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Sample records for 2-mercapto benzothiazolate ligand

  1. 2-Mercapto-5-benzimidazolesulfonic acid: an effective multimodal ligand for the separation of antibodies.

    PubMed

    Girot, Pierre; Averty, Emmanuelle; Flayeux, Isabelle; Boschetti, E

    2004-08-25

    The report describes the use of 2-mercapto-5-benzimidazolesulfonic acid (MBISA) as a ligand for the separation of antibodies by chromatography. The ligand shows a relatively specific adsorption property for antibodies from very crude biologicals at pH 5.0-5.5. At this pH range most of other proteins do not interact with the resin especially when the ionic strength is similar to physiological conditions. Several characterization studies are described such as antibody adsorption in different conditions of ionic strength, pH and temperature. These properties are advantageously used to selectively capture antibodies from very crude feed stocks without dilution or addition of lyotropic salts. Demonstration was made that the adsorption mechanism is neither based on ion exchange nor on hydrophobic associations, but rather as an assembly of a variety of properties of the ligand itself. Binding capacity in the described conditions ranges between 25 and 30 mg/mL of resin. The sorbent does not co-adsorb albumin (Alb) and seems compatible with a large variety of feedstocks. Quantitative antibody desorption occurs when the pH is raised above 8.5. The final purity of the antibody depends on the nature of the feedstock, and can reach levels of purity as high as 98%. Even with very crude biological liquids such as ascites fluids, cell culture supernatants and Chon fraction II + III from human plasma fractionation where the number of protein impurities is particularly large, immunoglobumins G (IgG) were separated at high purity level in a single step. PMID:15236682

  2. 2-Mercapto-1-t-butylimidazolyl as a Bridging Ligand: Synthesis and Structural Characterization of Nickel and Palladium Paddlewheel Complexes‡

    PubMed Central

    Pang, Keliang; Figueroa, Joshua S.; Tonks, Ian A.; Sattler, Wesley

    2009-01-01

    Nickel and palladium paddlewheel complexes that feature 2-mercapto-1-t-butylimidazolyl (mimBut) bridging ligands, namely Ni2[mim But]4 and Pd2[mim But]4, have been synthesized and structurally characterized by X–ray diffraction. Since the mim But ligand bridges in an asymmetric manner via a sulfur and nitrogen donor, paddlewheel compounds of the type M2[mim But]4 may exist as isomers that are distinguished by the relative orientations of the ligands. In this regard, the (4,0)-Ni2[mim But]4 and trans-(2,2)-Ni2[mim But]4 isomers have been isolated for the nickel system, while the (4,0)-Pd2[mim But]4 and (3,1)-Pd2[mim But]4 isomers have been isolated for the palladium system. PMID:20161357

  3. New platinum(II) complexes with benzo-thia-zole ligands.

    PubMed

    Carmona-Negrón, José A; Cádiz, Mayra E; Moore, Curtis E; Rheingold, Arnold L; Meléndez, Enrique

    2016-03-01

    Four new platinum(II) complexes, namely tetra-ethyl-ammonium tri-bromido-(2-methyl-1,3-benzo-thia-zole-κN)platinate(II), [NEt4][PtBr3(C8H7NS)] (1), tetra-ethyl-ammonium tri-bromido-(6-meth-oxy-2-methyl-1,3-benzo-thia-zole-κN)platinate(II), [NEt4][PtBr3(C9H9NOS)] (2), tetra-ethyl-ammonium tri-bromido-(2,5,6-trimethyl-1,3-benzo-thia-zole-κN)platinate(II), [NEt4][PtBr3(C10H11NS)] (3), and tetra-ethyl-ammonium tri-bromido-(2-methyl-5-nitro-1,3-benzo-thia-zole-κN)platinate(II), [NEt4][PtBr3(C8H6N2O2S)] (4), have been synthesized and structurally characterized by single-crystal X-ray diffraction techniques. These species are precursors of compounds with potential application in cancer chemotherapy. All four platinum(II) complexes adopt the expected square-planar coordination geometry, and the benzo-thia-zole ligand is engaged in bonding to the metal atom through the imine N atom (Pt-N). The Pt-N bond lengths are normal: 2.035 (5), 2.025 (4), 2.027 (5) and 2.041 (4) Å for complexes 1, 2, 3 and 4, respectively. The benzo-thia-zole ligands are positioned out of the square plane, with dihedral angles ranging from 76.4 (4) to 88.1 (4)°. The NEt4 cation in 3 is disordered with 0.57/0.43 occupancies. PMID:27006819

  4. 40 CFR 721.10380 - Benzoic acid, 3-amino-2-mercapto-.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Benzoic acid, 3-amino-2-mercapto-. 721... Substances § 721.10380 Benzoic acid, 3-amino-2-mercapto-. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as benzoic acid, 3-amino-2-mercapto- (PMN...

  5. 40 CFR 721.10380 - Benzoic acid, 3-amino-2-mercapto-.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Benzoic acid, 3-amino-2-mercapto-. 721... Substances § 721.10380 Benzoic acid, 3-amino-2-mercapto-. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as benzoic acid, 3-amino-2-mercapto- (PMN...

  6. 40 CFR 721.10380 - Benzoic acid, 3-amino-2-mercapto-.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Benzoic acid, 3-amino-2-mercapto-. 721... Substances § 721.10380 Benzoic acid, 3-amino-2-mercapto-. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as benzoic acid, 3-amino-2-mercapto- (PMN...

  7. Cu(II) and Cu(I) coordination complexes involving two tetrathiafulvalene-1,3-benzothiazole hybrid ligands and their radical cation salts.

    PubMed

    Yokota, Sayo; Tsujimoto, Keijiro; Hayashi, Sadayoshi; Pointillart, Fabrice; Ouahab, Lahcène; Fujiwara, Hideki

    2013-06-01

    Preparations, crystal structure analyses, and magnetic property investigations on a new Cu(II)(hfac)2 complex coordinated with two TTF-CH═CH-BTA ligands, where hfac is hexafluoroacetylacetonate, TTF is tetrathiafulvalene, and BTA is 1,3-benzothiazole, are reported together with those of its dicationic AsF6(-) salt, [Cu(hfac)2(TTF-CH═CH-BTA)2](AsF6)2, in which each TTF part is in a radical cation state. In these Cu(II)(hfac)2 complexes, two ligands are bonded to the central Cu atom of the Cu(hfac)2 part through the nitrogen atom of the 1,3-benzothiazole ring and occupy the two apical positions of the Cu(hfac)2 complex with an elongated octahedral geometry. These two ligands are located parallelly in a transverse head-to-tail manner, and the Cu(hfac)2 moiety is closely sandwiched by these two ligands. In the AsF6(-) salt of the Cu(hfac)2 complex, each TTF dimer is separated by the AsF6(-) anions and has no overlap with each other within the one-dimensional arrays, resulting in an insulating behavior. Both Cu(hfac)2 complexes showed the simple Curie-like temperature dependence of paramagnetic susceptibilities (χM), indicating that no interaction exists between the paramagnetic Cu(II) d spins. Furthermore, crystal structure analysis and magnetic/conducting properties of a radical cation ReO4(-) salt of the Cu(I) complex with two TTF-CH═CH-BTA ligands, [Cu(TTF-CH═CH-BTA)2](ReO4)2, are also described. Two nitrogen atoms of the ligands are connected to the central Cu(I) in a linear dicoordination with a Cu-N bond length of 1.879(9) Å. Two TTF parts of the neighboring complexes form a dimerized structure, and such a TTF dimer forms a one-dimensional uniform array along the a direction with a short S-S contact of 3.88 Å. Magnetic property measurement suggested the existence of a strongly antiferromagnetic one-dimensional uniform chain of S = 1/2 spins that originate from the radical cation states of the TTF dimers. Due to the construction of the one

  8. Inhibition of Brass Corrosion by 2-Mercapto-1-methylimidazole in Weakly Alkaline Solution

    NASA Astrophysics Data System (ADS)

    Radovanovic, Milan B.; Antonijevic, Milan M.

