However, whether Gal-1 ligands are functionally expressed on melanoma cells to help control intrinsic malignant features remains poorly understood. Here, we analyzed expression, identity and function of Gal-1 ligands in melanoma progression. Immunofluorescent analysis of benign and malignant human melanocytic neoplasms revealed that Gal-1 ligands were abundant in severely-dysplastic nevi as well as in primary and metastatic melanomas. Biochemical assessments indicated that melanoma cell adhesion molecule (MCAM) was a major Gal-1 ligand on melanoma cells that was largely dependent on its N-glycans. Other melanoma cell Gal-1 ligand activity conferred by O-glycans was negatively regulated by α2,6 sialyltransferase ST6GalNAc2. In Gal-1-deficient mice, MCAM-silenced (MCAMKD) or ST6GalNAc2-overexpressing (ST6O/E) melanoma cells exhibited slower growth rates, underscoring a key role for melanoma cell Gal-1 ligands and host Gal-1 in melanoma growth. Further analysis of MCAMKD or ST6O/E melanoma cells in cell migration assays indicated that Gal-1 ligand-dependent melanoma cell migration was severely inhibited. These findings provide a refined perspective on Gal-1 – melanoma cell Gal-1 ligand interactions as contributors to melanoma malignancy. PMID:25756799

  15. Characterisation of iron binding ligands in seawater by reverse titration.

    PubMed

    Hawkes, Jeffrey A; Gledhill, Martha; Connelly, Douglas P; Achterberg, Eric P

    2013-03-01

    Here we demonstrate the use of reverse titration - competitive ligand exchange-adsorptive cathodic stripping voltammetry (RT-CLE-ACSV) for the analysis of iron (Fe) binding ligands in seawater. In contrast to the forward titration, which examines excess ligands in solution, RT-CLE-ACSV examines the existing Fe-ligand complexes by increasing the concentration of added (electroactive) ligand (1-nitroso-2-naphthol) and analysis of the proportion of Fe bound to the added ligand. The data manipulation allows the accurate characterisation of ligands at equal or lower concentrations than Fe in seawater, and disregards electrochemically inert dissolved Fe such as some colloidal phases. The method is thus superior to the forward titration in environments with high Fe and low ligand concentrations or high concentrations of inert Fe. We validated the technique using the siderophore ligand ferrioxamine B, and observed a stability constant [Formula: see text] of 0.74-4.37×10(21) mol(-1), in agreement with previous results. We also successfully analysed samples from coastal waters and a deep ocean hydrothermal plume. Samples from these environments could not be analysed with confidence using the forward titration, highlighting the effectiveness of the RT-CLE-ACSV technique in waters with high concentrations of inert Fe.

  16. 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.

  17. 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.

  18. 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. PMID:24834870

  19. Ligand Release Pathways Obtained with WExplore: Residence Times and Mechanisms.

    PubMed

    Dickson, Alex; Lotz, Samuel D

    2016-06-23

    The binding of ligands with their molecular receptors is of tremendous importance in biology. Although much emphasis has been placed on characterizing binding sites and bound poses that determine the binding thermodynamics, the pathway by which a ligand binds importantly determines the binding kinetics. The computational study of entire unbiased ligand binding and release pathways is still an emerging field, made possible only recently by advances in computational hardware and sampling methodologies. We have developed one such method (WExplore) that is based on a weighted ensemble of trajectories, which we apply to ligand release for the first time, using a set of three previously characterized interactions between low-affinity ligands and the protein FKBP-12 (FK-506 binding protein). WExplore is found to be more efficient that conventional sampling, even for the nanosecond-scale unbinding events observed here. From a nonequilibrium ensemble of unbinding trajectories, we obtain ligand residence times and release pathways without using biasing forces or a Markovian assumption of transitions between regions. We introduce a set of analysis tools for unbinding transition pathways, including using von Mises-Fisher distributions to model clouds of ligand exit points, which provide a quantitative proxy for ligand surface diffusion. Differences between the transition pathway ensembles of the three ligands are identified and discussed.

  20. The Dynamics of Ligand Barrier Crossing Inside the Acetylcholinesterase Gorge

    SciTech Connect

    Bui, Jennifer M.; Henchman, Richard H.; Mccammon, Andy

    2003-10-01

    The dynamics of ligand movement through the constricted region of the acetylcholinesterase gorge is important in understanding how the ligand gains access to and is released from the active site of the enzyme. Molecular dynamics simulations of the simple ligand, tetramethylammonium, crossing this bottleneck region are conducted using umbrella potential sampling and activated .ux techniques. The low potential of mean force obtained is consistent with the fast reaction rate of acetylcholinesterase observed experimentally. From the results of the activated dynamics simulations, local conformational .uctuations of the gorge residues and larger scale collective motions of the protein are found to correlate highly with the ligand crossing.

  1. 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

  2. Ligand Release Pathways Obtained with WExplore: Residence Times and Mechanisms.

    PubMed

    Dickson, Alex; Lotz, Samuel D

    2016-06-23

    The binding of ligands with their molecular receptors is of tremendous importance in biology. Although much emphasis has been placed on characterizing binding sites and bound poses that determine the binding thermodynamics, the pathway by which a ligand binds importantly determines the binding kinetics. The computational study of entire unbiased ligand binding and release pathways is still an emerging field, made possible only recently by advances in computational hardware and sampling methodologies. We have developed one such method (WExplore) that is based on a weighted ensemble of trajectories, which we apply to ligand release for the first time, using a set of three previously characterized interactions between low-affinity ligands and the protein FKBP-12 (FK-506 binding protein). WExplore is found to be more efficient that conventional sampling, even for the nanosecond-scale unbinding events observed here. From a nonequilibrium ensemble of unbinding trajectories, we obtain ligand residence times and release pathways without using biasing forces or a Markovian assumption of transitions between regions. We introduce a set of analysis tools for unbinding transition pathways, including using von Mises-Fisher distributions to model clouds of ligand exit points, which provide a quantitative proxy for ligand surface diffusion. Differences between the transition pathway ensembles of the three ligands are identified and discussed. PMID:27231969

  3. Riboswitch structure: an internal residue mimicking the purine ligand

    PubMed Central

    Delfosse, Vanessa; Bouchard, Patricia; Bonneau, Eric; Dagenais, Pierre; Lemay, Jean-François; Lafontaine, Daniel A.; Legault, Pascale

    2010-01-01

    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. PMID:20022916

  4. Multivalent Ligand-Receptor Binding on Supported Lipid Bilayers

    PubMed Central

    Jung, Hyunsook; Robison, Aaron D.; Cremer, Paul S.

    2009-01-01

    Fluid supported lipid bilayers provide an excellent platform for studying multivalent protein-ligand interactions because the two-dimensional fluidity of the membrane allows for lateral rearrangement of ligands in order to optimize binding. Our laboratory has combined supported lipid bilayer-coated microfluidic platforms with total internal reflection fluorescence microscopy (TIRFM) to obtain equilibrium dissociation constant (KD) data for these systems. This high throughput, on-chip approach provides highly accurate thermodynamic information about multivalent binding events while requiring only very small sample volumes. Herein, we review some of the most salient findings from these studies. In particular, increasing ligand density on the membrane surface can provide a modest enhancement or attenuation of ligand-receptor binding depending upon whether the surface ligands interact strongly with each other. Such effects, however, lead to little more than one order of magnitude change in the apparent KD values. On the other hand, the lipophilicity and presentation of lipid bilayer-conjugated ligands can have a much greater impact. Indeed, changing the way a particular ligand is conjugated to the membrane can alter the apparent KD value by at least three orders of magnitude. Such a result speaks strongly to the role of ligand availability for multivalent ligand-receptor binding. PMID:19508894

  5. 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.

  6. 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.

  7. [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.

  8. 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. PMID:27408925

  9. 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

    2016-09-01

    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. PMID:27548713

  10. Tetraspecific ligand for tumor-targeted delivery of nanomaterials.

    PubMed

    Kim, Dongwook; Friedman, Adam D; Liu, Rihe

    2014-07-01

    The polygenetic nature of most cancers emphasizes the necessity of cancer therapies that target multiple essential signaling pathways. However, there is a significant paucity of targeting ligands with multi-specificities for targeted delivery of biomaterials. To address this unmet need, we generated a tetraspecific targeting ligand that recognizes four different cancer biomarkers, including VEGFR2, αvβ3 integrin, EGFR, and HER2 receptors, which have been implicated in numerous malignant tumors. The tetraspecific targeting ligand was constructed by sequentially connecting four targeting ligand subunits via flexible linkers, yielding a fusion protein that can be highly expressed in Escherichia coli and readily purified to near homogeneity. Surface Plasmon Resonance (SPR), Bio-Layer Interferometry (BLI) studies and extensive cellular binding analyses indicated that all the targeting ligand subunits in the tetraspecific fusion protein recognized their target receptors proximately to the corresponding monospecific ligands. The resulting tetraspecific targeting ligand was applied for the delivery of nanomaterials such as gold nanoparticles (AuNPs) for targeted hyperthermic killing of various cancer cell lines with biomarkers of interest expressed. We demonstrate that the tetraspecific ligand can be facilely introduced on the surface of AuNPs and efficient target-dependent killing of cancer cells can be achieved only when the AuNPs are conjugated with the tetraspecific ligand. Significantly, the tetraspecific ligand simultaneously interacts with more than one receptors, such as EGFR and HER2 receptors, when they are expressed on the surface of the same cell, as demonstrated by in vitro binding assays and cell binding analyses. Our results demonstrate that the tetraspecific ligand, through multivalency and synergistic binding, can be readily used to generate various 'smart' biomaterials with greatly broadened tumor targeting range for simultaneous targeting of multiple

  11. Tetraspecific Ligand for Tumor-Targeted Delivery of Nanomaterials

    PubMed Central

    Kim, Dongwook; Friedman, Adam D.; Liu, Rihe

    2014-01-01

    The polygenetic nature of most cancers emphasizes the necessity of cancer therapies that target multiple essential signaling pathways. However, there is a significant paucity of targeting ligands with multi-specificities for targeted delivery of biomaterials. To address this unmet need, we generated a tetraspecific targeting ligand that recognizes four different cancer biomarkers, including VEGFR2, αvβ3 integrin, EGFR, and HER2 receptors, which have been implicated in numerous malignant tumors. The tetraspecific targeting ligand was constructed by sequentially connecting four targeting ligand subunits via flexible linkers, yielding a fusion protein that can be highly expressed in E. coli and readily purified to near homogeneity. Surface Plasmon Resonance (SPR), Bio-Layer Interferometry (BLI) studies and extensive cellular binding analyses indicated that all the targeting ligand subunits in the tetraspecific fusion protein recognized their target receptors proximately to the corresponding monospecific ligands. The resulting tetraspecific targeting ligand was applied for the delivery of nanomaterials such as gold nanoparticles (AuNPs) for targeted hyperthermic killing of various cancer cell lines with biomarkers of interest expressed. We demonstrate that the tetraspecific ligand can be facilely introduced on the surface of AuNPs and efficient target-dependent killing of cancer cells can be achieved only when the AuNPs are conjugated with the tetraspecific ligand. Significantly, the tetraspecific ligand simultaneously interacts with more than one receptors, such as EGFR and HER2 receptors, when they are expressed on the surface of the same cell, as demonstrated by in vitro binding assays and cell binding analyses. Our results demonstrate that the tetraspecific ligand, through multivalency and synergistic binding, can be readily used to generate various ‘smart’ biomaterials with greatly broadened tumor targeting range for simultaneous targeting of multiple

  12. Functional metal-organic frameworks via ligand doping: influences of ligand charge and steric demand.

    PubMed

    Wang, Cheng; Liu, Demin; Xie, Zhigang; Lin, Wenbin

    2014-02-01

    Doping a functional ligand into a known crystalline system built from ligands of similar shape and length provides a powerful strategy to construct functional metal-organic frameworks (MOFs) with desired functionality and structural topology. This mix-and-match approach mimics the widely applied metal ion doping (or solid solution formation) in traditional inorganic materials, such as metal oxides, wherein maintaining charge balance of the doped lattice and ensuring size match between doped metal ions and the parent lattice are key to successful doping. In this work, we prepared three sterically demanding dicarboxylate ligands based on Ir/Ru-phosphors with similar structures and variable charges (-2 to 0), [Ir(ppy)3]-dicarboxylate (L1, ppy is 2-phenylpyridine), [Ir(bpy)(ppy)2](+)-dicarboxylate (L2, bpy is 2,2'-bipyridine), and Ru(bpy)3](2+)-dicarboxylate (L3), and successfully doped them into the known IRMOF-9/-10 structures by taking advantage of matching length between 4,4'-biphenyl dicarboxylate (BPDC) and L1-L3. We systematically investigated the effects of size and charge of the doping ligand on the MOF structures and the ligand doping levels in these MOFs. L1 carries a -2 charge to satisfy the charge requirement of the parent Zn4O(BPDC)3 framework and can be mixed into the IRMOF-9/-10 structure in the whole range of H2L1/H2BPDC ratios from 0 to 1. The steric bulk of L1 induces a phase transition from the interpenetrated IRMOF-9 structure to the non-interpenetrated IRMOF-10 counterpart. L2 and L3 do not match the dinegative charge of BPDC in order to maintain the charge balance for a neutral IRMOF-9/-10 framework and can only be doped into the IRMOF-9 structure to a certain degree. L2 and L3 form a charge-balanced new phase with a neutral framework structure at higher doping levels (>8% For L2 and >6% For L3). This systematic investigation reveals the influences of steric demand and charge balance on ligand doping in MOFs, a phenomenon that has been well

  13. Structure of human PNP complexed with ligands.

    PubMed

    Canduri, Fernanda; Silva, Rafael Guimarães; dos Santos, Denis Marangoni; Palma, Mário Sérgio; Basso, Luiz Augusto; Santos, Diógenes Santiago; de Azevedo, Walter Filgueira

    2005-07-01

    Purine nucleoside phosphorylase (PNP) is a key enzyme in the purine-salvage pathway, which allows cells to utilize preformed bases and nucleosides in order to synthesize nucleotides. PNP is specific for purine nucleosides in the beta-configuration and exhibits a strong preference for purines containing a 6-keto group and ribosyl-containing nucleosides relative to the corresponding analogues. PNP was crystallized in complex with ligands and data collection was performed using synchrotron radiation. This work reports the structure of human PNP in complex with guanosine (at 2.80 A resolution), 3'-deoxyguanosine (at 2.86 A resolution) and 8-azaguanine (at 2.85 A resolution). These structures were compared with the PNP-guanine, PNP-inosine and PNP-immucillin-H complexes solved previously.

  14. 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.

  15. Ligand-directed trafficking of receptor stimulus.

    PubMed

    Chilmonczyk, Zdzisław; Bojarski, Andrzej J; Sylte, Ingebrigt

    2014-12-01

    GPCRs are seven transmembrane-spanning receptors that convey specific extracellular stimuli to intracellular signalling. They represent the largest family of cell surface proteins that are therapeutically targeted. According to the traditional two-state model of receptor theory, GPCRs were considered as operating in equilibrium between two functional conformations, an active (R*) and inactive (R) state. Thus, it was assumed that a GPCR can exist either in an "off" or "on" conformation causing either no activation or equal activation of all its signalling pathways. Over the past several years it has become evident that this model is too simple and that GPCR signalling is far more complex. Different studies have presented a multistate model of receptor activation in which ligand-specific receptor conformations are able to differentiate between distinct signalling partners. Recent data show that beside G proteins numerous other proteins, such as β-arrestins and kinases, may interact with GPCRs and activate intracellular signalling pathways. GPCR activation may therefore involve receptor desensitization, coupling to multiple G proteins, Gα or Gβγ signalling, and pathway activation that is independent of G proteins. This latter effect leads to agonist "functional selectivity" (also called ligand-directed receptor trafficking, stimulus trafficking, biased agonism, biased signalling), and agonist intervention with functional selectivity may improve the therapy. Many commercially available drugs with beneficial efficacy also show various undesirable side effects. Further studies of biased signalling might facilitate our understanding of the side effects of current drugs and take us to new avenues to efficiently design pathway-specific medications.

  16. 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.

  17. Designing Ligand-Enhanced Optical Absorption of Thiolated Gold Nanoclusters

    SciTech Connect

    Sementa, Luca; Barcaro, Giovanni; Dass, Amala; Stener, Mauro; Fortunelli, Alessandro

    2015-05-07

    The optical spectra of thiolated Au25(SR)18/Au23(SR)16 clusters with different R residues are investigated via TDDFT simulations. Significant enhancements in the optical region and effective electron delocalization are simultaneously achieved by tuning the ligands' steric hindrance and electronic conjugating features, producing a resonance phenomenon between the Au–S core motif and the ligand fragments.

  18. 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.

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

    PubMed

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

    2016-09-01

    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

  20. 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

  1. 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.

  2. Fluorescent ligands to investigate GPCR binding properties and oligomerization.

    PubMed

    Cottet, Martin; Faklaris, Orestis; Falco, Amadine; Trinquet, Eric; Pin, Jean-Philippe; Mouillac, Bernard; Durroux, Thierry

    2013-02-01

    Fluorescent ligands for GPCRs (G-protein-coupled receptors) have been synthesized for a long time but their use was usually restricted to receptor localization in the cell by fluorescent imaging microscopy. During the last two decades, the emergence of new fluorescence-based strategies and the concomitant development of fluorescent measurement apparatus have dramatically widened the use of fluorescent ligands. Among the various strategies, TR (time-resolved)-FRET (fluorescence resonance energy transfer) approaches exhibit an interesting potential to study GPCR interactions with various partners. We have derived various sets of ligands that target different GPCRs with fluorophores, which are compatible with TR-FRET strategies. Fluorescent ligands labelled either with a fluorescent donor (such as europium or terbium cryptate) or with a fluorescent acceptor (such as fluorescein, dy647 or Alexa Fluor® 647), for example, kept high affinities for their cognate receptors. These ligands turn out to be interesting tools to develop FRET-based binding assays. We also used these fluorescent ligands to analyse GPCR oligomerization by measuring FRET between ligands bound to receptor dimers. In contrast with FRET strategies, on the basis of receptor labelling, the ligand-based approach we developed is fully compatible with the study of wild-type receptors and therefore with receptors expressed in native tissues. Therefore, by using fluorescent analogues of oxytocin, we demonstrated the existence of oxytocin receptor dimers in the mammary gland of lactating rats.

  3. 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.

  4. New carbon- and sulfur-based ligands in catalysis.

    PubMed

    Dorta, Reto

    2011-01-01

    Homogeneous catalysis is a field of research that has gained central importance in both organic and inorganic chemistry and the use of well-defined ligand systems in the synthesis of transition metal complexes has had an enormous impact on the development of such catalysts. Neutral, two-electron donor ligands based on phosphorous and nitrogen have been tremendously successful as ancillary entities for late-transition metal (LTM) catalysts, whereas ligands based on anionic nitrogen, oxygen and the cyclopentadienyl motif (Cp(-)) have propelled early-transition metal (ETM) catalysis forward. We believe that expanding the ligand families capable of acting as successful entities in metal-mediated reactivity and catalysis is crucial for future discoveries in this field. Research in our group therefore tries to identify new non-chiral and chiral ligands for late-transition metal chemistry that are based on neutral, two-electron carbon and sulfur donor atoms. In particular, we have until now focused on the development of modular, monodentate N-heterocyclic carbene ligands (NHCs) that can serve as a basis for the development of chiral ligand frameworks for the application to asymmetric catalytic transformations. In the second major research project developed over the last six years, we have started an investigation on the use of chelating sulfoxide-based ligands in asymmetric late transition-metal based catalysis.

  5. Synthesis of 3-alkyl naphthalenes as novel estrogen receptor ligands

    SciTech Connect

    Fang, Jing; Akwabi-Ameyaw, Adwoa; Britton, Jonathan E.; Katamreddy, Subba R.; Navas III, Frank; Miller, Aaron B.; Williams, Shawn P.; Gray, David W.; Orband-Miller, Lisa A.; Shearin, Jean; Heyer, Dennis

    2009-06-24

    A series of estrogen receptor ligands based on a 3-alkyl naphthalene scaffold was synthesized using an intramolecular enolate-alkyne cycloaromatization as the key step. Several of these compounds bearing a C6-OH group were shown to be high affinity ligands. All compounds had similar ER{alpha} and ER{beta} binding affinity ranging from micromolar to low nanomolar.

  6. Polypharmacology: in silico methods of ligand design and development.

    PubMed

    McKie, Samuel A

    2016-04-01

    How to design a ligand to bind multiple targets, rather than to a single target, is the focus of this review. Rational polypharmacology draws on knowledge that is both broad ranging and hierarchical. Computer-aided multitarget ligand design methods are described according to their nested knowledge level. Ligand-only and then receptor-ligand strategies are first described; followed by the metabolic network viewpoint. Subsequently strategies that view infectious diseases as multigenomic targets are discussed, and finally the disease level interpretation of medicinal therapy is considered. As yet there is no consensus on how best to proceed in designing a multitarget ligand. The current methodologies are bought together in an attempt to give a practical overview of how polypharmacology design might be best initiated. PMID:27105127

  7. Automated identification of crystallographic ligands using sparse-density representations

    SciTech Connect

    Carolan, C. G.; Lamzin, V. S.

    2014-07-01

    A novel procedure for identifying ligands in macromolecular crystallographic electron-density maps is introduced. Density clusters in such maps can be rapidly attributed to one of 82 different ligands in an automated manner. 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.

  8. Affinity screening using competitive binding with fluorine-19 hyperpolarized ligands.

    PubMed

    Kim, Yaewon; Hilty, Christian

    2015-04-13

    Fluorine-19 NMR and hyperpolarization form a powerful combination for drug screening. Under a competitive equilibrium with a selected fluorinated reporter ligand, the dissociation constant (K(D)) of other ligands of interest is measurable using a single-scan Carr-Purcell-Meiboom-Gill (CPMG) experiment, without the need for a titration. This method is demonstrated by characterizing the binding of three ligands with different affinities for the serine protease trypsin. Monte Carlo simulations show that the highest accuracy is obtained when about one-half of the bound reporter ligand is displaced in the binding competition. Such conditions can be achieved over a wide range of affinities, allowing for rapid screening of non-fluorinated compounds when a single fluorinated ligand for the binding pocket of interest is known.

  9. 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.

  10. Polypharmacology: in silico methods of ligand design and development.

    PubMed

    McKie, Samuel A

    2016-04-01

    How to design a ligand to bind multiple targets, rather than to a single target, is the focus of this review. Rational polypharmacology draws on knowledge that is both broad ranging and hierarchical. Computer-aided multitarget ligand design methods are described according to their nested knowledge level. Ligand-only and then receptor-ligand strategies are first described; followed by the metabolic network viewpoint. Subsequently strategies that view infectious diseases as multigenomic targets are discussed, and finally the disease level interpretation of medicinal therapy is considered. As yet there is no consensus on how best to proceed in designing a multitarget ligand. The current methodologies are bought together in an attempt to give a practical overview of how polypharmacology design might be best initiated.

  11. Dynamic control of chirality in phosphine ligands for enantioselective catalysis

    PubMed Central

    Zhao, Depeng; Neubauer, Thomas M.; Feringa, Ben L.

    2015-01-01

    Chirality plays a fundamental role in biology and chemistry and the precise control of chirality in a catalytic conversion is a key to modern synthesis most prominently seen in the production of pharmaceuticals. In enantioselective metal-based catalysis, access to each product enantiomer is commonly achieved through ligand design with chiral bisphosphines being widely applied as privileged ligands. Switchable phosphine ligands, in which chirality is modulated through an external trigger signal, might offer attractive possibilities to change enantioselectivity in a catalytic process in a non-invasive manner avoiding renewed ligand synthesis. Here we demonstrate that a photoswitchable chiral bisphosphine based on a unidirectional light-driven molecular motor, can be used to invert the stereoselectivity of a palladium-catalysed asymmetric transformation. It is shown that light-induced changes in geometry and helicity of the switchable ligand enable excellent selectivity towards the racemic or individual enantiomers of the product in a Pd-catalysed desymmetrization reaction. PMID:25806856

  12. In vivo screening of ligand-dependent hammerhead ribozymes.

    PubMed

    Saragliadis, Athanasios; Klauser, Benedikt; Hartig, Jörg S

    2012-01-01

    The development of artificial switches of gene expression is of high importance for future applications in biotechnology and synthetic biology. We have developed a powerful RNA-based system which allows for the ligand-dependent and reprogrammable control of gene expression in Escherichia coli. Our system makes use of the hammerhead ribozyme (HHR) which acts as molecular scaffold for the sequestration of the ribosome binding site (RBS), mimicking expression platforms in naturally occurring riboswitches. Aptamer domains can be attached to the ribozyme as exchangeable ligand-sensing modules. Addition of ligands to the bacterial growth medium changes the activity of the ligand-dependent self-cleaving ribozyme which in turn switches gene expression. In this chapter, we describe the in vivo screening procedure allowing for reprogramming the ligand-specificity of our system. PMID:22315086

  13. Detection and Identification of Ligands for Mammalian RPTP Extracellular Domains.

    PubMed

    Stoker, Andrew William

    2016-01-01

    Receptor protein tyrosine phosphatases (RPTPs) form a group of over 20 enzymes in vertebrates, each with unique ectodomains subject to potential extracellular interactions with ligands. It has recently become clear that a remarkably diverse range of ligands exist, including homophilic binders, adhesion molecules, neurotrophin receptors, and proteoglycans. Individual RPTPs can bind several ligands, and vice versa, suggesting that complex cell signaling networks exist. The identification of RPTP ligands and where they are located in tissues remains a challenge for a large number of these enzymes. Here we describe some powerful methods that have proved successful for several research groups, leading to our improved understanding of RPTP-ligand interactions and functional regulation. PMID:27514811

  14. Ligand-ligand charge-transfer excited states of Os(II) complexes

    SciTech Connect

    Perkins, T.A.; Schanze, K.S. ); Pourreau, D.B.; Netzel, T.L. )

    1989-06-01

    This paper examines the photophysics of metal-to-ligand charge-transfer (MLCT) and ligand-to-ligand charge-transfer (LLCT) excited states in a series of ((bpy){sub 2}Os{sup II}(CO)L){sup 2+} (Os-L) complexes. For each of the complexes studied, the d{pi}(Os) {yields} {pi}*(bpy) absorption band is the lowest energy transition that is apparent. For L = pyridine and benzonitrile, only long-lived, highly luminescent MLCT states are observed. However, when L = an electron-donor aminobenzonitrile (ABN) species (DMABN, TMABN, or CMI; see text), MLCT emission is quenched and in < 30 ps LLCT excited states are formed, *((bpy{sup {sm bullet}{minus}})-(bpy)OS{sup II}(CO)ABN{sup {sm bullet}+}){sup 2+}. The observed, weight-average radiationless decays of the LLCT excited states in acetonitrile and dichloromethane follow the squence Os-DMABN < Os-TMABN < Os-CMI in each solvent, and the calculated energies of the LLCT states for these complexes are in inverse order to the decay rates as expected if an energy gap law is followed. Finally, multiexponential relaxations of the LLCT states are pronounced in the nonpolar solvent dichloromethane. The dependence of these relaxations on the concentration of added electrolyte suggests that they may be due to ion-pair structure and dynamics.

  15. Sulfa drugs: thermodynamic proton-ligand and metal-ligand stability constants.

    PubMed

    Agrawal, Y K; Giridhar, R; Menon, S K

    1987-12-01

    The thermodynamic proton-ligand stability constants of sulfa drugs have been determined in different mole fractions of dioxane (0.083-0.174) at 25 and 35 +/- 0.1 degrees C. Empirical corrections to pH meter readings in mixed aqueous media have been applied. The pKa varies linearly with the mole fraction of dioxane. Numerical equations expressing this linear relationship have been obtained using the method of least squares, and relevant correlation coefficients have been calculated. The thermodynamic parameters delta G degrees, delta H degrees, and delta S degrees are calculated. The effect of solvent and the change in free energy from mixed aqueous media, delta, is discussed. The thermodynamic metal-ligand stability constants of Cu(II), Pd(II), and Ce(IV) with sulfa drugs in 50% aqueous dioxane at 35 +/- 0.1 degrees C have been determined. The effect of basicity of the ligand and the order of the stability constant is discussed.

  16. Identifying ligand-specific signalling within biased responses: focus on δ opioid receptor ligands

    PubMed Central

    Charfi, I; Audet, N; Bagheri Tudashki, H; Pineyro, G

    2015-01-01

    Opioids activate GPCRs to produce powerful analgesic actions but at the same time induce side effects and generate tolerance, which restrict their clinical use. Reducing this undesired response profile has remained a major goal of opioid research and the notion of ‘biased agonism’ is raising increasing interest as a means of separating therapeutic responses from unwanted side effects. However, to fully exploit this opportunity, it is necessary to confidently identify biased signals and evaluate which type of bias may support analgesia and which may lead to undesired effects. The development of new computational tools has made it possible to quantify ligand-dependent signalling and discriminate this component from confounders that may also yield biased responses. Here, we analyse different approaches to identify and quantify ligand-dependent bias and review different types of confounders. Focus is on δ opioid receptor ligands, which are currently viewed as promising agents for chronic pain management. LINKED ARTICLES This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2 PMID:24665881

  17. Ligand-size and ligand-chain hydrophilicity effects on the relaxometric properties of ultrasmall Gd2O3 nanoparticles

    NASA Astrophysics Data System (ADS)

    Tegafaw, Tirusew; Xu, Wenlong; Lee, Sang Hyup; Chae, Kwon Seok; Cha, Hyunsil; Chang, Yongmin; Lee, Gang Ho

    2016-06-01

    The relaxometric properties of ultrasmall Gd2O3 nanoparticles coated with various ligands were investigated. These ligands include small diacids with hydrophobic chains, namely, succinic acid (Mw = 118.09 amu), glutaric acid (Mw = 132.12 amu), and terephthalic acid (Mw = 166.13 amu), and large polyethylenimines (PEIs) with hydrophilic chains, namely, PEI-1300 ( M ¯ n = 1300 ) and PEI-10000 ( M ¯ n = 10000 ). Ligand-size and ligand-chain hydrophilicity effects were observed. The longitudinal (r1) and transverse (r2) water proton relaxivities generally decreased with increasing ligand-size (the ligand-size effect). The ligand-size effect was weaker for PEI because its hydrophilic chains allow water molecules to access the nanoparticle (the ligand-chain hydrophilicity effect). This result was explained on the basis of the magnetic dipole interaction between the dipoles of the nanoparticle and water proton. In addition, all samples were found to be non-toxic in cellular cytotoxicity tests.

  18. Developing Ligands for Palladium(II)-Catalyzed C–H Functionalization: Intimate Dialogue between Ligand and Substrate

    PubMed Central

    Engle, Keary M.; Yu, Jin-Quan

    2013-01-01

    Homogeneous transition metal–catalyzed reactions are indispensable to all facets of modern chemical synthesis. It is thus difficult to imagine that for much of the early 20th century, the reactivity and selectivity of all known homogeneous metal catalysts paled in comparison to their heterogeneous and biological counterparts. In the intervening decades, advances in ligand design bridged this divide, such that today some of the most demanding bond-forming events are mediated by ligand-supported homogeneous metal species. While ligand design has propelled many areas of homogeneous catalysis, in the field of Pd(II)-catalyzed C–H functionalization, suitable ligand scaffolds are lacking, which has hampered the development of broadly practical transformations based on C–H functionalization logic. In this review, we offer an account of our research employing three ligand scaffolds, mono-N-protected amino acids, 2,6-disubstituted pyridines, and 2,2′-bipyridines, to address challenges posed by several synthetically versatile substrate classes. Drawing on this work, we discuss principles of ligand design, such as the need to match a ligand to a particular substrate class, and how ligand traits such as tunability and modularity can be advantageous in reaction discovery. PMID:23565982

  19. Prediction of ligand-binding sites of proteins by molecular docking calculation for a random ligand library.

    PubMed

    Fukunishi, Yoshifumi; Nakamura, Haruki

    2011-01-01

    A new approach to predicting the ligand-binding sites of proteins was developed, using protein-ligand docking computation. In this method, many compounds in a random library are docked onto the whole protein surface. We assumed that the true ligand-binding site would exhibit stronger affinity to the compounds in the random library than the other sites, even if the random library did not include the ligand corresponding to the true binding site. We also assumed that the affinity of the true ligand-binding site would be correlated to the docking scores of the compounds in the random library, if the ligand-binding site was correctly predicted. We call this method the molecular-docking binding-site finding (MolSite) method. The MolSite method was applied to 89 known protein-ligand complex structures extracted from the Protein Data Bank, and it predicted the correct binding sites with about 80-99% accuracy, when only the single top-ranked site was adopted. In addition, the average docking score was weakly correlated to the experimental protein-ligand binding free energy, with a correlation coefficient of 0.44.

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

    SciTech Connect

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

    2010-10-01

    Structures of the Grb2 SH2 domain complexed with a series of flexible and constrained replacements of the phosphotyrosine residue in tripeptides derived from Ac-pYXN (where X = V, I, E and Q) were compared to determine what, if any, structural differences arise as a result of ligand preorganization. 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-NH{sub 2} (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

  1. 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.

  2. Scoring ligand similarity in structure-based virtual screening.

    PubMed

    Zavodszky, Maria I; Rohatgi, Anjali; Van Voorst, Jeffrey R; Yan, Honggao; Kuhn, Leslie A

    2009-01-01

    Scoring to identify high-affinity compounds remains a challenge in virtual screening. On one hand, protein-ligand scoring focuses on weighting favorable and unfavorable interactions between the two molecules. Ligand-based scoring, on the other hand, focuses on how well the shape and chemistry of each ligand candidate overlay on a three-dimensional reference ligand. Our hypothesis is that a hybrid approach, using ligand-based scoring to rank dockings selected by protein-ligand scoring, can ensure that high-ranking molecules mimic the shape and chemistry of a known ligand while also complementing the binding site. Results from applying this approach to screen nearly 70 000 National Cancer Institute (NCI) compounds for thrombin inhibitors tend to support the hypothesis. EON ligand-based ranking of docked molecules yielded the majority (4/5) of newly discovered, low to mid-micromolar inhibitors from a panel of 27 assayed compounds, whereas ranking docked compounds by protein-ligand scoring alone resulted in one new inhibitor. Since the results depend on the choice of scoring function, an analysis of properties was performed on the top-scoring docked compounds according to five different protein-ligand scoring functions, plus EON scoring using three different reference compounds. The results indicate that the choice of scoring function, even among scoring functions measuring the same types of interactions, can have an unexpectedly large effect on which compounds are chosen from screening. Furthermore, there was almost no overlap between the top-scoring compounds from protein-ligand versus ligand-based scoring, indicating the two approaches provide complementary information. Matchprint analysis, a new addition to the SLIDE (Screening Ligands by Induced-fit Docking, Efficiently) screening toolset, facilitated comparison of docked molecules' interactions with those of known inhibitors. The majority of interactions conserved among top-scoring compounds for a given scoring

  3. 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.