    2016-03-01

    The electrochemical behavior of brass and anticorrosion effect of 2-mercapto-1-methylimidazole (2-MMI) in weakly alkaline solution with and without presence of chloride ions was investigated using electrochemical techniques in addition to SEM-EDS analysis. Results show that inhibition efficiency depended on inhibitor concentration and immersion time of brass electrode in inhibitor solution. Inhibition mechanism of 2-mercapto-1-methylimidazole includes adsorption of inhibitor on active sites on electrode surface which was confirmed by SEM-EDS analysis of the brass. Adsorption of the 2-MMI in sodium tetraborate solution obeys Flory-Huggins adsorption isotherm, while in the presence of chloride, ions adsorption of inhibitor obeys Langmuir adsorption isotherm.

  9. Evaluation of usefulness of 2-mercapto-ethanol treatment in serodiagnosis of swine leptospirosis.

    PubMed

    Awad-Masalmeh, A; Willinger, H

    1983-04-01

    Serum samples of piglets infected artificially or naturally, respectively, with Leptospira pomona were treated with 2-mercapto-ethanol (ME) and tested in the microscopic agglutination test in comparison with untreated sera. Serum-treatment with ME showed two beneficial effects, one being the total elimination of heterotypic reactions, the other the reduction or elimination, respectively, of early antibodies, presumably belonging to the IgM class. Accordingly, two practical implications can be derived from our results. The ratio of ME-sensitive and ME-resistant antibody titers allows the recognition of early leptospira infections. The total suppression by ME of heterotypic agglutination eliminates the danger of determining the wrong leptospira type as causative agent, a crucial problem encountered not infrequently with agglutination testing of untreated sera. Recognition of early cases of swine leptospirosis by ME-treatment of sera is particularly useful, as the complement fixative reaction, successfully used in other species for the same purpose, is inappropriate in swine sera owing to their autolytic properties. Furthermore by elimination of all heterotypic reactions the ME-method gives better chances for the determination of the causative agent and hence for correct interpretation of serological results. ME-treatment is considered as a useful help in serodiagnosis of field samples, in which determination of duration of infection is essential or in which heterotypic agglutination is obscuring the etiological leptospira type. PMID:6688116

  10. Solid phase extraction-preconcentration and high performance liquid chromatographic determination of 2-mercapto-(benzothiazole, benzoxazole and benzimidazole) using copper oxide nanoparticles.

    PubMed

    Parham, Hooshang; Khoshnam, Farzaneh

    2013-09-30

    This study introduces a novel method of solid phase extraction (SPE), preconcentration and HPLC determination of 2-mercaptobenzimidazole (2MBI), 2-mercaptobenzoxazole (2MBO) and 2-mercaptobenzothiazole (2MBT) from an aqueous solution by a SPE cartridge loaded with copper oxide nanoparticles. Results demonstrated that copper oxide nanoparticles are quite efficient for extraction and preconcentration of trace amounts of these mercaptans at room temperature. The study also investigated the effects of parameters such as pH, buffer and its volume, electrolyte concentration, flow rate of the test solution, composition and volume of the desorbing solvent, accepted tolerable volume, amount of adsorbent, reusability of cartridges and evidence of some co-existing species on extraction and determination of the above mentioned mercaptans. The method showed good linearity for determination of these mercaptans in the range of 0.01-10 μg mL(-1) with regression coefficients better than 0.9969. The limits of detection (LODs) evaluations were 0.0021, 0.0027 and 0.0019 μg mL(-1) for 2MBT, 2MBO and 2MBI, respectively. The relative standard deviations (RSDs) for 0.2 μg mL(-1) and 5 μg mL(-1) of the measured mercaptans were below 3.04% and 4.23%, respectively. Ramin Power Plant (3000 MW, Ahvaz, Iran) cooling water containing some 2MBT (as corrosion inhibitor) was used as the real sample. Recovery tests with spiked levels of 2MBT, 2MBI and 2MBO were carried out and satisfied results were obtained. PMID:23953446

  11. The spectroscopic (FT-IR, FT-Raman and NMR), first order hyperpolarizability and HOMO-LUMO analysis of 2-mercapto-4(3H)-quinazolinone.

    PubMed

    Prabavathi, N; Senthil Nayaki, N

    2014-08-14

    The FTIR and FT-Raman spectra of 2-mercapto-4(3H) quinazolinone have been recorded in the region 4000-450 and 4000-100 cm(-1), respectively. The optimized geometry, frequency and intensity of the vibrational bands of 2-mercapto-4(3H) quinazolinone (2MQ) were obtained by the density functional theory (DFT) using 6-311++G(d,p) basis set. The harmonic vibrational frequencies were calculated and the scaled values have been compared with experimental FTIR and FT-Raman spectra. The (1)H and (13)C nuclear magnetic resonance chemical shifts of the molecule were also calculated using the gauge independent atomic orbital (GIAO) method. The theoretical UV-VIS spectrum of the compound and the electronic properties, such as HOMO (highest occupied molecular orbital) and LUMO (lowest occupied molecular orbital) energies were performed by time-dependent DFT (TD-DFT) approach. The change in electron density (ED) in the σ(*) antibonding orbitals and stabilization energies E((2)) have been calculated by natural bond (NBO) analysis, to give clear evidence of stabilization originating in the hyper conjugation of hydrogen-bonded interactions. Information about the size, shape, charge density distribution and site of chemical reactivity of the molecule has been obtained by mapping electron density isosurface with molecular electrostatic potential (MESP). PMID:24815813

  12. Synthesis 4-[2-(2-mercapto-4-oxo-4H-quinazolin-3-yl)-ethyl]-benzenesulfonamides with subnanomolar carbonic anhydrase II and XII inhibitory properties.

    PubMed

    Bozdag, Murat; Alafeefy, Ahmed M; Carta, Fabrizio; Ceruso, Mariangela; Al-Tamimi, Abdul-Malek S; Al-Kahtani, Abdulla A; Alasmary, Fatmah A S; Supuran, Claudiu T

    2016-09-15

    Condensation of substituted anthranilic acids with 4-isothiocyanatoethyl-benzenesulfonamide led to series of heterocyclic benzenesulfonamides incorporating 2-mercapto-quinazolin-4-one tails. These sulfonamides were investigated as inhibitors of the human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms hCA I and II (cytosolic isozymes), as well as hCA XII (a transmembrane, tumor-associated enzyme also involved in glaucoma-genesis). The new sulfonamides acted as medium potency inhibitors of hCA I (KIs of 28.5-2954nM), being highly effective as hCA II (KIs in the range of 0.62-12.4nM) and XII (KIs of 0.54-7.11nM) inhibitors. All substitution patterns present in these compounds (e.g., halogens, methyl and methoxy moieties, in positions 6, 7 and/or 8 of the 2-mercapto-quinazolin-4-one ring) led to highly effective hCA II/XII inhibitors. These compounds should thus be of interest as preclinical candidates in pathologies in which the activity of these enzymes should be inhibited, such as glaucoma (CA II and XII as targets) or some tumors in which the activity of isoforms CA II and XII is dysregulated. PMID:27396930

  13. Platinum chloride complexes containing 6-[9,9-di(2-ethylhexyl)-7-R-9H-fluoren-2-yl]-2,2'-bipyridine ligand (R = NO2, CHO, benzothiazol-2-yl, n-Bu, carbazol-9-yl, NPh2): tunable photophysics and reverse saturable absorption.

    PubMed

    Li, Zhongjing; Badaeva, Ekaterina; Ugrinov, Angel; Kilina, Svetlana; Sun, Wenfang

    2013-07-01

    Six new platinum(II) chloride complexes 1-6 containing a 6-[9,9-di(2-ethylhexyl)-7-R-9H-fluoren-2-yl]-2,2'-bipyridine (R = NO2, CHO, benzothiazol-2-yl (BTZ), n-Bu, carbazol-9-yl (CBZ), NPh2) ligand were synthesized and characterized. The influence of the electron-donating or electron-withdrawing substituent at the 7-position of the fluorenyl component on the photophysics of these complexes was systematically investigated by spectroscopic methods and simulated by time-dependent density functional theory (TDDFT). Electron-withdrawing or -donating substituents exert distinct effects on the photophysics of the complexes. All complexes feature a low-energy, broad (1)MLCT (metal-to-ligand charge transfer)/(1)ILCT (intraligand charge transfer)/(1)π,π* absorption band (tail) above ca. 430 nm and a major absorption band(s) between 320 and 430 nm, which admix (1)MLCT, (1)π,π*, (1)ILCT, and/or (1)LLCT (ligand-to-ligand charge transfer) characters. The contributions of different configurations to the major absorption band(s) vary depending on the nature of the substituent. Strong electron-donating or -withdrawing substituents (NPh2 and NO2) and the aromatic substituent BTZ cause a pronounced red-shift of the absorption spectra of 1, 3, and 6. All complexes are emissive at room temperature and at 77 K. The emitting excited state is dominated by (3)π,π* character in 1-3, with some contributions from (3)MLCT in 1 and 2, while the emission is predominantly from the (3)MLCT state for 4 and 5 but with some (3)π,π* character. For 6, the emitting state is (3)ILCT in nature. With the increased electron-donating ability of the substituent, the (3)π,π* character diminishes while charge transfer character increases. All complexes exhibit broad and strong triplet excited-state absorption (TA) from the near-UV to the near-IR spectral region. The TA band maxima are red-shifted for complexes 1-3 (which possess the electron-withdrawing substituents) compared to those of 4-6 (which

  14. Synthesis and X-ray diffraction study of palladium(II) 1,3-diphenyl-5-(benzothiazol-2-yl)formazanate

    SciTech Connect

    Zaidman, A. V. Pervova, I. G.; Rezinskikh, Z. G.; Lipunov, I. N.; Slepukhin, P. A.

    2010-05-15

    The behavior of 1,3-diphenyl-5-(benzothiazol-2-yl)formazan as a bidentate ligand in the synthesis of the mononuclear palladium complex was investigated using slow diffusion. According to the X-ray diffraction study, the PdN4 coordination unit has a distorted square structure. The ligands form two six-membered chelate rings formed through the N1 and N4 atoms of the formazan fragment.

  15. Development of 3-(4-aminosulphonyl)-phenyl-2-mercapto-3H-quinazolin-4-ones as inhibitors of carbonic anhydrase isoforms involved in tumorigenesis and glaucoma.

    PubMed

    Alafeefy, Ahmed M; Carta, Fabrizio; Ceruso, Mariangela; Al-Tamimi, Abdul-Malek S; Al-Kahtani, Abdulla A; Supuran, Claudiu T

    2016-03-15

    A series of heterocyclic benzenesulfonamides incorporating 2-mercapto-3H-quinazolin-4-one tails were prepared by condensation of substituted anthranilic acids with 4-isothiocyanato-benzenesulfonamide. These sulfonamides were investigated as inhibitors of the human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms hCA I and II (cytosolic isozymes), as well as hCA IX and XII (trans-membrane, tumor-associated enzymes). They acted as medium potency inhibitors of hCA I (KIs of 81.0-3084 nM), being highly effective as hCA II (KIs in the range of 0.25-10.8 nM), IX (KIs of 3.7-50.4 nM) and XII (KIs of 0.60-52.9 nM) inhibitors. These compounds should thus be of interest as preclinical candidates in pathologies in which the activity of these enzymes should be inhibited, such as glaucoma (CA II and XII as targets) or some tumors in which the activity of three isoforms (CA II, IX and XII) is dysregulated. PMID:26875933

  16. The thermodynamic properties of benzothiazole and benzoxazole

    SciTech Connect

    Steele, W.V.; Chirico, R.D.; Knipmeyer, S.E.; Nguyen, A.

    1991-08-01

    This research program, funded by the Department of Energy, Office of Fossil Energy, Advanced Extraction and Process Technology, provides accurate experimental thermochemical and thermophysical properties for key'' organic diheteroatom-containing compounds present in heavy petroleum feedstocks, and applies the experimental information to thermodynamic analyses of key hydrodesulfurization, hydrodenitrogenation, and hydrodeoxygenation reaction networks. Thermodynamic analyses, based on accurate information, provide insights for the design of cost-effective methods of heteroatom removal. The results reported here, and in a companion report to be completed, will point the way to the development of new methods of heteroatom removal from heavy petroleum. Measurements leading to the calculation of the ideal-gas thermodynamic properties are reported for benzothiazole and benzoxazole. Experimental methods included combustion calorimetry, adiabatic heat-capacity calorimetry, comparative ebulliometry, inclinded-piston gauge manometry, and differential-scanning calorimetry (d.s.c). Critical property estimates are made for both compounds. Entropies, enthalpies, and Gibbs energies of formation were derived for the ideal gas for both compounds for selected temperatures between 280 K and near 650 K. The Gibbs energies of formation will be used in a subsequent report in thermodynamic calculations to study the reaction pathways for the removal of the heteratoms by hydrogenolysis. The results obtained in this research are compared with values present in the literature. The failure of a previous adiabatic heat capacity study to see the phase transition in benzothiazole is noted. Literature vibrational frequency assignments were used to calculate ideal gas entropies in the temperature range reported here for both compounds. Resulting large deviations show the need for a revision of those assignments. 68 refs., 6 figs., 15 tabs.

  17. The thermodynamic properties of benzothiazole and benzoxazole

    NASA Astrophysics Data System (ADS)

    Steele, W. V.; Chirico, R. D.; Knipmeyer, S. E.; Nguyen, A.

    1991-08-01

    This research program, funded by the Department of Energy, Office of Fossil Energy, Advanced Extraction and Process Technology, provides accurate experimental thermochemical and thermophysical properties for key organic diheteroatom-containing compounds present in heavy petroleum feedstocks, and applies the experimental information to thermodynamic analyses of key hydrodesulfurization, hydrodenitrogenation, and hydrodeoxygenation reaction networks. Thermodynamic analyses, based on accurate information, provide insights for the design of cost-effective methods of heteroatom removal. The results reported here, and in a companion report to be completed, will point the way to the development of new methods of heteroatom removal from heavy petroleum. Measurements leading to the calculation of the ideal-gas thermodynamic properties are reported for benzothiazole and benzoxazole. Experimental methods included combustion calorimetry, adiabatic heat-capacity calorimetry, comparative ebulliometry, inclinded-piston gauge manometry, and differential-scanning calorimetry (d.s.c). Critical property estimates are made for both compounds. Entropies, enthalpies, and Gibbs energies of formation were derived for the ideal gas for both compounds for selected temperatures between 280 K and near 650 K. The Gibbs energies of formation will be used in a subsequent report in thermodynamic calculations to study the reaction pathways for the removal of the heteratoms by hydrogenolysis. The results obtained in this research are compared with values present in the literature. The failure of a previous adiabatic heat capacity study to see the phase transition in benzothiazole is noted. Literature vibrational frequency assignments were used to calculate ideal gas entropies in the temperature range reported here for both compounds. Resulting large deviations show the need for a revision of those assignments.

  18. Synthesis, structural characterization, thermal and electrochemical studies of Mn(II), Co(II), Ni(II) and Cu(II) complexes containing thiazolylazo ligands

    NASA Astrophysics Data System (ADS)

    Chavan, S. S.; Sawant, V. A.