  4. 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

  5. Ditopic boronic acid and imine-based naphthalimide fluorescence sensor for copper(II).

    PubMed

    Li, Meng; Ge, Haobo; Arrowsmith, Rory L; Mirabello, Vincenzo; Botchway, Stanley W; Zhu, Weihong; Pascu, Sofia I; James, Tony D

    2014-10-14

    Copper ions are essential for many biological processes. However, high concentrations of copper can be detrimental to the cell or organism. A novel naphthalimide derivative bearing a monoboronic acid group (BNP) was investigated as a Cu(2+) selective fluorescent sensor in living cells. This derivative is one of the rare examples of reversible fluorescent chemosensors for Cu(2+) which uses a boronic acid group for a binding site. Moreover, the adduct BNP-Cu(2+) displays a fluorescence enhancement with fructose. The uptake of this novel compound in HeLa cancer cells was imaged using confocal fluorescence microscopy techniques including two-photon fluorescence lifetime imaging microscopy. PMID:24919009

  6. VEGFR-2 conformational switch in response to ligand binding

    PubMed Central

    Sarabipour, Sarvenaz; Ballmer-Hofer, Kurt; Hristova, Kalina

    2016-01-01

    VEGFR-2 is the primary regulator of angiogenesis, the development of new blood vessels from pre-existing ones. VEGFR-2 has been hypothesized to be monomeric in the absence of bound ligand, and to undergo dimerization and activation only upon ligand binding. Using quantitative FRET and biochemical analysis, we show that VEGFR-2 forms dimers also in the absence of ligand when expressed at physiological levels, and that these dimers are phosphorylated. Ligand binding leads to a change in the TM domain conformation, resulting in increased kinase domain phosphorylation. Inter-receptor contacts within the extracellular and TM domains are critical for the establishment of the unliganded dimer structure, and for the transition to the ligand-bound active conformation. We further show that the pathogenic C482R VEGFR-2 mutant, linked to infantile hemangioma, promotes ligand-independent signaling by mimicking the structure of the ligand-bound wild-type VEGFR-2 dimer. DOI: http://dx.doi.org/10.7554/eLife.13876.001 PMID:27052508

  7. Exchange Kinetics of a Hydrophobic Ligand Binding Protein

    NASA Astrophysics Data System (ADS)

    Vaughn, Jeff; Stone, Martin

    2002-03-01

    Conformational fluctuations of proteins are thought to be important for determining the functional roles in biological activity. In some cases, the rates of these conformational changes may be directly correlated to, for example, the rates of catalysis or ligand binding. We are studying the role of conformational fluctuations in the binding of small volatile hydrophobic pheromones by the mouse major urinary proteins (MUPs). Communication among mice occurs, in part, with the MUP-1 protein. This urinary protein binds pheromones as a way to increase the longevity of the pheromone in an extracellular environment. Of interest is that the crystal structure of MUP-1 with a pheromone ligand shows the ligand to be completely occluded from the solvent with no obvious pathway to enter or exit. This suggests that conformational exchange of the protein may be required for ligand binding and release to occur. We hypothesize that the rate of conformational exchange may be a limiting factor determining the rate of ligand association and dissociation. By careful measurement of the on- and off-rates of ligand binding and the rates of conformational changes of the protein, a more defined picture of the interplay between protein structure and function can be obtained. To this end, heteronuclear saturation transfer, ^15N-exchange and ^15N dynamics experiments have been employed to probe the kinetics of ligand binding to MUP-1.

  8. Influence of Ancillary Ligands in Dye-Sensitized Solar Cells.

    PubMed

    Pashaei, Babak; Shahroosvand, Hashem; Graetzel, Michael; Nazeeruddin, Mohammad Khaja

    2016-08-24

    Dye-sensitized solar cells (DSSCs) have motivated many researchers to develop various sensitizers with tailored properties involving anchoring and ancillary ligands. Ancillary ligands carry favorable light-harvesting abilities and are therefore crucial in determining the overall power conversion efficiencies. The use of ancillary ligands having aliphatic chains and/or π-extended aromatic units decreases charge recombination and permits the collection of a large fraction of sunlight. This review aims to provide insight into the relationship between ancillary ligand structure and DSSC properties, which can further guide the function-oriented design and synthesis of different sensitizers for DSSCs. This review outlines how the new and rapidly expanding class of chelating ancillary ligands bearing 2,2'-bipyridyl, 1,10-phenanthroline, carbene, dipyridylamine, pyridyl-benzimidazole, pyridyl-azolate, and other aromatic ligands provides a conduit for potentially enhancing the performance and stability of DSSCs. Finally, these classes of Ru polypyridyl complexes have gained increasing interest for feasible large-scale commercialization of DSSCs due to their more favorable light-harvesting abilities and long-term thermal and chemical stabilities compared with other conventional sensitizers. Therefore, the main idea is to inspire readers to explore new avenues in the design of new sensitizers for DSSCs based on different ancillary ligands. PMID:27479482

  9. Identification of Soft Matter Binding Peptide Ligands Using Phage Display.

    PubMed

    Günay, Kemal Arda; Klok, Harm-Anton

    2015-10-21

    Phage display is a powerful tool for the selection of highly affine, short peptide ligands. While originally primarily used for the identification of ligands to proteins, the scope of this technique has significantly expanded over the past two decades. Phage display nowadays is also increasingly applied to identify ligands that selectively bind with high affinity to a broad range of other substrates including natural and biological polymers as well as a variety of low-molecular-weight organic molecules. Such peptides are of interest for various reasons. The ability to selectively and with high affinity bind to the substrate of interest allows the conjugation or immobilization of, e.g., nanoparticles or biomolecules, or generally, facilitates interactions at materials interfaces. On the other hand, presentation of peptide ligands that selectively bind to low-molecular-weight organic materials is of interest for the development of sensor surfaces. The aim of this article is to highlight the opportunities provided by phage display for the identification of peptide ligands that bind to synthetic or natural polymer substrates or to small organic molecules. The article will first provide an overview of the different peptide ligands that have been identified by phage display that bind to these "soft matter" targets. The second part of the article will discuss the different characterization techniques that allow the determination of the affinity of the identified ligands to the respective substrates. PMID:26275106

  10. Characterization of methacrylate chromatographic monoliths bearing affinity ligands.

    PubMed

    Černigoj, Urh; Vidic, Urška; Nemec, Blaž; Gašperšič, Jernej; Vidič, Jana; Lendero Krajnc, Nika; Štrancar, Aleš; Podgornik, Aleš

    2016-09-16

    We investigated effect of immobilization procedure and monolith structure on chromatographic performance of methacrylate monoliths bearing affinity ligands. Monoliths of different pore size and various affinity ligands were prepared and characterized using physical and chromatographic methods. When testing protein A monoliths with different protein A ligand densities, a significant nonlinear effect of ligand density on dynamic binding capacity (DBC) for IgG was obtained and accurately described by Langmuir isotherm curve enabling estimation of protein A utilization as a function of ligand density. Maximal IgG binding capacity was found to be at least 12mg/mL exceeding theoretical monolayer adsorption value of 7.8mg/mL assuming hexagonal packing and IgG hydrodynamic diameter of 11nm. Observed discrepancy was explained by shrinkage of IgG during adsorption on protein A experimentally determined through calculated adsorbed IgG layer thickness of 5.4nm from pressure drop data. For monoliths with different pore size maximal immobilized densities of protein A as well as IgG dynamic capacity linearly correlates with monolith surface area indicating constant ligand utilization. Finally, IgGs toward different plasma proteins were immobilized via the hydrazide coupling chemistry to provide oriented immobilization. DBC was found to be flow independent and was increasing with the size of bound protein. Despite DBC was lower than IgG capacity to immobilized protein A, ligand utilization was higher. PMID:27554023

  11. 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

  12. 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

  13. Screening Ligands by X-ray crystallography.

    PubMed

    Davies, Douglas R

    2014-01-01

    X-ray crystallography is an invaluable technique in structure-based drug discovery, including fragment-based drug discovery, because it is the only technique that can provide a complete three dimensional readout of the interaction between the small molecule and its macromolecular target. X-ray diffraction (XRD) techniques can be employed as the sole method for conducting a screen of a fragment library, or it can be employed as the final technique in a screening campaign to confirm putative "hit" compounds identified by a variety of biochemical and/or biophysical screening techniques. Both approaches require an efficient technique to prepare dozens to hundreds of crystals for data collection, and a reproducible way to deliver ligands to the crystal. Here, a general method for screening cocktails of fragments is described. In cases where X-ray crystallography is employed as a method to verify putative hits, the cocktails of fragments described below would simply be replaced with single fragment solutions. PMID:24590727

  14. Ligand Affinities Estimated by Quantum Chemical Calculations.

    PubMed

    Söderhjelm, Pär; Kongsted, Jacob; Ryde, Ulf

    2010-05-11

    We present quantum chemical estimates of ligand-binding affinities performed, for the first time, at a level of theory for which there is a hope that dispersion and polarization effects are properly accounted for (MP2/cc-pVTZ) and at the same time effects of solvation, entropy, and sampling are included. We have studied the binding of seven biotin analogues to the avidin tetramer. The calculations have been performed by the recently developed PMISP approach (polarizable multipole interactions with supermolecular pairs), which treats electrostatic interactions by multipoles up to quadrupoles, induction by anisotropic polarizabilities, and nonclassical interactions (dispersion, exchange repulsion, etc.) by explicit quantum chemical calculations, using a fragmentation approach, except for long-range interactions that are treated by standard molecular-mechanics Lennard-Jones terms. In order to include effects of sampling, 10 snapshots from a molecular dynamics simulation are studied for each biotin analogue. Solvation energies are estimated by the polarized continuum model (PCM), coupled to the multipole-polarizability model. Entropy effects are estimated from vibrational frequencies, calculated at the molecular mechanics level. We encounter several problems, not previously discussed, illustrating that we are first to apply such a method. For example, the PCM model is, in the present implementation, questionable for large molecules, owing to the use of a surface definition that gives numerous small cavities in a protein. PMID:26615702

  15. Expression of Fas ligand in murine ovary.

    PubMed

    Guo, M W; Xu, J P; Mori, E; Sato, E; Saito, S; Mori, T

    1997-05-01

    Corresponding to the expression of Fas in the ovarian oocytes as previously reported (Guo et al., Biochem Biophys Res Commun 1994; 203:1438-1446; Mori et al., JSIR 1995; 9:49-50), the expression of Fas ligand (FasL) in the ovarian follicle was found to be restricted in the area of granulosa cells by the indirect immunofluorescence (IIF) test. Reverse transcriptase/polymerase chain reaction (RT/PCR) technique coupled with Southern blot hybridization analysis showed that the highest level of FasL mRNA was demonstrated in murine ovaries and granulosa cells 1 day after the administration of pregnant mare's serum gonadotropin (PMSG), while the level of FasL mRNA became very weak on the day 5, respectively. The observed gradual decrease in FasL mRNA could not be attributed to a generalized degradation of cellular RNA during atresia, as evidenced by the presence of constitutive expression of elongation factor 1 alpha (EF-1 alpha) mRNA in murine ovaries and granulosa cells treated with PMSG. Furthermore, in situ hybridization analysis with a FasL-specific probe confirmed that FasL was specifically localized in the granulosa cells of most follicles and its expression was regulated by PMSG administration. FasL localized in granulosa cells might possibly play an important role in the formation of the ovarian atretic follicles, most likely depending on PMSG administration. PMID:9196798

  16. 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

  17. Ligand-based identification of environmental estrogens

    SciTech Connect

    Waller, C.L.; Oprea, T.I.; Chae, K.

    1996-12-01

    Comparative molecular field analysis (CoMFA), a three-dimensional quantitative structure-activity relationship (3D-QSAR) paradigm, was used to examine the estrogen receptor (ER) binding affinities of a series of structurally diverse natural, synthetic, and environmental chemicals of interest. The CoMFA/3D-QSAR model is statistically robust and internally consistent, and successfully illustrates that the overall steric and electrostatic properties of structurally diverse ligands for the estrogen receptor are both necessary and sufficient to describe the binding affinity. The ability of the model to accurately predict the ER binding affinity of an external test set of molecules suggests that structure-based 3D-QSAR models may be used to supplement the process of endocrine disrupter identification through prioritization of novel compounds for bioassay. The general application of this 3D-QSAR model within a toxicological framework is, at present, limited only by the quantity and quality of biological data for relevant biomarkers of toxicity and hormonal responsiveness. 28 refs., 12 figs., 9 tabs.

  18. 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

  19. 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

  20. 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.

  1. 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

  2. Effect of size and conformation of the ligand on asialoglycoprotein receptor-mediated ligand internalization and degradation in rat hepatocytes

    SciTech Connect

    Chang, C.H.; Chang, T.M.

    1987-05-01

    The rates of internalization and degradation of /sup 125/-I-labeled desialylated cyanogen bromide fragment I of orosomucoid (AS-CNBr-I) and its reduced and carboxymethylated derivative (AS-RC-CNBr-I) were compared with those of /sup 125/I-labeled asialoorosomucoid (ASOR) in rat hepatocytes. At 30 nM the rates of internalization and degradation of /sup 125/I-AS-CNBr-I were greater than those of /sup 125/I-ASOR. /sup 125/I-AS-RC-CNBr-I also had a lower rate of internalization and degradation. In contrast to /sup 125/I-ASOR, when degradation was inhibited by 5 ..mu..M colchicine there was a significant intracellular accumulation of the smaller ligands. At 4/sup 0/C the hepatocytes were found to bind the fragmented ligands more than /sup 125/I-ASOR. Incubation of the cells with bound ligand at 37/sup 0/ indicated that diacytosis of /sup 125/I-ASOR was greater than the smaller ligands. Colchincine markedly enhanced diacytosis of /sup 125/I-ASOR. On the other hand, there were marked accumulation of the smaller ligands by colchicine. These results suggest that the rates of internalization, degradation and diacytosis of the ligand are affected by the size and conformation of the ligand through different rates of receptor binding and intracellular transport.

  3. Study on effects of molecular crowding on G-quadruplex-ligand binding and ligand-mediated telomerase inhibition.

    PubMed

    Yaku, Hidenobu; Murashima, Takashi; Tateishi-Karimata, Hisae; Nakano, Shu-ichi; Miyoshi, Daisuke; Sugimoto, Naoki

    2013-11-01

    The telomere G-quadruplex-binding and telomerase-inhibiting capacity of two cationic (TMPyP4 and PIPER) and two anionic (phthalocyanine and Hemin) G-quadruplex-ligands were examined under conditions of molecular crowding (MC). Osmotic experiments showed that binding of the anionic ligands, which bind to G-quadruplex DNA via π-π stacking interactions, caused some water molecules to be released from the G-quadruplex/ligand complex; in contrast, a substantial number of water molecules were taken up upon electrostatic binding of the cationic ligands to G-quadruplex DNA. These behaviors of water molecules maintained or reduced the binding affinity of the anionic and the cationic ligands, respectively, under MC conditions. Consequently, the anionic ligands (phthalocyanine and Hemin) robustly inhibited telomerase activity even with MC; in contrast, the inhibition of telomerase caused by cationic TMPyP4 was drastically reduced by MC. These results allow us to conclude that the binding of G-quadruplex-ligands to G-quadruplex via non-electrostatic interactions is preferable for telomerase inhibition under physiological conditions.

  4. Study on effects of molecular crowding on G-quadruplex-ligand binding and ligand-mediated telomerase inhibition.

    PubMed

    Yaku, Hidenobu; Murashima, Takashi; Tateishi-Karimata, Hisae; Nakano, Shu-ichi; Miyoshi, Daisuke; Sugimoto, Naoki

    2013-11-01

    The telomere G-quadruplex-binding and telomerase-inhibiting capacity of two cationic (TMPyP4 and PIPER) and two anionic (phthalocyanine and Hemin) G-quadruplex-ligands were examined under conditions of molecular crowding (MC). Osmotic experiments showed that binding of the anionic ligands, which bind to G-quadruplex DNA via π-π stacking interactions, caused some water molecules to be released from the G-quadruplex/ligand complex; in contrast, a substantial number of water molecules were taken up upon electrostatic binding of the cationic ligands to G-quadruplex DNA. These behaviors of water molecules maintained or reduced the binding affinity of the anionic and the cationic ligands, respectively, under MC conditions. Consequently, the anionic ligands (phthalocyanine and Hemin) robustly inhibited telomerase activity even with MC; in contrast, the inhibition of telomerase caused by cationic TMPyP4 was drastically reduced by MC. These results allow us to conclude that the binding of G-quadruplex-ligands to G-quadruplex via non-electrostatic interactions is preferable for telomerase inhibition under physiological conditions. PMID:23562626

  5. Self-assembly of 1D mixed-metal tubular network with coordination bonds through the interconnection of organometallic metallamacrocycles by Ag(I) centers.

    PubMed

    Wang, Guo-Liang; Lin, Yue-Jian; Jin, Guo-Xin

    2011-05-21

    The combination of a ditopic ligand containing a functional "third site" as a bridge and organometallic half-sandwich iridium unit Cp*Ir as the corner leads to the formation of the tetranuclear metallamacrocycle 1, which is reacted with silver compound, resulting in the formation of mixed-metal infinitely tubular coordination network 2.

  6. Novel method for reducing plasma cholesterol: a ligand replacement therapy

    PubMed Central

    Anantharamaiah, GM; Goldberg, Dennis

    2015-01-01

    Despite wide use of statins, significant cardiovascular disease risk persists. High-density lipoprotein based therapy has not yielded any positive results in combating this disease. Newer methods to rapidly decrease plasma cholesterol are much needed. While apolipoprotein B is a ligand for low-density lipoprotein receptor, which clears low-density lipoprotein cholesterol in a highly regulated pathway, apolipoprotein E (apoE) is a ligand for clearing other apolipoprotein B containing atherogenic lipoproteins via an alternate receptor pathway, especially the heparin sulfate proteoglycans on the liver cell surface. We describe here a novel method that replaces apoE as a ligand to clear all of the atherogenic lipoproteins via the heparin sulfate proteoglycans pathway. This ligand replacement apoE mimetic peptide therapy, having been designated as an orphan drug by the US FDA, is in clinical trials. PMID:25937835

  7. 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

  8. 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.

  9. Europium (III) coordination complex with a novel phosphonated ligand

    NASA Astrophysics Data System (ADS)

    Villemin, E.; Elias, B.; Marchand-Brynaert, J.

    2013-02-01

    An original Eu(III) complex with a phosphonated half-cage ligand (CCNPh) was synthesized and characterized. Coordination between Eu(III) and the selected ligand was investigated by FT-IR, 1H, 13C and 31P NMR spectroscopies. The stoichiometry of the Eu(III) complex in acetonitrile was determined by titrations using 1H, 31P NMR and photoluminescence. The 1M:2L stoichiometry, i.e. two CCNPh ligands for one Eu(III), has been measured. In contrast, the 1M:3L stoichiometry occurred in the solid state, from the elemental analysis. This particular behavior may be explained by the addition of a third CCNPh ligand to Eu(III) metallic core during the treatment and evaporation process for the obtention of the solid sample. An antenna effect has been observed consisting in the energy transfer from N-Ph (λexc = 276 nm) to Eu(III) (λem = 618 nm).

  10. High affinity ligands from in vitro selection: Complex targets

    PubMed Central

    Morris, Kevin N.; Jensen, Kirk B.; Julin, Carol M.; Weil, Michael; Gold, Larry

    1998-01-01

    Human red blood cell membranes were used as a model system to determine if the systematic evolution of ligands by exponential enrichment (SELEX) methodology, an in vitro protocol for isolating high-affinity oligonucleotides that bind specifically to virtually any single protein, could be used with a complex mixture of potential targets. Ligands to multiple targets were generated simultaneously during the selection process, and the binding affinities of these ligands for their targets are comparable to those found in similar experiments against pure targets. A secondary selection scheme, deconvolution-SELEX, facilitates rapid isolation of the ligands to targets of special interest within the mixture. SELEX provides high-affinity compounds for multiple targets in a mixture and might allow a means for dissecting complex biological systems. PMID:9501188

  11. 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)

  12. Adenosine receptor ligands: differences with acute versus chronic treatment

    PubMed Central

    Jacobson, Kenneth A.; von Lubitz, Dag K. J. E.; Daly, John W.; Fredholm, Bertil B.

    2012-01-01

    Adenosine receptors have been the target of intense research with respect to potential use of selective ligands in a variety of therapeutic areas. Caffeine and theophylline are adenosine receptor antagonists, and over the past three decades a wide range of selective agonists and antagonists for adenosine receptor subtypes have been developed. A complication to the therapeutic use of adenosine receptor ligands is the observation that the effects of acute administration of a particular ligand can be diametrically opposite to the chronic effects of the same ligand. This ‘effect inversion’ is discussed here by Ken Jecobson and colleagues, and has been observed for effects on cognitive processes, seizures and ischaemic damage. PMID:8936347

  13. 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. PMID:11911421

  14. 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.

  15. 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.

  16. 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

  17. 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. PMID:20655477

  18. Protoglobin: structure and ligand-binding properties.

    PubMed

    Pesce, Alessandra; Bolognesi, Martino; Nardini, Marco

    2013-01-01

    Protoglobin is the first globin identified in Archaea; its biological role is still unknown, although it can bind O2, CO and NO reversibly in vitro. The X-ray structure of Methanosarcina acetivorans protoglobin revealed several peculiar structural features. Its tertiary structure can be considered as an expanded version of the canonical globin fold, characterised by the presence of a pre-A helix (named Z) and a 20-residue N-terminal extension. Other unusual trends are a large distortion of the haem moiety, and its complete burial in the protein matrix due to the extended CE and FG loops and the 20-residue N-terminal loop. Access of diatomic ligands to the haem has been proposed to be granted by two tunnels, which are mainly defined by helices B/G (tunnel 1) and B/E (tunnel 2), and whose spatial orientation and topology give rise to an almost orthogonal two-tunnel system unprecedented in other globins. At a quaternary level, protoglobin forms a tight dimer, mostly based on the inter-molecular four-helix bundle built by the G- and H-helices, similar to that found in globin-coupled sensor proteins, which share with protoglobin a common phylogenetic origin. Such unique structural properties, together with an unusually low O2 dissociation rate and a selectivity ratio for O2/CO binding that favours O2 ligation, make protoglobin a peculiar case for gaining insight into structure to function relationships within the globin superfamily. While recent structural and biochemical data have given answers to important questions, the functional issue is still unclear and it is expected to represent the major focus of future investigations. PMID:24054795

  19. An Aggregation Advisor for Ligand Discovery.

    PubMed

    Irwin, John J; Duan, Da; Torosyan, Hayarpi; Doak, Allison K; Ziebart, Kristin T; Sterling, Teague; Tumanian, Gurgen; Shoichet, Brian K

    2015-09-10

    Colloidal aggregation of organic molecules is the dominant mechanism for artifactual inhibition of proteins, and controls against it are widely deployed. Notwithstanding an increasingly detailed understanding of this phenomenon, a method to reliably predict aggregation has remained elusive. Correspondingly, active molecules that act via aggregation continue to be found in early discovery campaigns and remain common in the literature. Over the past decade, over 12 thousand aggregating organic molecules have been identified, potentially enabling a precedent-based approach to match known aggregators with new molecules that may be expected to aggregate and lead to artifacts. We investigate an approach that uses lipophilicity, affinity, and similarity to known aggregators to advise on the likelihood that a candidate compound is an aggregator. In prospective experimental testing, five of seven new molecules with Tanimoto coefficients (Tc's) between 0.95 and 0.99 to known aggregators aggregated at relevant concentrations. Ten of 19 with Tc's between 0.94 and 0.90 and three of seven with Tc's between 0.89 and 0.85 also aggregated. Another three of the predicted compounds aggregated at higher concentrations. This method finds that 61 827 or 5.1% of the ligands acting in the 0.1 to 10 μM range in the medicinal chemistry literature are at least 85% similar to a known aggregator with these physical properties and may aggregate at relevant concentrations. Intriguingly, only 0.73% of all drug-like commercially available compounds resemble the known aggregators, suggesting that colloidal aggregators are enriched in the literature. As a percentage of the literature, aggregator-like compounds have increased 9-fold since 1995, partly reflecting the advent of high-throughput and virtual screens against molecular targets. Emerging from this study is an aggregator advisor database and tool ( http://advisor.bkslab.org ), free to the community, that may help distinguish between

  20. 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.

  1. 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.

  2. Chlorophenylpiperazine analogues as high affinity dopamine transporter ligands.

    PubMed

    Motel, William C; Healy, Jason R; Viard, Eddy; Pouw, Buddy; Martin, Kelly E; Matsumoto, Rae R; Coop, Andrew

    2013-12-15

    Selective σ2 ligands continue to be an active target for medications to attenuate the effects of psychostimulants. In the course of our studies to determine the optimal substituents in the σ2-selective phenyl piperazines analogues with reduced activity at other neurotransmitter systems, we discovered that 1-(3-chlorophenyl)-4-phenethylpiperazine actually had preferentially increased affinity for dopamine transporters (DAT), yielding a highly selective DAT ligand. PMID:24211020

  3. Delivering carbide ligands to sulfide-rich clusters.

    PubMed

    Reinholdt, Anders; Herbst, Konrad; Bendix, Jesper

    2016-02-01

    The propensity of the terminal ruthenium carbide Ru(C)Cl2(PCy3)2 (RuC) to form carbide bridges to electron-rich transition metals enables synthetic routes to metal clusters with coexisting carbide and sulfide ligands. Electrochemical experiments show the Ru≡C ligand to exert a relatively large electron-withdrawing effect compared with PPh3, effectively shifting redox potentials.

  4. Metallogel formation in aqueous DMSO by perfluoroalkyl decorated terpyridine ligands.

    PubMed

    Tatikonda, Rajendhraprasad; Bhowmik, Sandip; Rissanen, Kari; Haukka, Matti; Cametti, Massimo

    2016-08-01

    Terpyridine based ligands 1 and 2, decorated with a C8F17 perfluorinated tag, are able to form stable thermoreversible gels in the presence of several d-block metal chloride salts. The gel systems obtained have been characterized by NMR, X-ray diffraction, electron microscopies and Tgel experiments in order to gain insights into the observed different behaviour of the two similar ligands, also in terms of the effect of additional common anionic species. PMID:27460754

  5. 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.

  6. 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

  7. Novel peptide ligand with high binding capacity for antibody purification.

    PubMed

    Lund, Line Naomi; Gustavsson, Per-Erik; Michael, Roice; Lindgren, Johan; Nørskov-Lauritsen, Leif; Lund, Martin; Houen, Gunnar; Staby, Arne; St Hilaire, Phaedria M

    2012-02-17

    Small synthetic ligands for protein purification have become increasingly interesting with the growing need for cheap chromatographic materials for protein purification and especially for the purification of monoclonal antibodies (mAbs). Today, Protein A-based chromatographic resins are the most commonly used capture step in mAb down stream processing; however, the use of Protein A chromatography is less attractive due to toxic ligand leakage as well as high cost. Whether used as an alternative to the Protein A chromatographic media or as a subsequent polishing step, small synthetic peptide ligands have an advantage over biological ligands; they are cheaper to produce, ligand leakage by enzymatic degradation is either eliminated or significantly reduced, and they can in general better withstand cleaning in place (CIP) conditions such as 0.1M NaOH. Here, we present a novel synthetic peptide ligand for purification of human IgG. Immobilized on WorkBeads, an agarose-based base matrix from Bio-Works, the ligand has a dynamic binding capacity of up to 48 mg/mL and purifies IgG from harvest cell culture fluid with purities and recovery of >93%. The binding affinity is ∼10⁵ M⁻¹ and the interaction is favorable and entropy-driven with an enthalpy penalty. Our results show that the binding of the Fc fragment of IgG is mediated by hydrophobic interactions and that elution at low pH is most likely due to electrostatic repulsion. Furthermore, we have separated aggregated IgG from non-aggregated IgG, indicating that the ligand could be used both as a primary purification step of IgG as well as a subsequent polishing step.

  8. Persistent Binding of Ligands to the Aryl Hydrocarbon Receptor

    PubMed Central

    Bohonowych, Jessica E.; Denison, Michael S.

    2010-01-01

    The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates many of the biological and toxic effects of halogenated aromatic hydrocarbons (HAHs), polycyclic aromatic hydrocarbons (PAHs), and other structurally diverse ligands. While HAHs are several orders of magnitude more potent in producing AhR-dependent biochemical effects than PAHs or other AhR agonists, only the HAHs have been observed to produce AhR-dependent toxicity in vivo. Here we have characterized the dissociation of a prototypical HAH ligand ([3H] 2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD]) and PAH-like ligand ([3H] β-naphthoflavone [βNF]) from the guinea pig, hamster, mouse, and rat hepatic cytosolic AhR in order to elucidate the relationship between the apparent ligand-binding affinities and the divergent potency of these chemicals. Both compounds dissociated very slowly from the AhR with the amount of specific binding remaining at 96 h ranging from 53% to 70% for [3H]TCDD and 26% to 85% for [3H] βNF, depending upon the species examined. The rate of ligand dissociation was unaffected by protein concentration or incubation temperature. Preincubation of cytosol with 2,3,7,8-tetrachlorodibenzofuran, carbaryl, or primaquine, prior to the addition of [3H]TCDD, shifted the apparent IC50 of these compounds as competitive AhR ligands by ∼10- to 50-fold. Our results support the need for reassessment of previous AhR ligand-binding affinity calculations and competitive binding analysis since these measurements are not carried out at equilibrium binding conditions. Our studies suggest that AhR binding affinity/occupancy has little effect on the observed differences in the persistence of gene expression by HAHs and PAHs. PMID:17431010

  9. 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…

  10. 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.

  11. Analysis of cell locomotion on ligand gradient substrates.

    PubMed

    Sarvestani, Alireza S; Jabbari, Esmaiel

    2009-06-01

    Directional cell motility plays a key role in many biological processes like morphogenesis, inflammation, wound repair, angiogenesis, immune response, and tumor metastasis. Cells respond to the gradient in surface ligand density by directed locomotion towards the direction of higher ligand density. Theoretical models which address the physical basis underlying the regulatory effect of ligand gradient on cell motility are highly desirable. Predictive models not only contribute to a better understanding of biological processes, but they also provide a quantitative interconnection between cell motility and biophysical properties of the extracellular matrix (ECM) for rational design of biomaterials as scaffolds in tissue engineering. In this work, we consider a one-dimensional (1D) continuum viscoelastic model to predict the cell velocity in response to linearly increasing density of surface ligands on a substrate. The cell is considered as a 1D linear viscoelastic object with position dependent elasticity due to the variation in actin network density. The cell-substrate interaction is characterized by a frictional force, controlled by the density of ligand-receptor pairs. The generation of contractile stresses is described in terms of kinetic equations for the reactions between actins, myosins, and guanine nucleotide regulatory proteins. The model predictions show a reasonable agreement with experimentally measured cell speeds, considering biologically relevant values for the model parameters. The model predicts a biphasic relationship between cell speed and slope of gradient as well as a maximum limiting speed after a finite migration time. For a given slope of ligand gradient, the onset of the limiting speed appears at longer times for substrates with lower ligand gradients. The model can be applied to the design of biomaterials as scaffolds for guided tissue regeneration as it predicts an optimum range for the slope of ligand gradient. PMID:19205048

  12. 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

  13. 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.

  14. Tetrapyrroles as Endogenous TSPO Ligands in Eukaryotes and Prokaryotes: Comparisons with Synthetic Ligands.

    PubMed

    Veenman, Leo; Vainshtein, Alex; Yasin, Nasra; Azrad, Maya; Gavish, Moshe

    2016-01-01

    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

  15. 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. PMID:26284384

  16. A general framework improving teaching ligand binding to a macromolecule.

    PubMed

    Haiech, Jacques; Gendrault, Yves; Kilhoffer, Marie-Claude; Ranjeva, Raoul; Madec, Morgan; Lallement, Christophe

    2014-10-01

    The interaction of a ligand with a macromolecule has been modeled following different theories. The tenants of the induced fit model consider that upon ligand binding, the protein-ligand complex undergoes a conformational change. In contrast, the allosteric model assumes that only one among different coexisting conformers of a given protein is suitable to bind the ligand optimally. In the present paper, we propose a general framework to model the binding of ligands to a macromolecule. Such framework built on the binding polynomial allows opening new ways to teach in a unified manner ligand binding, enzymology and receptor binding in pharmacology. Moreover, we have developed simple software that allows building the binding polynomial from the schematic description of the biological system under study. Taking calmodulin as a canonical example, we show here that the proposed tool allows the easy retrieval of previously experimental and computational reports. This article is part of a Special Issue entitled: Calcium Signaling in Health and Disease. Guest Editors: Geert Bultynck, Jacques Haiech, Claus W. Heizmann, Joachim Krebs, and Marc Moreau.

  17. 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.

  18. 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.

  19. 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.

  20. Ligand-Dependent Conformational Dynamics of Dihydrofolate Reductase

    PubMed Central

    Reddish, Michael J.; Vaughn, Morgan B.; Fu, Rong; Dyer, R. Brian

    2016-01-01

    Enzymes are known to change among several conformational states during turnover. The role of such dynamic structural changes in catalysis is not fully understood. The influence of dynamics in catalysis can be inferred, but not proven, by comparison of equilibrium structures of protein variants and protein–ligand complexes. A more direct way to establish connections between protein dynamics and the catalytic cycle is to probe the kinetics of specific protein motions in comparison to progress along the reaction coordinate. We have examined the enzyme model system dihydrofolate reductase (DHFR) from Escherichia coli with tryptophan fluorescence-probed temperature-jump spectroscopy. We aimed to observe the kinetics of the ligand binding and ligand-induced conformational changes of three DHFR complexes to establish the relationship among these catalytic steps. Surprisingly, in all three complexes, the observed kinetics do not match a simple sequential two-step process. Through analysis of the relationship between ligand concentration and observed rate, we conclude that the observed kinetics correspond to the ligand binding step of the reaction and a noncoupled enzyme conformational change. The kinetics of the conformational change vary with the ligand's identity and presence but do not appear to be directly related to progress along the reaction coordinate. These results emphasize the need for kinetic studies of DHFR with highly specific spectroscopic probes to determine which dynamic events are coupled to the catalytic cycle and which are not. PMID:26901612

  1. 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.

  2. 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.

  3. 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

  4. Agonists and Antagonists of TGF-β Family Ligands.

    PubMed

    Chang, Chenbei

    2016-08-01

    The discovery of the transforming growth factor β (TGF-β) family ligands and the realization that their bioactivities need to be tightly controlled temporally and spatially led to intensive research that has identified a multitude of extracellular modulators of TGF-β family ligands, uncovered their functions in developmental and pathophysiological processes, defined the mechanisms of their activities, and explored potential modulator-based therapeutic applications in treating human diseases. These studies revealed a diverse repertoire of extracellular and membrane-associated molecules that are capable of modulating TGF-β family signals via control of ligand availability, processing, ligand-receptor interaction, and receptor activation. These molecules include not only soluble ligand-binding proteins that were conventionally considered as agonists and antagonists of TGF-β family of growth factors, but also extracellular matrix (ECM) proteins and proteoglycans that can serve as "sink" and control storage and release of both the TGF-β family ligands and their regulators. This extensive network of soluble and ECM modulators helps to ensure dynamic and cell-specific control of TGF-β family signals. This article reviews our knowledge of extracellular modulation of TGF-β growth factors by diverse proteins and their molecular mechanisms to regulate TGF-β family signaling.

  5. 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.