    2010-02-01

    Some thiazolylazo derivatives and their metal complexes of the type [M(L)(H 2O)Cl]; M = Mn(II), Co(II), Ni(II), Cu(II) and L = 6-(2'-thiazolylazo)-2-mercapto-quinazolin-4-one (HL 1), 6-(4'-phenyl-2'-thiazolylazo)-2-mercapto-quinazolin-4-one (HL 2), 6-(2'-thiazolylazo)-2-mercapto-3-( m-tolyl)-quinazolin-4-one (HL 3) and 6-(4'-phenyl-2'-thiazolylazo)-2-mercapto-3-( m-tolyl)-quinazolin-4-one (HL 4) have been prepared. All the complexes were characterized on the basis of elemental analysis, molar conductance, magnetic moment, IR, UV-vis, ESR, TG-DTA and powder X-ray diffraction studies. IR spectra of these complexes reveal that the complex formation occurred through thiazole nitrogen, azo nitrogen, imino nitrogen and sulfur atom of the ligands. On the basis of electronic spectral data and magnetic susceptibility measurement octahedral geometry has been proposed for the Mn(II), Co(II) and Ni(II) complexes and distorted octahedral geometry for the Cu(II) complexes. Electrochemical behavior of Ni(II) complexes exhibit quasireversible oxidation corresponding to Ni(III)/Ni(II) couple along with ligand reduction. X-ray diffraction study is used to elucidate the crystal structure of the complexes.

  19. Benzothiazole sulfide compatibilized polypropylene/halloysite nanotubes composites

    NASA Astrophysics Data System (ADS)

    Liu, Mingxian; Guo, Baochun; Lei, Yanda; Du, Mingliang; Jia, Demin

    2009-02-01

    Clay-philic benzothiazole sulfide, capable of donating electrons, is grafted onto polypropylene (PP) backbones when N-cyclohexyl-2-benzothiazole sulfonamide (CBS), a commonly used accelerator in the tire industry, is included in the processing of PP/halloysite nanotubes (HNTs) composites. CBS decomposes at elevated temperature and yields benzothiazole sulfide radicals, which react with the PP polymeric free radicals generated during the processing of the composites. On the other hand, the benzothiazole group of CBS is reactive to HNTs via electron transferring. The compatibilization between HNTs and PP is thus realized via interfacial grafting and electron transferring mechanism. The interfacial interactions in the compatibilized systems were fully characterized. Compared with the control sample, the dispersion of HNTs and the interfacial bonding are enhanced substantially in the compatibilized composites. The significantly improved mechanical properties and thermal properties of benzothiazole sulfide compatibilized PP/HNTs composites are correlated to the enhanced interfacial property. The present work demonstrates a novel interfacial design via interfacial grafting/electron transferring for the compatibilization of PP/clay composites.

  20. Initial Transformations in the Biodegradation of Benzothiazoles by Rhodococcus Isolates

    PubMed Central

    De Wever, Helene; Vereecken, Karen; Stolz, Andreas; Verachtert, Hubert

    1998-01-01

    Benzothiazole-2-sulfonate (BTSO3) is one of the side products occurring in 2-mercaptobenzothiazole (MBT) production wastewater. We are the first to isolate an axenic culture capable of BTSO3 degradation. The isolate was identified as a Rhodococcus erythropolis strain and also degraded 2-hydroxybenzothiazole (OBT) and benzothiazole (BT), but not MBT, which was found to inhibit the biodegradation of OBT, BT, and BTSO3. In anaerobic resting cell assays, BTSO3 was transformed into OBT in stoichiometric amounts. Under aerobic conditions, OBT was observed as an intermediate in BT breakdown and an unknown compound transiently accumulated in several assays. This product was identified as a dihydroxybenzothiazole. Benzothiazole degradation pathways seem to converge into OBT, which is then transformed further into the dihydroxy derivative. PMID:9726870

  1. Occurrence and removal efficiencies of benzotriazoles and benzothiazoles in a wastewater treatment plant in Greece.

    PubMed

    Asimakopoulos, Alexandros G; Ajibola, Akinranti; Kannan, Kurunthachalam; Thomaidis, Nikolaos S

    2013-05-01

    Despite the widespread use of benzotriazoles and benzothiazoles and the occurrence of these compounds in wastewater treatment plants (WWTPs), no earlier study has comprehensively examined their fate in WWTPs. In this study, an integrated liquid chromatography-tandem mass spectrometry (LC-ESI(+)MS/MS) method was developed and validated for simultaneous determination of four benzotriazoles and four benzothiazoles in dissolved and particulate phases of wastewater (raw and treated), and in dewatered sewage sludge. The target benzotriazoles (BTRs) were 1H-benzotriazole, 1-hydroxy-benzotriazole, tolyltriazole, and xylyltriazole (or 5,6-dimethyl-1H-benzotriazole), and the target benzothiazoles (BTHs) were benzothiazole, 2-hydroxy-benzothiazole, 2-methylthio-benzothiazole, and 2-amino-benzothiazole. The limits of detection ranged from 0.08 (2-methylthio-benzothiazole) to 17 ng/L (benzothiazole) for dissolved phase samples, and from 0.04 (2-methylthio-benzothiazole) to 13 ng/g dry weight (dw) (benzothiazole) for particular matter and sludge samples. The method was applied in the analysis of wastewater and sludge samples from the WWTP in Athens, Greece. All target chemicals were detected in wastewater samples, and in some cases the concentrations were significant, on the order of a few μg/L. In sludge samples, benzothiazole and tolyltriazole were present at the highest concentrations (174 and 116 ng/g dw, respectively). For benzotriazole and tolyltriazole, the removal efficiency was below 68%, and for benzothiazoles, the removal efficiency was greater than 64% in the activated sludge treatment process. Both BTRs and BTHs showed low solid-liquid distribution coefficients. PMID:23500410

  2. Synthesis and 11C-Radiolabelling of 2-Carboranyl Benzothiazoles.

    PubMed

    Gona, Kiran B; Thota, Jaya Lakshmi V N P; Baz, Zuriñe; Gómez-Vallejo, Vanessa; Llop, Jordi

    2015-01-01

    Dicarba-closo-dodecaboranes, commonly known as carboranes, possess unique physico-chemical properties and can be used as hydrophobic moieties during the design of new drugs or radiotracers. In this work, we report the synthesis of two analogues of 2-(4-aminophenyl)benzothiazole (a compound that was found to elicit pronounced inhibitory effects against certain breast cancer cell lines in vitro) in which the phenyl ring has been substituted by a m-carborane cage. Two different synthetic strategies have been used. For the preparation of 1-(9-amino-1,7-dicarba-closo-dodecaboran-1-yl)-benzo-thiazole, the benzothiazole group was first introduced on one of the cluster carbon atoms of m-carborane and the amine group was further attached in three steps. For the synthesis of 1-(9-amino-1,7-dicarba-closo-dodecaboran-1-yl)-6-hydroxybenzothiazole, iodination was performed before introducing the benzothiazole group, and the amino group was subsequently introduced in six steps. Both compounds were radiolabelled with carbon-11 using [11C]CH3OTf as the labelling agent. Radiolabelling yields and radiochemical purities achieved should enable subsequent in vitro and in vivo investigations. PMID:25915463

  3. Antimicrobial Applications of Transition Metal Complexes of Benzothiazole Based Terpolymer: Synthesis, Characterization, and Effect on Bacterial and Fungal Strains

    PubMed Central

    Riswan Ahamed, Mohamed A.; Azarudeen, Raja S.; Kani, N. Mujafar

    2014-01-01

    Terpolymer of 2-amino-6-nitro-benzothiazole-ethylenediamine-formaldehyde (BEF) has been synthesized and characterized by elemental analysis and various spectral techniques like FTIR, UV-Visible, and 1H and 13C-NMR. The terpolymer metal complexes were prepared with Cu2+, Ni2+, and Zn2+ metal ions using BEF terpolymer as a ligand. The complexes have been characterized by elemental analysis and IR, UV-Visible, ESR, 1H-NMR, and 13C-NMR spectral studies. Gel permeation chromatography was used to determine the molecular weight of the ligand. The surface features and crystalline behavior of the ligand and its complexes were analyzed by scanning electron microscope and X-ray diffraction methods. Thermogravimetric analysis was used to analyze the thermal stability of the ligand and its metal complexes. Kinetic parameters such as activation energy (Ea) and order of reaction (n) and thermodynamic parameters, namely, ΔS, ΔF, S*, and Z, were calculated using Freeman-Carroll (FC), Sharp-Wentworth (SW), and Phadnis-Deshpande (PD) methods. Thermal degradation model of the terpolymer and its metal complexes was also proposed using PD method. Biological activities of the ligand and its complexes were tested against Shigella sonnei, Escherichia coli, Klebsiella species, Staphylococcus aureus, Bacillus subtilis, and Salmonella typhimurium bacteria and Aspergillus flavus, Aspergillus niger, Penicillium species, Candida albicans, Cryptococcus neoformans, Mucor species fungi. PMID:25298760

  4. In vivo and in vitro effects of benzothiazole on sheepshead minnow (Cyprinodon variegatus).

    PubMed

    Evans, J J; Shoemaker, C A; Klesius, P H

    2000-01-01

    Benzothiazole, a common chemical associated with tire manufacturing and industrial wastewater, is a principal component of both fresh water and estuarine tire leachate, a neurotoxicant to larval sheepshead minnows (Cyprinodon variegatus) in in vivo estuarine studies. The neurotoxic potential of benzothiazole was investigated following in vivo and in vitro exposure of sheepshead minnows to 3.75, 7.5, 15, 30 and 60 mg/l benzothiazole. Following benzothiazole exposure, fish were evaluated for survival, growth and histological alterations. Fish mortality occurred after 5 days of exposure to 60 mg/l (LC50 = 41.9). Significant decreases in larval growth were noted at all concentrations. Histologically, gills had cellular alterations but the central nervous system lacked the severe cellular damage seen in previous tire leachate exposure studies. Benzothiazole cytotoxicity to primary cultures of brain cells from sheepshead minnow and tilapia (Oreochromis niloticus) and two epithelial cell lines was evaluated using a tetrazolium salt assay (MTT) at 1 and 4 days. In vitro results indicate primary cultures of brain cells are less sensitive to benzothiazole than epithelial cell lines. Significant cytotoxicity to the epithelial cell lines was noted at 30 and 60 mg/l concentrations. Histologically and cytotoxicologically, the present study indicates that benzothiazole is a gill toxicant and not a neurotoxicant. PMID:11460700

  5. A Comprehensive Review on Recent advances in Synthesis & Pharmacotherapeutic potential of Benzothiazoles.

    PubMed

    Seth, Sonakshi

    2015-01-01

    Heterocyclic analogues and their derivatives have attracted strong interest in medicinal chemistry due to their biological and pharmacological properties. Benzothiazole is a class of heterocyclic compounds having 2 hetero atoms namely, sulphur and nitrogen. The analogues of benzothiazoles and its derivatives have a significant role in research area especially in synthetic, medicinal and pharmaceutical chemistry because of their biological and pharmacological activity. These compounds have special significance in the field of Medicinal chemistry due to their remarkable pharmacological potentialities. Benzothiazole is an organosulfur heterocyclic compound, weakly basic in nature. They are widely found in bioorganic and medicinal chemistry with wide application in drug discovery. Benzothiazoles are fused membered rings, which contain the heterocycles bearing thiazole as central moiety. A large number of therapeutic agents are synthesized with the help of benzothiazoles nucleus. In addition, benzothiazoles act as core nucleus in various drugs due to their various activities e.g. pramipexole, probenazole, lubeluzole, zopolrestat, ethoxazolamide and bentaluron etc. and their derivatives have attracted a great deal of interest due to their wide range of biological activities such as anticancer, antimicrobial, antitubercular, anti-HIV, cardiovascular, local anaesthetic, anti-inflammatory, anticonvulsant and anti-diabetic. The therapeutic properties of the heterocycles have encouraged the medicinal chemist to synthesize a large number of novel chemotherapeutic agents. This review is mainly an attempt to present the research work reported in the recent scientific literature focusing on different biological activities of benzothiazoles compounds. PMID:26017385

  6. A fluorescent benzothiazole probe with efficient two-photon absorption

    NASA Astrophysics Data System (ADS)

    Echevarria, Lorenzo; Moreno, Iván; Camacho, José; Salazar, Mary Carmen; Hernández, Antonio

    2012-11-01

    In this work, we report the two-photon absorption of 2-[4-(dimethylamino)phenyl]-1,3-benzothiazole-6-carbonitrile (DBC) in DMSO solution pumping at 779 nm with a 10 ns pulse laser-Nd:YAG system. The obtained two-photon absorption cross-section in DBC (407 ± 18 GM) is considerably high. Because DBC is a novel compound and have high values of fluorescence quantum yield, this result is expected to have an impact in biomolecules detection, diagnosis and treatment of cancer. Similar structures have previously been reported to show remarkable antitumour effects.

  7. Coumarin benzothiazole derivatives as chemosensors for cyanide anions

    NASA Astrophysics Data System (ADS)

    Wang, Kangnan; Liu, Zhiqiang; Guan, Ruifang; Cao, Duxia; Chen, Hongyu; Shan, Yanyan; Wu, Qianqian; Xu, Yongxiao

    2015-06-01

    Four coumarin benzothiazole derivatives, N-(benzo[d]thiazol-2-yl)-2-oxo-2H-chromene-3-carboxamide (1), (Z)-N-(3-methylbenzo[d]thiazol-2(3H)-ylidene)-2-oxo-2H-chromene-3-carboxamide (2), 7-(diethylamino)-N-(benzo[d]thiazol-2-yl)-2-oxo-2H-chromene-3-carboxamide (3) and (Z)-7-(diethylamino)-N-(3-methylbenzo[d]thiazol-2(3H)-ylidene)-2-oxo-2H-chromene-3-carboxamide) (4), have been synthesized. Their crystal structures, photophysical properties in acetonitrile and recognition properties for cyanide anions have been investigated. All the compounds are generally planar, especially compound 1 exhibits perfect planarity with dihedral angle between benzothiazolyl group and coumarin group being only 3.63°. Coumarin benzothiazole compounds 1 and 3 can recognize cyanide anions by Michael addition reaction and compound 3 exhibits color change from yellow to colorless and green fluorescence was quenched completely, which can be observed by naked eye. Coumarin benzothiazolyliden compound 4 can recognize cyanide anions with fluorescence turn-on response based on the copper complex ensemble displacement mechanism.

  8. Transition Metal-Free Amidoalkylation of Benzothiazoles and Amidoalkylarylation of Activated Alkenes with N,N-Dialkylamides.

    PubMed

    Wang, Jian; Li, Jing; Huang, Jinbo; Zhu, Qiang

    2016-04-01

    A general and practical amidoalkylation reaction, using N,N-dialkylamides in the presence of potassium persulfate as the sole reagent, has been developed. 2-Amidoalkylated benzothiazole- and 3-amidoalkyl-substituted indolinone derivatives were obtained by using benzothiazoles and N-aryl-N-methyl-methacrylamides as substrates, respectively. The transformation proceeded smoothly through amidoalkyl radical intermediates that were trapped by benzothiazoles or activated alkenes. PMID:26974600

  9. Inhibition of TNF-{alpha}-mediated inflammatory responses by a benzodioxolylacetylamino-linked benzothiazole analog in human fibroblast-like synoviocytes

    SciTech Connect

    Lee, Young-Rae; Jin, Guo Hua; Lee, Sang-Myeong; Park, Jin-Woo; Ryu, Jae-Ha; Jeon, Raok; Park, Byung-Hyun

    2011-05-20

    Highlights: {yields} We synthesized SPA0537, a benzothiazole analog. {yields} SPA0537 is a potent NF-{kappa}B inhibitor. {yields} SPA0537 suppresses the production of proinflammatory mediators in human rheumatoid fibroblast-like synoviocytes. {yields} SPA0537 is effective at suppressing osteoclast differentiation. -- Abstract: The pathologic processes of rheumatoid arthritis are mediated by a number of cytokines, chemokines, and matrix metalloproteinases, the expressions of which are controlled by NF-{kappa}B. This study was performed to explore the effects of a benzothiazole analog, SPA0537, on the control of the NF-{kappa}B activation pathway. We also investigated whether SPA0537 had any anti-inflammatory effects in human rheumatoid fibroblast-like synoviocytes (FLS). SPA0537 inhibited the nuclear translocation and the DNA binding of NF-{kappa}B subunits, which correlated with the inhibitory effects on IKK phosphorylation and I{kappa}B{alpha} degradation in TNF-{alpha}-stimulated rheumatoid FLS. These events further suppressed chemokine production, matrix metalloproteinase secretion, and TNF-{alpha}-induced cell proliferation. In addition, SPA0537 inhibited the osteoclast differentiation induced by macrophage colony-stimulating factor (MCSF) and receptor activator of the NF-{kappa}B ligand (RANKL) in bone marrow macrophages. These findings suggest that SPA0537 exerts anti-inflammatory effects in rheumatoid FLS through the inhibition of the NF-{kappa}B pathway. Therefore, it may have therapeutic value for the treatment of rheumatoid arthritis.