  6. Ligands turning around in the midst of protein conformers: the origin of ligand-protein mating. A NMR view.

    PubMed

    Pertinhez, T A; Spisni, A

    2011-01-01

    Protein-ligand binding is a puzzling process. Many theories have been devised since the pioneering key-and-lock hypothesis based on the idea that both the protein and the ligand have a rigid single conformation. Indeed, molecular motion is the essence of the universe. Consequently, not only proteins are characterized by an extraordinary conformational freedom, but ligands too can fluctuate in a rather vast conformational space. In this scenario, the quest to understand how do they match is fascinating. Recognizing that the inherent dynamics of molecules is the key factor controlling the success of the binding and, subsequently, their chemical/biological function, here we present a view of this process from the NMR stand point. A description of the most relevant NMR parameters that can provide insights, at atomic level, on the mechanisms of protein-ligand binding is provided in the final section.

  7. 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.

  8. 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.

  9. 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.

  10. 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

  11. DFT Study of Acceptorless Alcohol Dehydrogenation Mediated by Ruthenium Pincer Complexes: Ligand Tautomerization Governing Metal Ligand Cooperation.

    PubMed

    Hou, Cheng; Zhang, Zhihan; Zhao, Cunyuan; Ke, Zhuofeng

    2016-07-01

    Metal ligand cooperation (MLC) catalysis is a popular strategy to design highly efficient transition metal catalysts. In this presented theoretical study, we describe the key governing factor in the MLC mechanism, with the Szymczak's NNN-Ru and the Milstein's PNN-Ru complexes as two representative catalysts. Both the outer-sphere and inner-sphere mechanisms were investigated and compared. Our calculated result indicates that the PNN-Ru pincer catalyst will be restored to aromatic state during the catalytic cycle, which can be considered as the driving force to promote the MLC process. On the contrary, for the NNN-Ru catalyst, the MLC mechanism leads to an unfavored tautomerization in the pincer ligand, which explains the failure of the MLC mechanism in this system. Therefore, the strength of the driving force provided by the pincer ligand actually represents a prerequisite factor for MLC. Spectator ligands such as CO, PPh3, and hydride are important to ensure the catalyst follow a certain mechanism as well. We also evaluate the driving force of various bifunctional ligands by computational methods. Some proposed pincer ligands may have the potential to be the new pincer catalysts candidates. The presented study is expected to offer new insights for MLC catalysis and provide useful guideline for future catalyst design. PMID:27322755

  12. Free Energy Calculations of Mutations Involving a Tightly Bound Water Molecule and Ligand Substitutions in a Ligand-Protein Complex.

    PubMed

    García-Sosa, Alfonso T; Mancera, Ricardo L

    2010-09-17

    The accurate calculation of the free energy of interaction of protein-water-ligand systems has an important role in molecular recognition and drug design that is often not fully considered. We report free energy thermodynamic integration calculations used to evaluate the effects of inclusion, neglect, and targeting and removal (i.e., systematic substitution by ligand functional groups) of an important, tightly bound, water molecule in the SH3 domain of Abl tyrosine kinase. The effects of this water molecule on the free energies of interaction of several Abl-SH3 domain-ligand systems reveal that there is an unfavourable free energy change associated with its removal into the bulk solvent. Only three substitutions by an additional functional group (out of methyl, ethyl, hydroxyl, amino, and amide groups) in the phenyl ring of a tyrosine in the peptide ligand resulted in a favourable change in the free energy of binding upon replacement of the ordered water molecule. This computational approach provides a direct route to the systematic and rigorous prediction of the thermodynamic influence of ordered, structural water molecules on ligand modification and optimization in drug design by calculating free energy changes in protein-water-ligand systems. PMID:27463454

  13. Steric and Electronic Factors Associated with the Photoinduced Ligand Exchange of Bidentate Ligands Coordinated to Ru(II).

    PubMed

    Albani, Bryan A; Whittemore, Tyler; Durr, Christopher B; Turro, Claudia

    2015-01-01

    In an effort to create a molecule that can absorb low energy visible or near-infrared light for photochemotherapy (PCT), the new complexes [Ru(biq)2 (dpb)](PF6 )2 (1, biq = 2,2'-biquinoline, dpb = 2,3-bis(2-pyridyl)benzoquinoxaline) and [(biq)2 Ru(dpb)Re(CO)3 Cl](PF6 )2 (2) were synthesized and characterized. Complexes 1 and 2 were compared to [Ru(bpy)2 (dpb)](PF6 )2 (3, bpy = 2,2'-bipyridine) and [Ru(biq)2 (phen)](PF6 )2 (4, phen = 1,10-phenanthroline). Distortions around the metal and biq ligands were used to explain the exchange of one biq ligand in 4 upon irradiation. Complex 1, however, undergoes photoinduced dissociation of the dpb ligand rather than biq under analogous experimental conditions. Complex 3 is not photoactive, providing evidence that the biq ligands are crucial for ligand photodissociation in 1. The crystal structures of 1 and 4 are compared to explain the difference in photochemistry between the complexes. Complex 2 absorbs lower energy light than 1, but is photochemically inert although its crystal structure displays significant distortions. These results indicate that both the excited state electronic structure and steric bulk play key roles in bidentate photoinduced ligand dissociation. The present work also shows that it is possible to stabilize sterically hindered Ru(II) complexes by the addition of another metal, a property that may be useful for other applications. PMID:25403564

  14. Development of a membrane-anchored ligand and receptor yeast two-hybrid system for ligand-receptor interaction identification

    PubMed Central

    Li, Jingjing; Gao, Jin; Han, Lei; Zhang, Yinjie; Guan, Wen; Zhou, Liang; Yu, Yan; Han, Wei

    2016-01-01

    Identifying interactions between ligands and transmembrane receptors is crucial for understanding the endocrine system. However, the present approaches for this purpose are still not capable of high-throughput screening. In this report, a membrane-anchored ligand and receptor yeast two-hybrid (MALAR-Y2H) system was established. In the method, an extracellular ligand is linked with an intracellular split-ubiquitin reporter system via a chimeric transmembrane structure. Meanwhile, the prey proteins of transmembrane receptors are fused to the other half of the split-ubiquitin reporter system. The extracellular interaction of ligands and receptors can lead to the functional recovery of the ubiquitin reporter system in yeast, and eventually lead to the expression of report genes. Consequently, the system can be used to detect the interactions between extracellular ligands and their transmembrane receptors. To test the efficiency and universality of the method, interactions between several pairs of ligands and receptors of mouse were analyzed. The detecting results were shown to be thoroughly consistent with the present knowledge, indicating MALAR-Y2H can be utilized for such purpose with high precision, high efficiency and strong universality. The characteristics of the simple procedure and high-throughput potential make MALAR-Y2H a powerful platform to study protein-protein interaction networks between secreted proteins and transmembrane proteins. PMID:27762338

  15. Biotechnological Fluorescent Ligands of the Bradykinin B1 Receptor: Protein Ligands for a Peptide Receptor

    PubMed Central

    Charest-Morin, Xavier; Marceau, François

    2016-01-01

    The bradykinin (BK) B1 receptor (B1R) is a peculiar G protein coupled receptor that is strongly regulated to the point of being inducible in immunopathology. Limited clinical evidence suggests that its expression in peripheral blood mononuclear cells is a biomarker of active inflammatory states. In an effort to develop a novel imaging/diagnostic tool, we report the rational design and testing of a fusion protein that is a ligand of the human B1R but not likely to label peptidases. This ligand is composed of a fluorescent protein (FP) (enhanced green FP [EGFP] or mCherry) prolonged at its N-terminus by a spacer peptide and a classical peptide agonist or antagonist (des-Arg9-BK, [Leu8]des-Arg9-BK, respectively). The design of the spacer-ligand joint peptide was validated by a competition assay for [3H]Lys-des-Arg9-BK binding to the human B1R applied to 4 synthetic peptides of 18 or 19 residues. The labeling of B1R-expressing cells with EGFP or mCherry fused with 7 of such peptides was performed in parallel (microscopy). Both assays indicated that the best design was FP-(Asn-Gly)n-Lys-des-Arg9-BK; n = 15 was superior to n = 5, suggesting benefits from minimizing steric hindrance between the FP and the receptor. Cell labeling concerned mostly plasma membranes and was inhibited by a B1R antagonist. EGFP-(Asn-Gly)15-Lys-des-Arg9-BK competed for the binding of [3H]Lys-des-Arg9-BK to human recombinant B1R, being only 10-fold less potent than the unlabeled form of Lys-des-Arg9-BK to do so. The fusion protein did not label HEK 293a cells expressing recombinant human BK B2 receptors or angiotensin converting enzyme. This study identifies a modular C-terminal sequence that can be adapted to protein cargoes, conferring high affinity for the BK B1R, with possible applications in diagnostic cytofluorometry, histology and drug delivery (e.g., in oncology). PMID:26844555

  16. Biotechnological Fluorescent Ligands of the Bradykinin B1 Receptor: Protein Ligands for a Peptide Receptor.

    PubMed

    Charest-Morin, Xavier; Marceau, François

    2016-01-01

    The bradykinin (BK) B1 receptor (B1R) is a peculiar G protein coupled receptor that is strongly regulated to the point of being inducible in immunopathology. Limited clinical evidence suggests that its expression in peripheral blood mononuclear cells is a biomarker of active inflammatory states. In an effort to develop a novel imaging/diagnostic tool, we report the rational design and testing of a fusion protein that is a ligand of the human B1R but not likely to label peptidases. This ligand is composed of a fluorescent protein (FP) (enhanced green FP [EGFP] or mCherry) prolonged at its N-terminus by a spacer peptide and a classical peptide agonist or antagonist (des-Arg9-BK, [Leu8]des-Arg9-BK, respectively). The design of the spacer-ligand joint peptide was validated by a competition assay for [3H]Lys-des-Arg9-BK binding to the human B1R applied to 4 synthetic peptides of 18 or 19 residues. The labeling of B1R-expressing cells with EGFP or mCherry fused with 7 of such peptides was performed in parallel (microscopy). Both assays indicated that the best design was FP-(Asn-Gly)n-Lys-des-Arg9-BK; n = 15 was superior to n = 5, suggesting benefits from minimizing steric hindrance between the FP and the receptor. Cell labeling concerned mostly plasma membranes and was inhibited by a B1R antagonist. EGFP-(Asn-Gly)15-Lys-des-Arg9-BK competed for the binding of [3H]Lys-des-Arg9-BK to human recombinant B1R, being only 10-fold less potent than the unlabeled form of Lys-des-Arg9-BK to do so. The fusion protein did not label HEK 293a cells expressing recombinant human BK B2 receptors or angiotensin converting enzyme. This study identifies a modular C-terminal sequence that can be adapted to protein cargoes, conferring high affinity for the BK B1R, with possible applications in diagnostic cytofluorometry, histology and drug delivery (e.g., in oncology).

  17. Critical ligand binding reagent preparation/selection: when specificity depends on reagents.

    PubMed

    Rup, Bonita; O'Hara, Denise

    2007-05-11

    Throughout the life cycle of biopharmaceutical products, bioanalytical support is provided using ligand binding assays to measure the drug product for pharmacokinetic, pharmacodynamic, and immunogenicity studies. The specificity and selectivity of these ligand binding assays are highly dependent on the ligand binding reagents. Thus the selection, characterization, and management processes for ligand binding reagents are crucial to successful assay development and application. This report describes process considerations for selection and characterization of ligand binding reagents that are integral parts of the different phases of assay development. Changes in expression, purification, modification, and storage of the ligand binding reagents may have a profound effect on the ligand binding assay performance. Thus long-term management of the critical ligand binding assay reagents is addressed including suggested characterization criteria that allow ligand binding reagents to be used in as consistent a manner as possible. Examples of challenges related to the selection, modification, and characterization of ligand binding reagents are included.

  18. Essential role of conformational selection in ligand binding

    PubMed Central

    Vogt, Austin D.; Pozzi, Nicola; Chen, Zhiwei; Di Cera, Enrico

    2013-01-01

    Two competing and mutually exclusive mechanisms of ligand recognition – conformational selection and induced fit - have dominated our interpretation of ligand binding in biological macromolecules for almost six decades. Conformational selection posits the pre-existence of multiple conformations of the macromolecule from which the ligand selects the optimal one. Induced fit, on the other hand, postulates the existence of conformational rearrangements of the original conformation into an optimal one that is induced by binding of the ligand. In the former case, conformational transitions precede the binding event; in the latter, conformational changes follow the binding step. Kineticists have used a facile criterion to distinguish between the two mechanisms based on the dependence of the rate of relaxation to equilibrium, kobs, on the ligand concentration, [L]. A value of kobs decreasing hyperbolically with [L] is seen as diagnostic of conformational selection, while a value of kobs increasing hyperbolically with [L] is considered diagnostic of induced fit. However, this simple conclusion is only valid in the rather unrealistic assumption of conformational transitions being much slower than binding and dissociation events. In general, induced fit only produces values of kobs that increase with [L] but conformational selection is more versatile and is associated with values of kobs that increase, decrease with or are independent of [L]. The richer repertoire of kinetic properties of conformational selection applies to kinetic mechanisms with single or multiple saturable relaxations and explains the behavior of nearly all experimental systems reported in the literature thus far. Conformational selection is always sufficient and often necessary to account for the relaxation kinetics of ligand binding to a biological macromolecule and is therefore an essential component of any binding mechanism. On the other hand, induced fit is never necessary and only sufficient in a

  19. Nanomaterials can dynamically steer cell responses to biological ligands.

    PubMed

    Sharma, Ram I; Schwarzbauer, Jean E; Moghe, Prabhas V

    2011-01-17

    Traditional tissue regeneration approaches to activate cell behaviors on biomaterials rely on the use of extracellular-matrix-based or soluble growth-factor cues. In this article, a novel approach is highlighted to dynamically steer cellular phenomena such as cell motility based on nanoscale substratum features of biological ligands. Albumin-derived nanocarriers (ANCs) with variable nanoscale-size features are functionalized with fibronectin III9-10 matrix ligands, and their effects on primary human keratinocyte activation are investigated. The presentation of fibronectin fragments from ANCs significantly enhances cell migration as compared to free ligands at equivalent concentrations. Notably, cell migration is influenced by the size of the underlying ANCs even for variably sized ANCs covered in comparable levels of fibronectin fragment. For equivalent ligand concentrations, cell migration on the smaller-sized ANCs (30 and 50 nm) is significantly enhanced as compared to that on larger-sized ANCs (75 and 100 nm). In contrast, the enhancement of cell migration on nanocarriers is abolished by the use of immobilized, biofunctionalized ANCs, indicating that "dynamic" nanocarrier internalization events underlie the role of nanocarrier geometry on the differential regulation of cell migration kinetics. Uptake studies using fluorescent ANCs indicate that larger-sized ANCs cause delayed endocytic kinetics and hence could present barriers for internalization during the cell adhesion and motility processes. Motile cells exhibit diminished migration upon exposure to clathrin inhibitors, but not caveolin inhibitors, suggesting the role of clathrin-mediated endocytosis in facilitating cell migratory responsiveness to the nanocarriers. Overall, a monotonic relationship is found between the nanocarrier cytointernalization rate and the cell migration rate, suggesting the possibility of designing biointerfacial features for the dynamic control of cell migration. Thus, the

  20. Regulatory roles for NKT cell ligands in environmentally induced autoimmunity.

    PubMed

    Vas, Jaya; Mattner, Jochen; Richardson, Stewart; Ndonye, Rachel; Gaughan, John P; Howell, Amy; Monestier, Marc

    2008-11-15

    The development of autoimmune diseases is frequently linked to exposure to environmental factors such as chemicals, drugs, or infections. In the experimental model of metal-induced autoimmunity, administration of subtoxic doses of mercury (a common environmental pollutant) to genetically susceptible mice induces an autoimmune syndrome with rapid anti-nucleolar Ab production and immune system activation. Regulatory components of the innate immune system such as NKT cells and TLRs can also modulate the autoimmune process. We examined the interplay among environmental chemicals and NKT cells in the regulation of autoimmunity. Additionally, we studied NKT and TLR ligands in a tolerance model in which preadministration of a low dose of mercury in the steady state renders animals tolerant to metal-induced autoimmunity. We also studied the effect of Sphingomonas capsulata, a bacterial strain that carries both NKT cell and TLR ligands, on metal-induced autoimmunity. Overall, NKT cell activation by synthetic ligands enhanced the manifestations of metal-induced autoimmunity. Exposure to S. capsulata exacerbated autoimmunity elicited by mercury. Although the synthetic NKT cell ligands that we used are reportedly similar in their ability to activate NKT cells, they displayed pronounced differences when coinjected with environmental agents or TLR ligands. Individual NKT ligands differed in their ability to prevent or break tolerance induced by low-dose mercury treatment. Likewise, different NKT ligands either dramatically potentiated or inhibited the ability of TLR9 agonistic oligonucleotides to disrupt tolerance to mercury. Our data suggest that these differences could be mediated by the modification of cytokine profiles and regulatory T cell numbers.

  1. Evaluating ligands for use in polymer ligand film (PLF) for plutonium and uranium extraction

    DOE PAGESBeta

    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.

  2. 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.

  3. Coarse-grained molecular dynamics simulations of protein-ligand binding.

    PubMed

    Negami, Tatsuki; Shimizu, Kentaro; Terada, Tohru

    2014-09-30

    Coarse-grained molecular dynamics (CGMD) simulations with the MARTINI force field were performed to reproduce the protein-ligand binding processes. We chose two protein-ligand systems, the levansucrase-sugar (glucose or sucrose), and LinB-1,2-dichloroethane systems, as target systems that differ in terms of the size and shape of the ligand-binding pocket and the physicochemical properties of the pocket and the ligand. Spatial distributions of the Coarse-grained (CG) ligand molecules revealed potential ligand-binding sites on the protein surfaces other than the real ligand-binding sites. The ligands bound most strongly to the real ligand-binding sites. The binding and unbinding rate constants obtained from the CGMD simulation of the levansucrase-sucrose system were approximately 10 times greater than the experimental values; this is mainly due to faster diffusion of the CG ligand in the CG water model. We could obtain dissociation constants close to the experimental values for both systems. Analysis of the ligand fluxes demonstrated that the CG ligand molecules entered the ligand-binding pockets through specific pathways. The ligands tended to move through grooves on the protein surface. Thus, the CGMD simulations produced reasonable results for the two different systems overall and are useful for studying the protein-ligand binding processes.