  10. Synthesis, structure, terahertz spectroscopy and luminescent properties of copper(I) complexes with mercaptan ligands and triphenylphosphine

    NASA Astrophysics Data System (ADS)

    Qiu, Qi-Ming; Liu, Min; Li, Zhong-Feng; Jin, Qiong-Hua; Huang, Xu; Zhang, Zhen-Wei; Zhang, Cun-Lin; Meng, Qing-Xuan

    2014-03-01

    The reactions of copper(I) halides with triphenylphosphine (PPh3) and mercaptan ligand [2-mercapto-6-nitrobenzothiazole (HMNBT), 2-amino-5-mercapto-1,3,4-thiadiazole (HAMTD) and 2-mercapto-5-methyl-benzimidazole (MMBD)] yielded seven complexes, [CuCl(HMNBT)(PPh3)2] (1), [CuX(HMNBT)(PPh3)]2 (X = Cl, Br) (2-3), [Cu(MNBT)(HMNBT)(PPh3)2] (4), [CuBr(HAMTD)(PPh3)2]·CH3OH (5) and [CuX(MMBD)(PPh3)2]·2CH3OH (X = Br, I) (6-7). These complexes were characterized by elemental analysis, X-ray diffraction, 1H NMR and 31P NMR spectroscopy. In these complexes the mercaptan ligands act as monodentate or bridged ligand with S as the coordination atom. In complexes 1 and 4, hydrogen bonds CH⋯X and weak interactions CH⋯π lead to the formation of chains and 2D network respectively, while complexes 2 and 3 are dinuclear. In 5-7, intramolecular hydrogen bonds link the [CuX(thione)(PPh3)2] molecules and the solvated methanol molecules into centrosymmetric dimers. Complexes 1-5 represent first copper(I) halide complexes of HMNBT and HAMTD. The complexes 1, 5, 6 and 7 exhibit interesting fluorescence in the solid state at room temperature and their terahertz (THz) time-domain spectroscopy was also studied.

  11. Effects of the microbial secondary metabolite benzothiazole on the nutritional physiology and enzyme activities of Bradysia odoriphaga (Diptera: Sciaridae).

    PubMed

    Zhao, Yunhe; Xu, Chunmei; Wang, Qiuhong; Wei, Yan; Liu, Feng; Xu, Shuangyu; Zhang, Zhengqun; Mu, Wei

    2016-05-01

    Bradysia odoriphaga (Diptera: Sciaridae) is the major pest that damages Chinese chive production. As a volatile compound derived from microbial secondary metabolites, benzothiazole has been determined to possess fumigant activity against B. odoriphaga. However, the mechanism of action of benzothiazole is not well understood. In the present study, fourth-instar larvae of B. odoriphaga were exposed to LC10 and LC30 of benzothiazole. Sublethal concentrations (LC10 and LC30) of benzothiazole significantly reduced the food consumption of the larvae on the second day after treatment (2 DAT). However, there were no significant changes in pupal weight among the different treatments. We also measured the protein, lipid, carbohydrate, and trehalose contents and the digestive enzyme activities of the larvae, and the results suggest that benzothiazole reduced the nutrient accumulation and decreased the digestive enzyme activities of B. odoriphaga. In addition, the activity of glutathione S-transferase was significantly decreased at 6h after treatment with benzothiazole, whereas general esterase activities were significantly increased at 6 and 24h after treatment. The results of this study indicate that benzothiazole interferes in the normal food consumption and digestion process by decreasing the activities of digestive enzymes. These results provide valuable information for understanding the toxicity of benzothiazole and for exploring volatile compound for the control of this pest. PMID:27017881

  12. Benzothiazole derivatives bearing amide moiety: potential cytotoxic and apoptosis-inducing agents against cervical cancer.

    PubMed

    Singh, Meenakshi; Modi, Arusha; Narayan, Gopeshwar; Singh, Sushil K

    2016-07-01

    Cervical cancer is a major cause of morbidity and mortality in women worldwide. In recent years, benzothiazole analogues have attracted considerable attention in anticancer research. Therefore, in this study, the earlier reported amide series of benzothiazole derivatives were investigated for their antiproliferative activity. The activity of amide derivatives was evaluated using the 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, flow cytometric analysis, apoptosis assay, and DNA fragmentation on two human cervical cancer cell lines: SiHa and C33-A. The data reported from this investigation indicated that benzothiazole derivatives show pronounced cytotoxicity in the HPV16-positive SiHa cells compared with HPV-negative C-33A cells. The in-vitro cytotoxicity of the compounds on the HEK-293 noncancer cell line was evaluated to establish selectivity. Cells treated with benzothiazole derivatives showed prominent morphological features as evidenced by cell shrinkage, membrane blebbing, apoptotic nuclei, and DNA fragmentation. The benzothiazole derivatives show accumulation of cells in the sub-G1 and S-phase of the cell cycle in SiHa and C33-A, respectively. In addition, these derivatives exert their beneficial effect by inducing apoptosis, in the chemoprevention of cervical cancer cells, and were further ascertained using a DNA fragmentation assay. The compounds studied showed potent cytotoxic and apoptotic properties against SiHa and C33-A cancer cell lines and thus represent an excellent starting point for further optimization of therapeutically effective anticancer drugs. PMID:26945135

  13. Chrysin-benzothiazole conjugates as antioxidant and anticancer agents.

    PubMed

    Mistry, Bhupendra M; Patel, Rahul V; Keum, Young-Soo; Kim, Doo Hwan

    2015-12-01

    7-(4-Bromobutoxy)-5-hydroxy-2-phenyl-4H-chromen-4-one, obtained from chrysin with 1,4-dibromobutane, was combined with a wide range of 6-substituted 2-aminobenzthiazoles, which had been prepared from the corresponding anilines with potassium thiocyanate. Free radical scavenging efficacies of newer analogues were measured using DPPH and ABTS assays, in addition to the assessment of their anticancer activity against cervical cancer cell lines (HeLa and CaSki) and ovarian cancer cell line (SK-OV-3) implementing the SRB assay. Cytotoxicity of titled compounds was checked using Madin-Darby canine kidney (MDCK) non-cancer cell line. Overall, 6a-r indicated remarkable antioxidant power as DPPH and ABTS(+) scavengers; particularly the presence of halogen(s) (6g, 6h, 6j-6l) was favourable with IC50 values comparable to the control ascorbic acid. Unsubstituted benzothiazole ring favored the activity of resultant compounds (6a and 6r) against HeLa cell line, whereas presence of chlorine (6g) or a di-fluoro group (6k) was a key to exert strong action against CaSki. Moreover, a mono-fluoro (6j) and a ketonic functionality (6o) were beneficial to display anticipated anticancer effects against ovarian cancer cell line SK-OV-3. The structural assignments of the new products were done on the basis of IR, (1)H NMR, (13)C NMR spectroscopy and elemental analysis. PMID:26514745

  14. Antimalarial Activity of Small-Molecule Benzothiazole Hydrazones.

    PubMed

    Sarkar, Souvik; Siddiqui, Asim A; Saha, Shubhra J; De, Rudranil; Mazumder, Somnath; Banerjee, Chinmoy; Iqbal, Mohd S; Nag, Shiladitya; Adhikari, Susanta; Bandyopadhyay, Uday

    2016-07-01

    We synthesized a new series of conjugated hydrazones that were found to be active against malaria parasite in vitro, as well as in vivo in a murine model. These hydrazones concentration-dependently chelated free iron and offered antimalarial activity. Upon screening of the synthesized hydrazones, compound 5f was found to be the most active iron chelator, as well as antiplasmodial. Compound 5f also interacted with free heme (KD [equilibrium dissociation constant] = 1.17 ± 0.8 μM), an iron-containing tetrapyrrole released after hemoglobin digestion by the parasite, and inhibited heme polymerization by parasite lysate. Structure-activity relationship studies indicated that a nitrogen- and sulfur-substituted five-membered aromatic ring present within the benzothiazole hydrazones might be responsible for their antimalarial activity. The dose-dependent antimalarial and heme polymerization inhibitory activities of the lead compound 5f were further validated by following [(3)H]hypoxanthine incorporation and hemozoin formation in parasite, respectively. It is worth mentioning that compound 5f exhibited antiplasmodial activity in vitro against a chloroquine/pyrimethamine-resistant strain of Plasmodium falciparum (K1). We also evaluated in vivo antimalarial activity of compound 5f in a murine model where a lethal multiple-drug-resistant strain of Plasmodium yoelii was used to infect Swiss albino mice. Compound 5f significantly suppressed the growth of parasite, and the infected mice experienced longer life spans upon treatment with this compound. During in vitro and in vivo toxicity assays, compound 5f showed minimal alteration in biochemical and hematological parameters compared to control. In conclusion, we identified a new class of hydrazone with therapeutic potential against malaria. PMID:27139466

  15. Comparative aquatic toxicity evaluation of 2-(thiocyanomethylthio)benzothiazole and selected degradation products using Ceriodaphnia dubia.

    PubMed

    Nawrocki, S T; Drake, K D; Watson, C F; Foster, G D; Maier, K J

    2005-04-01

    2-(Thiocyanomethylthio)benzothiazole (TCMTB) is a biocide used in the leather, pulp and paper, and water-treatment industries. TCMTB may enter aquatic ecosystems during its manufacture and use. TCMTB is environmentally unstable; therefore, it is important to evaluate the toxicity of the more persistent degradation products. This study compared the toxicity of TCMTB with its degradation products 2-mercaptobenzothiazole (2-MBT), 2-(methylthio)benzothiazole (MTBT), benzothiazole (BT), and 2-hydroxybenzothiazole (HOBT). Toxicity was determined using Ceriodaphnia dubia 48-hour acute and 7-day chronic test protocols. TCMTB was the most toxic compound evaluated in both the acute and chronic tests with EC50s of 15.3 and 9.64 microg/L, respectively. 2-MBT, the first degradation product, was the second most toxic compound with acute and chronic EC50s of 4.19 and 1.25 mg/L, respectively. The toxicity of MTBT and HOBT were similar with acute EC50s of 12.7 and 15.1 mg/L and chronic EC50s of 6.36 and 8.31 mg/L, respectively. The least toxic compound was BT with acute and chronic EC50s of 24.6 and 54.9 mg/L, respectively. TCMTB was orders of magnitude more toxic than its degradation products. Toxicity data on these benzothiazole degradation products is important because of concerns regarding their release, degradation, persistence, and non-target organism effects in aquatic ecosystems. PMID:15750776

  16. In vitro, ex vivo, and in vivo determination of thyroid hormone modulating activity of benzothiazoles

    EPA Science Inventory

    As in vitro assays are increasingly used to screen chemicals for their potential to produce endocrine disrupting adverse effects, it is important to understand their predictive capacity. The potential for a set of six benzothiazoles to affect endpoints related to thyroid hormone ...

  17. Evaluation of immunoglobulin adsorption on the hydrophobic charge-induction resins with different ligand densities and pore sizes.

    PubMed

    Lu, Hui-Li; Lin, Dong-Qiang; Gao, Dong; Yao, Shan-Jing

    2013-02-22

    Hydrophobic charge-induction chromatography (HCIC) is a novel technology for antibody purification. The ligand densities and pore properties of HCIC resins have significant effects on the separation behavior of protein, however, the understandings are quite limited. In the present work, new HCIC ligand, 2-mercapto-1-methylimidazole (MMI) was coupled to three agarose matrices with different pore sizes. A series of MMI resins with different ligand density and pore size was prepared by the control of ligand coupling. The adsorption isotherms and kinetics on the series of MMI resins were investigated with bovine serum immunoglobulin as the model IgG, and the effects of salt addition were studied. The Langmuir equation and pore diffusion model were used to fit the experimental data, and the influences of ligand density, pore size and salt addition on the saturated adsorption capacity, the dissociation constant and the effective diffusivity were discussed. It was found that the adsorption capacities and the effective pore diffusion coefficient increased with the increase of ligand density and pore size. The effects of salt addition on the adsorption behaviors were dependent on the ligand density. For low ligand density the IgG adsorption was salt-promoted, while the resins with high ligand density showed a salt-independent property. The results indicated that for a given protein the ligand density and pore size of HCIC resins should be optimized for improving the protein adsorption. PMID:23336945

  18. In Vitro, Ex Vivo, and In Vivo Determination of Thyroid Hormone Modulating Activity of Benzothiazoles.

    PubMed

    Hornung, Michael W; Kosian, Patricia A; Haselman, Jonathan T; Korte, Joseph J; Challis, Katie; Macherla, Chitralekha; Nevalainen, Erica; Degitz, Sigmund J

    2015-08-01

    As in vitro assays are increasingly used to screen chemicals for their potential to produce endocrine disrupting adverse effects, it is important to understand their predictive capacity. The potential for a set of 6 benzothiazoles to affect endpoints related to thyroid hormone synthesis inhibition were assessed using in vitro, ex vivo, and in vivo assays. Inhibition of thyroid peroxidase (TPO) derived from pig thyroid glands was determined for benzothiazole (BTZ), 2-mercaptobenzothiazole (MBT), 5-chloro-2-mercaptobenzothiazole (CMBT), 2-aminobenzothiazole (ABT), 2-hydroxybenzothiazole (HBT), and 2-methylthiobenzothiazole (MTBT). Their rank order potency for TPO inhibition was MBT=CMBT>ABT>BTZ, whereas HBT and MTBT exhibited no inhibitory activity. The benzothiazoles were tested further in a Xenopus laevis thyroid gland explant culture assay in which inhibition of thyroxine (T4) release was the measured endpoint. In this assay all 6 benzothiazoles inhibited T4 release. The activity of the benzothiazoles for disrupting thyroid hormone activity was verified in vivo using X. laevis tadpoles in a 7-day assay. The 2 most potent chemicals for TPO inhibition, MBT and CMBT, produced responses in vivo indicative of T4 synthesis inhibition including induction of sodium iodide symporter mRNA and decreases in glandular and circulating thyroid hormones. The capability to measure thyroid hormone levels in the glands and blood by ultrahigh performance LC-MS/MS methods optimized for small tissue samples was critical for effects interpretation. These results indicate that inhibition of TPO activity in vitro was a good indicator of a chemical's potential for thyroid hormone disruption in vivo and may be useful for prioritizing chemicals for further investigation. PMID:25953703

  19. One-Pot Synthesis of Benzothiazole-Tethered Chromanones/Coumarins via Claisen Rearrangement Using the Solid State Melt Reaction.