  4. Aluminum complexes of the redox-active [ONO] pincer ligand.

    PubMed

    Szigethy, Géza; Heyduk, Alan F

    2012-07-14

    A series of aluminum complexes containing the tridentate, redox-active ligand bis(3,5-di-tert-butyl-2-phenol)amine ([ONO]H(3)) in three different oxidation states were synthesized. The aluminum halide salts AlCl(3) and AlBr(3) were reacted with the doubly deprotonated form of the ligand to afford five-coordinate [ONHO(cat)]AlX(solv) complexes (1a, X = Cl, solv = OEt(2); 1b, X = Br, solv = THF), each having a trigonal bipyramidal coordination geometry at the aluminum and containing the [ONHO(cat)](2-) ligand with a protonated, sp(3)-hybridized nitrogen donor. The [ONO] ligand platform may also be added to aluminum through the use of the oxidized ligand salt [ONO(q)]K, which was reacted with AlCl(3) in the presence of either diphenylacetylacetonate (acacPh(2)(-)) or 8-oxyquinoline (quinO(-)) to afford [ONO(q)]Al(acacPh(2))Cl (2) or [ONO(q)]Al(quinO)Cl (3), respectively, with well-defined [ONO(q)](-) ligands. Quinonate complexes 2 and 3 were reduced by one electron to afford the corresponding complexes K{[ONO(sq)]Al(acacPh(2))(py)} (4) and K{[ONO(sq)]Al(quinO)(py)} (5), respectively, containing well-defined [ONO(sq)](2-) ligands. The addition of tetrachloro-1,2-quinone to 1a in the presence of pyridine resulted in the expulsion of HCl and the formation of an aluminum complex with two different redox active ligands, [ONO]Al(o-O(2)C(6)Cl(4))(py) (6). Similar results were obtained when 1a was reacted with 9,10-phenanthrenequinone to afford [ONO]Al(o-O(2)C(14)H(8))(py) (7) or with pyrene-4,5-dione to afford [ONO]Al(o-O(2)C(16)H(8))(py) (8). Structural, spectroscopic and preliminary magnetic measurements on 6-8 suggest ligand non-innocent redox behavior in these complexes. PMID:22669327

  5. Niobium tetrahalide complexes with neutral diphosphine ligands.

    PubMed

    Benjamin, Sophie L; Chang, Yao-Pang; Hector, Andrew L; Jura, Marek; Levason, William; Reid, Gillian; Stenning, Gavin

    2016-05-10

    The reactions of NbCl4 with diphosphine ligands o-C6H4(PMe2)2, Me2PCH2CH2PMe2 or Et2PCH2CH2PEt2 in a 1 : 2 molar ratio in MeCN solution produced eight-coordinate [NbCl4(diphosphine)2]. [NbBr4(diphosphine)2] (diphosphine = o-C6H4(PMe2)2 or Me2PCH2CH2PMe2) were made similarly from NbBr4. X-ray crystal structures show that [NbCl4{o-C6H4(PMe2)2}2] has a dodecahedral geometry, but the complexes with dimethylene-backboned diphosphines are distorted square antiprisms. The Nb-P distances and

  6. Chemodynamics of aquatic metal complexes: from small ligands to colloids.

    PubMed

    Van Leeuwen, Herman P; Buffle, Jacques

    2009-10-01

    Recent progress in understanding the formation/dissociation kinetics of aquatic metal complexes with complexants in different size ranges is evaluated and put in perspective, with suggestions for further studies. The elementary steps in the Eigen mechanism, i.e., diffusion and dehydration of the metal ion, are reviewed and further developed. The (de)protonation of both the ligand and the coordinating metal ion is reconsidered in terms of the consequences for dehydration rates and stabilities of the various outer-sphere complexes. In the nanoparticulate size range, special attention is given to the case of fulvic ligands, for which the impact of electrostatic interactions is especially large. In complexation with colloidal ligands (hard, soft, and combination thereof) the diffusive transport of metal ions is generally a slower step than in the case of complexation with small ligands in a homogeneous solution. The ensuing consequences for the chemodynamics of colloidal complexes are discussed in detail and placed in a generic framework, encompassing the complete range of ligand sizes.

  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. Ligand entry into the calyx of β-lactoglobulin.

    PubMed

    Bello, Martiniano; García-Hernández, Enrique

    2014-07-01

    Although the thermodynamic principles that control the binding of drug molecules to their protein targets are well understood, the detailed process of how a ligand reaches a protein binding site has been an intriguing question over decades. The short time interval between the encounter between a ligand and its receptor to the formation of the stable complex has prevented experimental observations. Bovine β-lactoglobulin (βlg) is a lipocalin member that carries fatty acids (FAs) and other lipids in the cellular environment. Βlg accommodates a FA molecule in its highly hydrophobic cavity and exhibits the capability of recognizing a wide variety of hydrophobic ligands. To elucidate the ligand entry process on βlg, we report molecular dynamics simulations of the encounter between palmitate (PA) or laurate (LA) and βlg. Our results show that residues localized in loops at the cavity entrance play an important role in the ligand penetration process. Analysis of the short-term interaction energies show that the forces operating on the systems lead to average conformations very close to the crystallographic holo-forms. Whereas the binding free energy analysis using the molecular mechanics Generalized Born surface area method shows that these conformations were thermodynamically favorable.

  9. 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

  10. Quantifying ligand bias at seven-transmembrane receptors.

    PubMed

    Rajagopal, Sudarshan; Ahn, Seungkirl; Rominger, David H; Gowen-MacDonald, William; Lam, Christopher M; Dewire, Scott M; Violin, Jonathan D; Lefkowitz, Robert J

    2011-09-01

    Seven transmembrane receptors (7TMRs), commonly referred to as G protein-coupled receptors, form a large part of the "druggable" genome. 7TMRs can signal through parallel pathways simultaneously, such as through heterotrimeric G proteins from different families, or, as more recently appreciated, through the multifunctional adapters, β-arrestins. Biased agonists, which signal with different efficacies to a receptor's multiple downstream pathways, are useful tools for deconvoluting this signaling complexity. These compounds may also be of therapeutic use because they have distinct functional and therapeutic profiles from "balanced agonists." Although some methods have been proposed to identify biased ligands, no comparison of these methods applied to the same set of data has been performed. Therefore, at this time, there are no generally accepted methods to quantify the relative bias of different ligands, making studies of biased signaling difficult. Here, we use complementary computational approaches for the quantification of ligand bias and demonstrate their application to two well known drug targets, the β2 adrenergic and angiotensin II type 1A receptors. The strategy outlined here allows a quantification of ligand bias and the identification of weakly biased compounds. This general method should aid in deciphering complex signaling pathways and may be useful for the development of novel biased therapeutic ligands as drugs.

  11. NKG2D ligands mediate immunosurveillance of senescent cells.

    PubMed

    Sagiv, Adi; Burton, Dominick G A; Moshayev, Zhana; Vadai, Ezra; Wensveen, Felix; Ben-Dor, Shifra; Golani, Ofra; Polic, Bojan; Krizhanovsky, Valery

    2016-02-01

    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

  12. PSCDB: a database for protein structural change upon ligand binding.

    PubMed

    Amemiya, Takayuki; Koike, Ryotaro; Kidera, Akinori; Ota, Motonori

    2012-01-01

    Proteins are flexible molecules that undergo structural changes to function. The Protein Data Bank contains multiple entries for identical proteins determined under different conditions, e.g. with and without a ligand molecule, which provides important information for understanding the structural changes related to protein functions. We gathered 839 protein structural pairs of ligand-free and ligand-bound states from monomeric or homo-dimeric proteins, and constructed the Protein Structural Change DataBase (PSCDB). In the database, we focused on whether the motions were coupled with ligand binding. As a result, the protein structural changes were classified into seven classes, i.e. coupled domain motion (59 structural changes), independent domain motion (70), coupled local motion (125), independent local motion (135), burying ligand motion (104), no significant motion (311) and other type motion (35). PSCDB provides lists of each class. On each entry page, users can view detailed information about the motion, accompanied by a morphing animation of the structural changes. PSCDB is available at http://idp1.force.cs.is.nagoya-u.ac.jp/pscdb/. PMID:22080505

  13. Analysis of protein-ligand interactions by fluorescence polarization

    PubMed Central

    Rossi, Ana M.; Taylor, Colin W.

    2011-01-01

    Quantification of the associations between biomolecules is required both to predict and understand the interactions that underpin all biological activity. Fluorescence polarization (FP) provides a non-disruptive means of measuring the association of a fluorescent ligand with a larger molecule. We describe an FP assay in which binding of fluorescein-labelled inositol 1,4,5-trisphosphate (IP3) to N-terminal fragments of IP3 receptors can be characterised at different temperatures and in competition with other ligands. The assay allows the standard Gibbs free energy (ΔG°), enthalpy (ΔH°) and entropy (ΔS°) changes of ligand binding to be determined. The method is applicable to any purified ligand-binding site for which an appropriate fluorescent ligand is available. FP can be used to measure low-affinity interactions in real-time without use of radioactive materials, it is non-destructive, and with appropriate care it can resolve ΔH° and ΔS°. The first part of the protocol, protein preparation, may take several weeks, while the FP measurements, once they have been optimised, would normally take 1-6 h. PMID:21372817

  14. PLIP: fully automated protein-ligand interaction profiler.

    PubMed

    Salentin, Sebastian; Schreiber, Sven; Haupt, V Joachim; Adasme, Melissa F; Schroeder, Michael

    2015-07-01

    The characterization of interactions in protein-ligand complexes is essential for research in structural bioinformatics, drug discovery and biology. However, comprehensive tools are not freely available to the research community. Here, we present the protein-ligand interaction profiler (PLIP), a novel web service for fully automated detection and visualization of relevant non-covalent protein-ligand contacts in 3D structures, freely available at projects.biotec.tu-dresden.de/plip-web. The input is either a Protein Data Bank structure, a protein or ligand name, or a custom protein-ligand complex (e.g. from docking). In contrast to other tools, the rule-based PLIP algorithm does not require any structure preparation. It returns a list of detected interactions on single atom level, covering seven interaction types (hydrogen bonds, hydrophobic contacts, pi-stacking, pi-cation interactions, salt bridges, water bridges and halogen bonds). PLIP stands out by offering publication-ready images, PyMOL session files to generate custom images and parsable result files to facilitate successive data processing. The full python source code is available for download on the website. PLIP's command-line mode allows for high-throughput interaction profiling.

  15. Mechanokinetics of receptor-ligand interactions in cell adhesion

    NASA Astrophysics Data System (ADS)

    Li, Ning; Lü, Shouqin; Zhang, Yan; Long, Mian

    2015-04-01

    Receptor-ligand interactions in blood flow are crucial to initiate such biological processes as inflammatory cascade, platelet thrombosis, as well as tumor metastasis. To mediate cell adhesion, the interacting receptors and ligands must be anchored onto two apposing surfaces of two cells or a cell and a substratum, i.e., two-dimensional (2D) binding, which is different from the binding of a soluble ligand in fluid phase to a receptor, i.e., three-dimensional (3D) binding. While numerous works have been focused on 3D kinetics of receptor-ligand interactions in the immune system, 2D kinetics and its regulations have been less understood, since no theoretical framework or experimental assays were established until 1993. Not only does the molecular structure dominate 2D binding kinetics, but the shear force in blood flow also regulates cell adhesion mediated by interacting receptors and ligands. Here, we provide an overview of current progress in 2D binding and regulations, mainly from our group. Relevant issues of theoretical frameworks, experimental measurements, kinetic rates and binding affinities, and force regulations are discussed.

  16. 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. PMID:23762824

  17. 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.

  18. PLIP: fully automated protein-ligand interaction profiler.

    PubMed

    Salentin, Sebastian; Schreiber, Sven; Haupt, V Joachim; Adasme, Melissa F; Schroeder, Michael

    2015-07-01

    The characterization of interactions in protein-ligand complexes is essential for research in structural bioinformatics, drug discovery and biology. However, comprehensive tools are not freely available to the research community. Here, we present the protein-ligand interaction profiler (PLIP), a novel web service for fully automated detection and visualization of relevant non-covalent protein-ligand contacts in 3D structures, freely available at projects.biotec.tu-dresden.de/plip-web. The input is either a Protein Data Bank structure, a protein or ligand name, or a custom protein-ligand complex (e.g. from docking). In contrast to other tools, the rule-based PLIP algorithm does not require any structure preparation. It returns a list of detected interactions on single atom level, covering seven interaction types (hydrogen bonds, hydrophobic contacts, pi-stacking, pi-cation interactions, salt bridges, water bridges and halogen bonds). PLIP stands out by offering publication-ready images, PyMOL session files to generate custom images and parsable result files to facilitate successive data processing. The full python source code is available for download on the website. PLIP's command-line mode allows for high-throughput interaction profiling. PMID:25873628

  19. Preparation and crystallization of riboswitch-ligand complexes.

    PubMed

    Pikovskaya, Olga; Serganov, Artem A; Polonskaia, Ann; Serganov, Alexander; Patel, Dinshaw J

    2009-01-01

    Riboswitches are mRNA regions that regulate the expression of genes in response to various cellular metabolites. These RNA sequences, typically situated in the untranslated regions of mRNAs, possess complex structures that dictate highly specific binding to certain ligands, such as nucleobases, coenzymes, amino acids, and sugars, without protein assistance. Depending on the presence of the ligand, metabolite-binding domains of riboswitches can adopt two alternative conformations, which define the conformations of the adjacent sequences involved in the regulation of gene expression. In order to understand in detail the nature of riboswitch-ligand interactions and the molecular basis of riboswitch-based gene expression control, it is necessary to determine the three-dimensional structures of riboswitch-ligand complexes. This chapter outlines the techniques that are employed to prepare riboswitch-ligand complexes for structure determination using X-ray crystallography. The chapter describes the principles of construct design, in vitro transcription, RNA purification, complex formation, and crystallization screening utilized during the successful crystallization of several riboswitches. PMID:19381556

  20. 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

  1. Structure-guided development of heterodimer-selective GPCR ligands

    PubMed Central

    Hübner, Harald; Schellhorn, Tamara; Gienger, Marie; Schaab, Carolin; Kaindl, Jonas; Leeb, Laurin; Clark, Timothy; Möller, Dorothee; Gmeiner, Peter

    2016-01-01

    Crystal structures of G protein-coupled receptor (GPCR) ligand complexes allow a rational design of novel molecular probes and drugs. Here we report the structure-guided design, chemical synthesis and biological investigations of bivalent ligands for dopamine D2 receptor/neurotensin NTS1 receptor (D2R/NTS1R) heterodimers. The compounds of types 1–3 consist of three different D2R pharmacophores bound to an affinity-generating lipophilic appendage, a polyethylene glycol-based linker and the NTS1R agonist NT(8-13). The bivalent ligands show binding affinity in the picomolar range for cells coexpressing both GPCRs and unprecedented selectivity (up to three orders of magnitude), compared with cells that only express D2Rs. A functional switch is observed for the bivalent ligands 3b,c inhibiting cAMP formation in cells singly expressing D2Rs but stimulating cAMP accumulation in D2R/NTS1R-coexpressing cells. Moreover, the newly synthesized bivalent ligands show a strong, predominantly NTS1R-mediated β-arrestin-2 recruitment at the D2R/NTS1R-coexpressing cells. PMID:27457610

  2. 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.

  3. Ligand structure and mechanical properties of single-nanoparticle thick membranes

    DOE PAGESBeta

    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 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

  4. Ligand structure and mechanical properties of single-nanoparticle-thick membranes.

    PubMed

    Salerno, K Michael; Bolintineanu, Dan S; Lane, J Matthew D; Grest, Gary S

    2015-06-01

    The high mechanical stiffness of single-nanoparticle-thick membranes is believed to result from 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 (CH(3)) 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. Moreover, the particular end group (COOH or CH(3)) 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.

  5. Ligand structure and mechanical properties of single-nanoparticle-thick membranes

    NASA Astrophysics Data System (ADS)

    Salerno, K. Michael; Bolintineanu, Dan S.; Lane, J. Matthew D.; Grest, Gary S.

    2015-06-01

    The high mechanical stiffness of single-nanoparticle-thick membranes is believed to result from 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. Moreover, 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.

  6. A synthetic chemomechanical machine driven by ligand-receptor bonding.

    PubMed

    Lavella, Gabriel J; Jadhav, Amol D; Maharbiz, Michel M

    2012-09-12

    The ability to create synthetic chemomechanical machines with engineered functionality promises large technological rewards. However, current efforts in molecular chemistry are restrained by the formidable challenges faced in molecular structure and function prediction. An alternative approach to engineering machines with tailorable chemomechanical functionality is to design Brownian ratchet devices using molecular assemblies. We demonstrate this through the creation of autonomous molecular machines that sense, mechanically react, and extract energy from ligand-receptor binding. We present a specific instantiation, measuring approximately 100 nm in length, which actuates upon detection of a streptavidin ligand. Machines were designed through the tailoring of energy landscapes on 3D DNA origami motifs. We also analyzed the response over a logarithmic concentration ratio (device:ligand) range from 1:10(1) to 1:10(5). PMID:22920279

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. Regulation of G Protein-Coupled Receptors by Allosteric Ligands

    PubMed Central

    2013-01-01

    Topographically distinct, druggable, allosteric sites may be present on all G protein-coupled receptors (GPCRs). As such, targeting these sites with synthetic small molecules offers an attractive approach to develop receptor-subtype selective chemical leads for the development of novel therapies. A crucial part of drug development is to understand the acute and chronic effects of such allosteric modulators at their corresponding GPCR target. Key regulatory processes including cell-surface delivery, endocytosis, recycling, and down-regulation tightly control the number of receptors at the surface of the cell. As many GPCR therapeutics will be administered chronically, understanding how such ligands modulate these regulatory pathways forms an essential part of the characterization of novel GPCR ligands. This is true for both orthosteric and allosteric ligands. In this Review, we summarize our current understanding of GPCR regulatory processes with a particular focus on the effects and implications of allosteric targeting of GPCRs. PMID:23398684

  12. Advances Towards The Discovery of GPR55 Ligands.

    PubMed

    Morales, Paula; Jagerovic, Nadine

    2016-01-01

    The G-protein-coupled receptor 55 (GPR55) was identified in 1999. It was proposed as a novel member of the endocannabinoid system due to the fact that some endogenous, plant-derived and synthetic cannabinoid ligands act on GPR55. However, the complexity of the cellular downstream signaling pathways related to GPR55 activation delayed the discovery of selective GPR55 ligands. It was only a few years ago that the high throughput screening of libraries of pharmaceutical companies and governmental organizations allowed to identify selective GPR55 agonists and antagonists. Since then, several GPR55 modulator scaffolds have been reported. The relevance of GPR55 has been explored in diverse physiological and pathological processes revealing its role in inflammation, neuropathic pain, bone physiology, diabetes and cancer. Considering GPR55 as a new promising therapeutic target, there is a clear need for new selective and potent GPR55 modulators. This review will address a current structural update of GPR55 ligands.

  13. Nicotinic acetylcholine receptor ligands; a patent review (2006-2011)

    PubMed Central

    Gündisch, Daniela; Eibl, Christoph

    2012-01-01

    Introduction Nicotinic acetylcholine receptors (nAChRs), pentameric ligand-gated cation channels, are potential targets for the development of therapeutics for a variety of disease states. Areas covered This article is reviewing recent advances in the development of small molecule ligands for diverse nAChR subtypes and is a continuation of an earlier review in this journal. Expert opinion The development of nAChR ligands with preference for α4β2 or α7 subtypes for the treatment of CNS disorders are in the most advanced developmental stage. In addition, there is a fast growing interest to generate so-called PAMs, positive allosteric modulators, to influence the channels’ functionalities. PMID:22098319

  14. 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

    2015-05-01

    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.

  15. Heterobifunctional PEG Ligands for Bioconjugation Reactions on Iron Oxide Nanoparticles

    PubMed Central

    Bloemen, Maarten; Van Stappen, Thomas; Willot, Pieter; Lammertyn, Jeroen; Koeckelberghs, Guy; Geukens, Nick; Gils, Ann; Verbiest, Thierry

    2014-01-01

    Ever since iron oxide nanoparticles have been recognized as promising scaffolds for biomedical applications, their surface functionalization has become even more important. We report the synthesis of a novel polyethylene glycol-based ligand that combines multiple advantageous properties for these applications. The ligand is covalently bound to the surface via a siloxane group, while its polyethylene glycol backbone significantly improves the colloidal stability of the particle in complex environments. End-capping the molecule with a carboxylic acid introduces a variety of coupling chemistry possibilities. In this study an antibody targeting plasminogen activator inhibitor-1 was coupled to the surface and its presence and binding activity was assessed by enzyme-linked immunosorbent assay and surface plasmon resonance experiments. The results indicate that the ligand has high potential towards biomedical applications where colloidal stability and advanced functionality is crucial. PMID:25275378

  16. Small-molecule microarrays as tools in ligand discovery

    PubMed Central

    Vegas, Arturo J.; Fuller, Jason H.; Koehler, Angela N.

    2009-01-01

    Small molecules that bind and modulate specific protein targets are increasingly used as tools to decipher protein function in a cellular context. Identifying specific small-molecule probes for each protein in the proteome will require miniaturized assays that permit screening large collections of compounds against large numbers of proteins in a highly parallel fashion. Simple and general binding assays involving small-molecule microarrays can be used to identify probes for nearly any protein in the proteome. The assay may be used to identify ligands for proteins in the absence of knowledge about structure or function. In this tutorial review, we introduce small-molecule microarrays (SMMs) as tools for ligand discovery; discuss methods for manufacturing SMMs, including both non-covalent and covalent attachment strategies; and provide examples of ligand discovery involving SMMs. PMID:18568164

  17. Mononuclear and Oligonuclear Manganese Complexes with Organic Multidentate Ligands

    NASA Astrophysics Data System (ADS)

    Mikuriya, Masahiro

    The crystal structures of manganese complexes with tridentate, tetradentate, pentadentate, hexadentate, and dodecadentate ligands with oxygen and nitrogen donors are described. Reactions of these ligands with manganese salts afforded mononuclear (MnII, MnIII, and MnIV), dinuclear (MnII2, MnIII2, and MnIIMnIII), trinuclear (MnIII3), and tetranuclear (MnII2MnIII2 and MnIII4) complexes. As for MnII complexes, octahedral, trigonal prismatic, capped trigonal prismatic, and square antiprismatic geometries were found depending on the combination of the organic and anionic ligands. In the case of MnIII complexes, the Jahn-Teller distortions due to the high-spin d4 electronic configuration were observed as elongated or compressed octahedral geometries. An octahedral geometry was confirmed for the Mn (IV) complexes.

  18. 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.

  19. Memetic algorithms for ligand expulsion from protein cavities.

    PubMed

    Rydzewski, J; Nowak, W

    2015-09-28

    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. PMID:26428990

  20. A Rapid Method for Refolding Cell Surface Receptors and Ligands

    PubMed Central

    Zhai, Lu; Wu, Ling; Li, Feng; Burnham, Robert S.; Pizarro, Juan C.; Xu, Bin

    2016-01-01

    Production of membrane-associated cell surface receptors and their ligands is often a cumbersome, expensive, and time-consuming process that limits detailed structural and functional characterization of this important class of proteins. Here we report a rapid method for refolding inclusion-body-based, recombinant cell surface receptors and ligands in one day, a speed equivalent to that of soluble protein production. This method efficiently couples modular on-column immobilized metal ion affinity purification and solid-phase protein refolding. We demonstrated the general utility of this method for producing multiple functionally active immunoreceptors, ligands, and viral decoys, including challenging cell surface proteins that cannot be produced using typical dialysis- or dilution-based refolding approaches. PMID:27215173

  1. Activation of Neuropeptide FF Receptors by Kisspeptin Receptor Ligands.

    PubMed

    Oishi, Shinya; Misu, Ryosuke; Tomita, Kenji; Setsuda, Shohei; Masuda, Ryo; Ohno, Hiroaki; Naniwa, Yousuke; Ieda, Nahoko; Inoue, Naoko; Ohkura, Satoshi; Uenoyama, Yoshihisa; Tsukamura, Hiroko; Maeda, Kei-Ichiro; Hirasawa, Akira; Tsujimoto, Gozoh; Fujii, Nobutaka

    2011-01-13

    Kisspeptin is a member of the RFamide neuropeptide family that is implicated in gonadotropin secretion. Because kisspeptin-GPR54 signaling is implicated in the neuroendocrine regulation of reproduction, GPR54 ligands represent promising therapeutic agents against endocrine secretion disorders. In the present study, the selectivity profiles of GPR54 agonist peptides were investigated for several GPCRs, including RFamide receptors. Kisspeptin-10 exhibited potent binding and activation of neuropeptide FF receptors (NPFFR1 and NPFFR2). In contrast, short peptide agonists bound with much lower affinity to NPFFRs while showing relatively high selectivity toward GPR54. The possible localization of secondary kisspeptin targets was also demonstrated by variation in the levels of GnRH release from the median eminence and the type of GPR54 agonists used. Negligible affinity of the reported NPFFR ligands to GPR54 was observed and indicates the unidirectional cross-reactivity between both ligands.

  2. Expression of notch receptors and ligands in the adult gut.

    PubMed

    Sander, Guy R; Powell, Barry C

    2004-04-01

    The Notch signaling pathway has become recognized as a vitally important pathway in regulating proliferative/differentiative decisions and cell fate. To explore the involvement of the Notch pathway in adult gut, we investigated the expression of Notch receptors and their ligands by Northern blotting and in situ hybridization. Notch receptors and ligands were expressed in both proliferative and post-mitotic cells throughout adult rat gut, variously in epithelial, immune, and endothelial cells. Expression of Notch1, Jagged1, and Jagged2 frequently overlapped, whereas Notch2 expression was restricted to specific crypt cells, the lamina propria of the large intestine, and Peyer's patch lymphocytes. We propose that the expression of multiple Notch receptors and ligands in a range of different intestinal cell types indicates that this signaling pathway underpins many of the processes involved in the maintenance and function of the adult gut.

  3. 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. PMID:25001925

  4. Protein-ligand and membrane-ligand interactions in pharmacology: the case of the translocator protein (TSPO).

    PubMed

    Hatty, Claire R; Banati, Richard B

    2015-10-01

    The targets of many small molecule drugs are membrane proteins, and traditionally the focus of pharmacology is on the interaction between such receptors and their small molecule drug ligands. However, the lipid membranes of cells and organelles are increasingly appreciated as diverse and dynamic structures that also specifically interact with small molecule drugs and peptides, causing profound changes in the properties of these membranes, and modulating the function of the membrane and the proteins within it. Drug-membrane interactions are likely to have a role in both the therapeutic and toxic activity of a variety of compounds, and their role in the overall pharmacological effect of a drug needs to be understood more clearly. This is the case for the 18 kDa translocator protein (TSPO) and its ligands, where functions that were established based on pharmacological studies are being called into question. Re-examining the putative functions of the TSPO and the effects of its ligands reveals a need to consider in more detail the interplay between protein-ligand and membrane-ligand interactions, and the modulatory relationship between TSPO and the lipid membrane.

  5. A tandem regression-outlier analysis of a ligand cellular system for key structural modifications around ligand binding

    PubMed Central

    2013-01-01

    Background A tandem technique of hard equipment is often used for the chemical analysis of a single cell to first isolate and then detect the wanted identities. The first part is the separation of wanted chemicals from the bulk of a cell; the second part is the actual detection of the important identities. To identify the key structural modifications around ligand binding, the present study aims to develop a counterpart of tandem technique for cheminformatics. A statistical regression and its outliers act as a computational technique for separation. Results A PPARγ (peroxisome proliferator-activated receptor gamma) agonist cellular system was subjected to such an investigation. Results show that this tandem regression-outlier analysis, or the prioritization of the context equations tagged with features of the outliers, is an effective regression technique of cheminformatics to detect key structural modifications, as well as their tendency of impact to ligand binding. Conclusions The key structural modifications around ligand binding are effectively extracted or characterized out of cellular reactions. This is because molecular binding is the paramount factor in such ligand cellular system and key structural modifications around ligand binding are expected to create outliers. Therefore, such outliers can be captured by this tandem regression-outlier analysis. PMID:23627990

  6. Conformational diversity of flexible ligand in metal-organic frameworks controlled by size-matching mixed ligands

    NASA Astrophysics Data System (ADS)

    Hua, Xiu-Ni; Qin, Lan; Yan, Xiao-Zhi; Yu, Lei; Xie, Yi-Xin; Han, Lei

    2015-12-01

    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-H2ndc) or 4,4‧-(hydroxymethylene)dibenzoic acid (H2hmdb), in the presence of cadmium(II) salts have given rise to two novel metal-organic frameworks based on flexible ligands (FL-MOFs), namely, [Cd2(2,6-ndc)2(bpp)(DMF)]·2DMF (1) and [Cd3(hmdb)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.

  7. New formamidine ligands and their mixed ligand palladium(II) oxalate complexes: Synthesis, characterization, DFT calculations and in vitro cytotoxicity

    NASA Astrophysics Data System (ADS)

    Soliman, Ahmed A.; Alajrawy, Othman I.; Attabi, Fawzy A.; Shaaban, Mohamed R.; Linert, W.

    2016-01-01

    A series of new ternary palladium(II) complexes of the type [Pd(L1-4)ox]·xH2O where L = formamidine ligands and ox = oxalate, were synthesized and characterized by elemental analyses, magnetic susceptibility, UV-Vis, infrared (IR) and mass spectroscopy and thermal analysis. The spectroscopic data indicated that the formamidine ligands act as bidentate N2 donors and the oxalate as O2 ligand. The complexes (1-4) are diamagnetic and the optimization of their structures indicated that the geometry is distorted square planer with O-Pd-O and N-Pd-N bond angles ranged 82.70-83.87° and 88.21-95.02°; respectively which is acceptable for the heteroleptic complexes. The dipole moment of the complexes (13.97-18.77 Debye) indicating that the complexes are more polarized than the ligands (1.93-4.96 Debye). The complexes are thermally stable as shown from their relatively higher overall activation energies (441-688 kJ mol-1). The ligands and the complexes are proved to have good cytotoxicity with IC50 (μM) in the range of (0.011-0.168) against MCF-7, (0.012-0.150) against HCT-116, (0.042-0.094) against PC-3 and (0.006-0.222) against HepG-2 cell lines, which open the field for further application as antitumor compounds.

  8. Terephthalamide-containing ligands: fast removal of iron from transferrin.

    PubMed

    Abergel, Rebecca J; Raymond, Kenneth N

    2008-02-01

    The mechanism and effectiveness of iron removal from transferrin by three series of new potential therapeutic iron sequestering agents have been analyzed with regard to the structures of the chelators. All compounds are hexadentate ligands composed of a systematically varied combination of methyl-3,2-hydroxypyridinone (Me-3,2-HOPO) and 2,3-dihydroxyterephthalamide (TAM) binding units linked to a polyamine scaffold through amide linkers; each series is based on a specific backbone: tris(2-aminoethyl)amine, spermidine, or 5-LIO(TAM), where 5-LIO is 2-(2-aminoethoxy)ethylamine. Rates of iron removal from transferrin were determined spectrophotometrically for the ten ligands, which all efficiently acquire ferric ion from diferric transferrin with a hyperbolic dependence on ligand concentration (saturation kinetics). The effect of the two iron-binding subunits Me-3,2-HOPO and TAM and of the scaffold structures on iron removal ability is discussed. At the low concentrations corresponding to therapeutic dose, TAM-containing ligands exhibit the fastest rates of iron removal, which correlates with their high affinity for ferric ion and suggests the insertion of such binding units into future therapeutic chelating agents. In addition, urea polyacrylamide gel electrophoresis was used to measure the individual microscopic rates of iron removal from the three iron-bound transferrin species (diferric transferrin, N-terminal monoferric transferrin, C-terminal monoferric transferrin) by the representative chelators 5-LIO(Me-3,2-HOPO)(2)(TAM) and 5-LIO(TAMmeg)(2)(TAM), where TAMmeg is 2,3-dihydroxy-1-(methoxyethylcarbamoyl)terephthalamide. Both ligands show preferential removal from the C-terminal site of the iron-binding protein. However, cooperative effects between the two binding sites differ with the chelator. Replacement of hydroxypyridinone moieties by terephthalamide groups renders the N-terminal site more accessible to the ligand and may represent an advantage for iron

  9. 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).

  10. Ligand Control of Manganese Telluride Molecular Cluster Core Nuclearity.

    PubMed

    Choi, Bonnie; Paley, Daniel W; Siegrist, Theo; Steigerwald, Michael L; Roy, Xavier

    2015-09-01

    We report the synthesis, structural diversity, and chemical behavior of a family of manganese telluride molecular clusters whose charge-neutral cores are passivated by two-electron donor ligands. We describe three different core structures: a cubane-type Mn4Te4, a prismane Mn6Te6, and a dicubane Mn8Te8. We use various trialkylphosphines and N-heterocyclic carbenes (NHCs) as surface ligands and demonstrate that the formation of the different cluster core structures is controlled by the choice of ligand: bulky ligands such as P(i)Pr3, PCy3, or (i)Pr2NHC ((i)Pr2NHC = 1,3-diisopropyl-4,5-dimethylimidazol-2-ylidene) form the cubane-type core, while the smaller PMe3 produces the prismane core. The intermediate-sized PEt3 produces both cubane and prismane species. These manganese telluride molecular clusters are labile, and the capping phosphines can be replaced by stronger ligands, while the internal core structure of the cluster remains intact. The interplay of structural diversity and ligand versatility and lability makes these clusters potentially useful building blocks for the assembly of larger aggregates and extended structures. We demonstrate the simplest prototype of these solid-forming reactions: the direct coupling of two Mn4Te4((i)Pr2NHC)4 units to form the dicubane Mn8Te8((i)Pr2NHC)6. We also postulate the prismatic Mn6Te6 as the common ancestor of both Chevrel-type M6E8 and octanuclear rhombododecahedral M8E6 molecular clusters (M = transition metal and E = chalcogen), and we discuss the core structure of our molecular clusters as recognizable building units for the zinc blende and the hypothetical wurtzite lattices of MnTe.

  11. Solvent fluctuations in hydrophobic cavity–ligand binding kinetics

    PubMed Central

    Setny, Piotr; Baron, Riccardo; Michael Kekenes-Huskey, Peter; McCammon, J. Andrew; Dzubiella, Joachim

    2013-01-01

    Water plays a crucial part in virtually all protein–ligand binding processes in and out of equilibrium. Here, we investigate the role of water in the binding kinetics of a ligand to a prototypical hydrophobic pocket by explicit-water molecular dynamics (MD) simulations and implicit diffusional approaches. The concave pocket in the unbound state exhibits wet/dry hydration oscillations whose magnitude and time scale are significantly amplified by the approaching ligand. In turn, the ligand’s stochastic motion intimately couples to the slow hydration fluctuations, leading to a sixfold-enhanced friction in the vicinity of the pocket entrance. The increased friction considerably decelerates association in the otherwise barrierless system, indicating the importance of molecular-scale hydrodynamic effects in cavity–ligand binding arising due to capillary fluctuations. We derive and analyze the diffusivity profile and show that the mean first passage time distribution from the MD simulation can be accurately reproduced by a standard Brownian dynamics simulation if the appropriate position-dependent friction profile is included. However, long-time decays in the water–ligand (random) force autocorrelation demonstrate violation of the Markovian assumption, challenging standard diffusive approaches for rate prediction. Remarkably, the static friction profile derived from the force correlations strongly resembles the profile derived on the Markovian assumption apart from a simple shift in space, which can be rationalized by a time–space retardation in the ligand’s downhill dynamics toward the pocket. The observed spatiotemporal hydrodynamic coupling may be of biological importance providing the time needed for conformational receptor–ligand adjustments, typical of the induced-fit paradigm. PMID:23297241

  12. 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

  13. Use of protein-engineered fabrics to identify design rules for integrin ligand clustering in biomaterials.

    PubMed

    Benitez, Patrick L; Mascharak, Shamik; Proctor, Amy C; Heilshorn, Sarah C

    2016-01-01

    While ligand clustering is known to enhance integrin activation, this insight has been difficult to apply to the design of implantable biomaterials because the local and global ligand densities that enable clustering-enhanced integrin signaling were unpredictable. Here, two general design principles for biomaterial ligand clustering are elucidated. First, clustering ligands enhances integrin-dependent signals when the global ligand density, i.e., the ligand density across the cellular length scale, is near the ligand's effective dissociation constant (KD,eff). Second, clustering ligands enhances integrin activation when the local ligand density, i.e., the ligand density across the length scale of individual focal adhesions, is less than an overcrowding threshold. To identify these principles, we fabricated a series of elastin-like, electrospun fabrics with independent control over the local (0 to 122 000 ligands μm(-2)) and global (0 to 71 000 ligand μm(-2)) densities of an arginine-glycine-aspartate (RGD) ligand. Antibody blocking studies confirmed that human umbilical vein endothelial cell adhesion to these protein-engineered biomaterials was primarily due to αVβ3 integrin binding. Clustering ligands enhanced cell proliferation, focal adhesion number, and focal adhesion kinase expression near the ligand's KD,eff of 12 000 RGD μm(-2). Near this global ligand density, cells on ligand-clustered fabrics behaved similarly to cells grown on fabrics with significantly larger global ligand densities but without clustering. However, this enhanced ligand-clustering effect was not observed above a threshold cut-off concentration. At a local ligand density of 122 000 RGD μm(-2), cell division, focal adhesion number, and focal adhesion kinase expression were significantly reduced relative to fabrics with identical global ligand density and lesser local ligand densities. Thus, when clustering results in overcrowding of ligands, integrin receptors are no longer

  14. [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.

  15. Design and synthesis of 60° dendritic donor ligands and their coordination-driven self-assembly into supramolecular rhomboidal metallodendrimers.

    PubMed

    Han, Qing; Li, Quan-Jie; He, Jiuming; Hu, Bingjie; Tan, Hongwei; Abliz, Zeper; Wang, Cui-Hong; Yu, Yihua; Yang, Hai-Bo

    2011-12-01

    The design and self-assembly of novel rhomboidal metallodendrimers via coordination-driven self-assembly is described. By employing newly designed 60° ditopic donor linkers substituted with Fréchet-type dendrons and appropriate 120° rigid di-Pt(II) acceptor subunits, a variety of [G-1]-[G-3] rhomboidal metallodendrimers with well-defined shape and size were prepared under mild conditions in high yields. The supramolecular metallodendrimers were characterized with multinuclear NMR ((1)H and (31)P), mass spectrometry (CSI-TOF-MS), and elemental analysis. Isotopically resolved mass spectrometry data support the existence of the metallodendrimers with rhomboidal cavities, and NMR data were consistent with the formation of all ensembles. The shape and size of all rhomboidal metallodendrimers were investigated with the PM6 semiempirical molecular orbital method.

  16. Discovery of Potent Dual PPARα Agonists/CB1 Ligands

    PubMed Central

    2011-01-01

    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. PMID:24936232

  17. Mesoporous organosilica nanotubes containing a chelating ligand in their walls

    NASA Astrophysics Data System (ADS)

    Liu, Xiao; Goto, Yasutomo; Maegawa, Yoshifumi; Ohsuna, Tetsu; Inagaki, Shinji

    2014-11-01

    We report the synthesis of organosilica nanotubes containing 2,2'-bipyridine chelating ligands within their walls, employing a single-micelle-templating method. These nanotubes have an average pore diameter of 7.8 nm and lengths of several hundred nanometers. UV-vis absorption spectra and scanning transmission electron microscopy observations of immobilized nanotubes with an iridium complex on the bipyridine ligands showed that the 2,2'-bipyridine groups were homogeneously distributed in the benzene-silica walls. The iridium complex, thus, immobilized on the nanotubes exhibited efficient catalytic activity for water oxidation using Ce4+, due to the ready access of reactants to the active sites in the nanotubes.

  18. 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. PMID:24936232

  19. 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.

  20. Bonding in titanocenyl complexes containing O,O‧-cyclic ligands

    NASA Astrophysics Data System (ADS)

    Conradie, Jeanet

    Density functional theory calculations show that the formal 16-electron count of d0 [Cp2TiIV(O,O‧-BID)]0/1 complexes containing a O,O‧-chelated bidentate ligand O,O‧-BID of different ring size, is increased via Ti←O π bonding when both the O donor atoms carry a formal negative charge. The Ti←O π bonding occurs by symmetry lowering of the complex by either symmetrical (Cs) or unsymmetrical (C2) folding of the O,O‧-BID ligand round the O···O axis. An NBO analysis confirms the Ti←O π charge transfer via back-bonding.

  1. 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.

  2. 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

  3. Luminescent cyclometallated iridium(III) complexes having acetylide ligands

    SciTech Connect

    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.

  4. Calculation of Mg(+)-ligand relative binding energies

    NASA Technical Reports Server (NTRS)

    Partridge, Harry; Bauschlicher, Charles W., Jr.

    1992-01-01

    The calculated relative binding energies of 16 organic molecules to Mg(+) are compared with experimental results where available. The geometries of the ligands and the Mg(+)-ligand complexes arc optimized at the self-consistent field level using a 6-31G* basis set. The Mg(+) binding energies are evaluated using second-order perturbation theory and basis sets of triple-sigma quality augmented with two sets of polarization functions. This level of theory is calibrated against higher levels of theory for selected systems. The computed binding energies are accurate to about 2 kcal/mol.

  5. 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.

  6. CHEMICAL GENETICS: LIGAND-BASED DISCOVERY OF GENE FUNCTION

    PubMed Central

    Stockwell, Brent R.

    2011-01-01

    Chemical genetics is the study of gene-product function in a cellular or organismal context using exogenous ligands. In this approach, small molecules that bind directly to proteins are used to alter protein function, enabling a kinetic analysis of the in vivo consequences of these changes. Recent advances have strongly enhanced the power of exogenous ligands such that they can resemble genetic mutations in terms of their general applicability and target specificity. The growing sophistication of this approach raises the possibility of its application to any biological process. PMID:11253651

  7. A liposomal drug platform overrides peptide ligand targeting to a cancer biomarker, irrespective of ligand affinity or density.

    PubMed

    Gray, Bethany Powell; McGuire, Michael J; Brown, Kathlynn C

    2013-01-01

    One method for improving cancer treatment is the use of nanoparticle drugs functionalized with targeting ligands that recognize receptors expressed selectively by tumor cells. In theory such targeting ligands should specifically deliver the nanoparticle drug to the tumor, increasing drug concentration in the tumor and delivering the drug to its site of action within the tumor tissue. However, the leaky vasculature of tumors combined with a poor lymphatic system allows the passive accumulation, and subsequent retention, of nanosized materials in tumors. Furthermore, a large nanoparticle size may impede tumor penetration. As such, the role of active targeting in nanoparticle delivery is controversial, and it is difficult to predict how a targeted nanoparticle drug will behave in vivo. Here we report in vivo studies for αvβ6-specific H2009.1 peptide targeted liposomal doxorubicin, which increased liposomal delivery and toxicity to lung cancer cells in vitro. We systematically varied ligand affinity, ligand density, ligand stability, liposome dosage, and tumor models to assess the role of active targeting of liposomes to αvβ6. In direct contrast to the in vitro results, we demonstrate no difference in in vivo targeting or efficacy for H2009.1 tetrameric peptide liposomal doxorubicin, compared to control peptide and no peptide liposomes. Examining liposome accumulation and distribution within the tumor demonstrates that the liposome, and not the H2009.1 peptide, drives tumor accumulation, and that both targeted H2009.1 and untargeted liposomes remain in perivascular regions, with little tumor penetration. Thus H2009.1 targeted liposomes fail to improve drug efficacy because the liposome drug platform prevents the H2009.1 peptide from both actively targeting the tumor and binding to tumor cells throughout the tumor tissue. Therefore, using a high affinity and high specificity ligand targeting an over-expressed tumor biomarker does not guarantee enhanced efficacy of a

  8. Tunable Phosphoramidite Ligands for Asymmetric Hydrovinylation: Ligands par excellence for Generation of All-Carbon Quaternary Centers

    PubMed Central

    Smith, Craig R.; Lim, Hwan Jung; Zhang, Aibin; RajanBabu, T. V.

    2009-01-01

    1-Alkylstyrenes undergo efficient hydrovinylation (addition of ethylene) in the presence of a Ni-catalyst prepared from [(allyl)NiBr]2, Na+ [BAr4]− (Ar = 3,5-bis-trifluromethylphenyl), and a phosphoramidite ligand giving products in excellent yields and enantioselectivities. In many cases phosphoramidites derived from achiral 2,2′-biphenol are almost as good as ligands derived from the more expensive enantiopure 2,2′-binaphthols. The hydrovinylation products, which carry two versatile latent functionalities, an aryl and a vinyl group, are potentially useful for the synthesis of several important natural products containing benzylic all-carbon quaternary centers. PMID:19763244

  9. 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.

  10. Mixed ligand complexes of bis(phenylimine) Schiff base ligands incorporating pyridinium moiety. Synthesis, characterization and antibacterial activity

    NASA Astrophysics Data System (ADS)

    Mohamed, Gehad G.; El-Wahab, Zeinab H. Abd

    2005-04-01

    The synthesis and structural characterization of mixed ligand complexes derived from 2,6-pyridinedicarboxaldehydebis( o-hydroxyphenylimine), 2,6-pyridinedicarboxaldehydebis( p-hydroxyphenylimine) (1 ry ligands) and 2-aminopyridne (2 ry ligand) are reported. The ligands and their transition metal complexes were characterized on the bases of their elemental analyses, IR, solid reflectance, magnetic moment, molar conductance and thermal analysis (TGA). The mixed ligand complexes are formed in the 1:1:1 (M:L 1 or L 2:L') ratio as found from the elemental analyses and found to have the formulae [MX 2(L 1 or L 2)(L')]· nH 2O where M = Co(II), Ni(II), Cu(II) and Zn(II), L 1 = 2,6-pyridinedicarboxaldehydebis( p-hydroxyphenylimine), L 2 = 2,6-pyridine dicarboxaldehydebis( o-hydroxyphenylimine), L' = 2-aminopyridine, X = Cl - in case of Cu(II) complex and Br - in case of Co(II), Ni(II) and Zn(II) complexes and y = 0-3. The molar conductance data reveal that the chelates are non-electrolytes. IR spectra show that the Schiff bases are coordinated to the metal ions in a terdentate manner with NNN donor sites of the pyridine- N and two azomethine- N. While 2-aminopyridine coordinated to the metal ions via its pyridine- N. Magnetic and solid reflectance spectra are used to infer the coordinating capacity of the ligand and the geometrical structure of these complexes are found to be octahedral. The thermal behaviour of these chelates shows that the hydrated water molecules and the anions are removed in a successive two steps followed immediately by decomposition of the ligands (L 1, L 2 and L') in the subsequent steps. The activation thermodynamic parameters, such as, E*, Δ H*, Δ S* and Δ G* are calculated from the TG curves and discussed. The ligands and their metal chelates have been screened for their antimicrobial activities and the findings have been reported, explained and compared with some known antibiotics.

  11. 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

  12. 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.

  13. Time-dynamic imaging of individual cell ligand binding kinetics

    NASA Astrophysics Data System (ADS)

    Gross, David; Chung, Johnson

    1997-05-01

    Ligand-binding assays are commonly applied to large numbers of cells in culture; the binding parameters derived from such assays reflect the ensemble average behavior of many cells. Equilibrium binding assays of epidermal growth factor (EGF) binding to the EGF receptor (EGFR) indicate that the EGFR exhibits two affinity states for EGF, one low affinity with Kd about 10 nM and one high affinity with Kd < 1 nM. Bulk binding studies cannot determined if such multiple ligand binding classes are due to cell population heterogeneity or are due to heterogeneity at the individual cell level. Here is described a technique based on single cell imaging of fluorescein-EGF (f-EGF) binding to individual human epidermoid carcinoma A431 cells that demonstrates that both classes of EGFR are found on all A431 cells, that the time course of f-EGF binding to individual cells shows two kinetic on-rates and two off-rates, that cell-to-cell heterogeneity of EGF binding is significant and that ligand binding kinetics vary across an individual cell. Contributions of cell autofluorescence photobleaching and f- EGF photobleaching in the measurement of fluorescent ligand binding are shown to be significant.

  14. Proteus and the Design of Ligand Binding Sites.

    PubMed

    Polydorides, Savvas; Michael, Eleni; Mignon, David; Druart, Karen; Archontis, Georgios; Simonson, Thomas

    2016-01-01

    This chapter describes the organization and use of Proteus, a multitool computational suite for the optimization of protein and ligand conformations and sequences, and the calculation of pK α shifts and relative binding affinities. The software offers the use of several molecular mechanics force fields and solvent models, including two generalized Born variants, and a large range of scoring functions, which can combine protein stability, ligand affinity, and ligand specificity terms, for positive and negative design. We present in detail the steps for structure preparation, system setup, construction of the interaction energy matrix, protein sequence and structure optimizations, pK α calculations, and ligand titration calculations. We discuss illustrative examples, including the chemical/structural optimization of a complex between the MHC class II protein HLA-DQ8 and the vinculin epitope, and the chemical optimization of the compstatin analog Ac-Val4Trp/His9Ala, which regulates the function of protein C3 of the complement system. PMID:27094287

  15. Peripheral benzodiazepine receptor (PBR) ligand cytotoxicity unrelated to PBR expression.

    PubMed

    Hans, Gregory; Wislet-Gendebien, Sabine; Lallemend, François; Robe, Pierre; Rogister, Bernard; Belachew, Shibeshih; Nguyen, Laurent; Malgrange, Brigitte; Moonen, Gustave; Rigo, Jean-Michel

    2005-03-01

    Some synthetic ligands of the peripheral-type benzodiazepine receptor (PBR), an 18 kDa protein of the outer mitochondrial membrane, are cytotoxic for several tumor cell lines and arise as promising chemotherapeutic candidates. However, conflicting results were reported regarding the actual effect of these drugs on cellular survival ranging from protection to toxicity. Moreover, the concentrations needed to observe such a toxicity were usually high, far above the affinity range for their receptor, hence questioning its specificity. In the present study, we have shown that micromolar concentrations of FGIN-1-27 and Ro 5-4864, two chemically unrelated PBR ligands are toxic for both PBR-expressing SK-N-BE neuroblastoma cells and PBR-deficient Jurkat lymphoma cells. We have thereby demonstrated that the cytotoxicity of these drugs is unrelated to their PBR-binding activity. Moreover, Ro 5-4864-induced cell death differed strikingly between both cell types, being apoptotic in Jurkat cells while necrotic in SK-N-BE cells. Again, this did not seem to be related to PBR expression since Ro 5-4864-induced death of PBR-transfected Jurkat cells remained apoptotic. Taken together, our results show that PBR is unlikely to mediate all the effects of these PBR ligands. They however confirm that some of these ligands are very effective cytotoxic drugs towards various cancer cells, even for reputed chemoresistant tumors such as neuroblastoma, and, surprisingly, also for PBR-lacking tumor cells.

  16. 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

  17. Titanium complex formation of organic ligands in titania gels.

    PubMed

    Nishikiori, Hiromasa; Todoroki, Kenta; Setiawan, Rudi Agus; Teshima, Katsuya; Fujii, Tsuneo; Satozono, Hiroshi

    2015-01-27

    Thin films of organic ligand-dispersing titania gels were prepared from titanium alkoxide sols containing ligand molecules by steam treatment without heating. The formation of the ligand-titanium complex and the photoinduced electron transfer process in the systems were investigated by photoelectrochemical measurements. The complex was formed between the 8-hydroxyquinoline (HQ) and titanium species, such as the titanium ion, on the titania nanoparticle surface through the oxygen and nitrogen atoms of the quinolate. A photocurrent was observed in the electrodes containing the complex due to the electron injection from the LUMO of the complex into the titania conduction band. A bidentate ligand, 2,3-dihydroxynaphthalene (DHN), formed the complex on the titania surface through dehydration between its two hydroxyl groups of DHN and two TiOH groups of the titania. The electron injection from the HOMO of DHN to the titania conduction band was observed during light irradiation. This direct electron injection was more effective than the two-step electron injection.

  18. 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.

  19. 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…

  20. 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…