    PubMed

    Bakthadoss, Manickam; Selvakumar, Raman

    2016-04-15

    A novel protocol has been successfully established for the efficient synthesis of benzothiazole-tethered chromanone/coumarin scaffolds via Claisen rearrangement using a solid state melt reaction in a one-pot manner. Benzothiazole formation and Claisen rearrangement involve the cleavage of S-S and C-O bonds and formation of C-S, C═N, and C-C bonds in a single operation without using a catalyst or solvent. PMID:26991666

  20. A Sandmeyer type reaction for bromination of 2-mercapto-1-methyl-imidazoline (N2C4H6S) into 2-bromo-1-methyl-imidazole (N2C4H5Br) in presence of copper(I) bromide.

    PubMed

    Lobana, Tarlok S; Sultana, Razia; Butcher, Ray J

    2011-11-21

    2-Mercapto-1-methyl-imidazoline (N(2)C(4)H(6)S) is converted at room temperature into 2-bromo-1-methyl-imidazole (N(2)C(4)H(5)Br) in presence of copper(I) bromide in acetonitrile-chloroform mixture via extrusion of sulfur as sulfate and oxidation of Cu(I) into Cu(II). 2-Bromo-1-methyl-imidazole was isolated as its self assembled tetranuclear Cu(II) cluster, [Cu(4)(η(1)-N-(N(2)C(4)H(5)Br)(4)(μ(4)-O)(μ-Br)(6)] 1 {η(1)-N-(N(2)C(4)H(5)Br) = 2-bromo-1-methyl-imidazole}. PMID:21960310

  1. Synthesis, conjugation and relaxation studies of gadolinium(III)-4-benzothiazol-2-yl-phenylamine as a potential brain specific MR contrast agent.

    PubMed

    Saini, Nisha; Varshney, Raunak; Tiwari, Anjani K; Kaul, Ankur; Allard, Michele; Ishar, M P S; Mishra, Anil K

    2013-04-14

    Magnetic resonance (MR) imaging is widely used in clinical research to map the structural and functional organization of the brain. We have designed and synthesized a Gd-based specific MR contrast agent that binds to regions in the brain. The presented compound {4-[(4-benzothiazol-2-yl-phenylcarbamoyl)-methyl]-7,10-bis-carboxymethyl-1,4,7,10-tetraazacyclododec-1-yl} acetic acid (DO3A-BT) was synthesized by conjugating the chloroacetylated product of 4-benzothiazol-2-yl-phenylamine with a trisubstituted cyclen. The lanthanide complex (Ln-DO3A-BT) was evaluated in vitro for both MR (Gd-DO3A-BT) and optical (Eu-DO3A-BT) imaging applications. The complex Gd-DO3A-BT displays a relaxivity of r1 = 4.18 mM(-1) s(-1) at 4.7 T which is 1.2 times greater than Dotarem and significantly higher than the brain specific MR contrast agent Luxol Fast Blue (LFB). The protonation constant of the ligand (pKa1 = 9.91, pKa2 = 8.22, pKa3 = 5.01) and the stability constant of the complex formed between Gd(III), Eu(III) and Ca(II) and ligand DO3A-BT (log βGdL = 18.4, log βEuL = 18.3, log βZn2L = 7.1, log βCa2L = 6.3) were recorded by potentiometric titration. The constants reflect the high stability of the ligand with lanthanides compared with endogenous metal ions. The transmetalation stability of Gd-DO3A-BT toward Zn proved to be excellent with a rate constant of 3.07 × 10(-5) s(-1) which is in line with other tetraazatetraacetic acid (DOTA)-monoamide complexes. The hydration number (q) was found to be 0.92, and is calculated from the difference in the luminescence lifetime of Eu-DO3A-BT in H2O and D2O solutions to determine the coordination state of this complex. The in vivo biodistribution of (99m)Tc-DO3A-BT in BALB/c mice showed a brain uptake of 1.2% ID g(-1) at 2 min post injection when injected with mannitol which disrupts the blood-brain-barrier (BBB) due to osmotic shock. In vitro binding on the brain homogenate revealed a high uptake by the neuronal/glial cells for in vivo

  2. Design, Synthesis and Biological Evaluation of Novel Benzothiazole Derivatives as Selective PI3Kβ Inhibitors.

    PubMed

    Cao, Shuang; Cao, Ruiyuan; Liu, Xialing; Luo, Xiang; Zhong, Wu

    2016-01-01

    A novel series of PI3Kβ (Phosphatidylinositol-3-kinases beta subunit) inhibitors with the structure of benzothiazole scaffold have been designed and synthesized. All the compounds have been evaluated for inhibitory activities against PI3Kα, β, γ, δ and mTOR (Mammalian target of rapamycin). Two superior compounds have been further evaluated for the IC50 values against PI3Ks/mTOR. The most promising compound 11 displays excellent anti-proliferative activity and selectivity in multiple cancer cell lines, especially in the prostate cancer cell line. Docking studies indicate the morpholine group in 2-position of benzothiazole is necessary for the potent antitumor activity, which confirms our design is reasonable. PMID:27384552

  3. Structural and spectral comparisons between isomeric benzisothiazole and benzothiazole based aromatic heterocyclic dyes

    NASA Astrophysics Data System (ADS)

    Wang, Yin-Ge; Wang, Yue-Hua; Tao, Tao; Qian, Hui-Fen; Huang, Wei

    2015-09-01

    A pair of isomeric heterocyclic compounds, namely 3-amino-5-nitro-[2,1]-benzisothiazole and 2-amino-6-nitrobenzothiazole, are used as the diazonium components to couple with two N-substituted 4-aminobenzene derivatives. As a result, two pairs of isomeric aromatic heterocyclic azo dyes have been produced and they are structurally and spectrally characterized and compared including single-crystal structures, electronic spectra, solvatochromism and reversible acid-base discoloration, thermal stability and theoretically calculations. It is concluded that both benzisothiazole and benzothiazole based dyes show planar molecular structures and offset π-π stacking interactions, solvatochromism and reversible acid-base discoloration. Furthermore, benzisothiazole based aromatic heterocyclic dyes exhibit higher thermal stability, larger solvatochromic effects and maximum absorption wavelengths than corresponding benzothiazole based ones, which can be explained successfully by the differences of their calculated isomerization energy, dipole moment and molecular band gaps.

  4. Oxidation of Refractory Benzothiazoles with PMS/CuFe2O4: Kinetics and Transformation Intermediates.

    PubMed

    Zhang, Tao; Chen, Yin; Leiknes, TorOve

    2016-06-01

    Benzothiazole (BTH) and its derivatives 2-(methylthio)bezothiazole (MTBT), 2-benzothiazolsulfonate (BTSA), and 2-hydroxybenzothiazole (OHBT) are refractory pollutants ubiquitously existing in urban runoff at relatively high concentrations. Here, we report their oxidation by CuFe2O4-activated peroxomonosulfate (PMS/CuFe2O4), focusing on kinetics and transformation intermediates. These benzothiazoles can be efficiently degraded by this oxidation process, which is confirmed to generate mainly sulfate radicals (with negligible hydroxyl-radical formation) under slightly acidic to neutral pH conditions. The molar exposure ratio of sulfate radical to residual PMS (i.e., Rct) for this process is a constant that is related to the reaction condition and can be easily determined. The reaction rate constants of these benzothiazoles toward sulfate radical are (3.3 ± 0.3) × 10(9), (1.4 ± 0.3) × 10(9), (1.5 ± 0.1) × 10(9), and (4.7 ± 0.5) × 10(9) M(-1) s(-1), respectively (pH 7 and 20 °C). On the basis of Rct and these rate constants, their degradation in the presence of organic matter can be well-predicted. A number of transformation products were detected and tentatively identified using triple-quadruple/linear ion trap MS/MS and high-resolution MS. It appears that sulfate radicals attack BTH, MTBT, and BTSA on their benzo ring via electron transfer, generating multiple hydroxylated intermediates that are reactive toward common oxidants. For OHBT oxidation, the thiazole ring is preferentially broken down. Due to competitions of the transformation intermediates, a minimum PMS/pollutant molar ratio of 10-20 is required for effective degradation. The flexible PMS/CuFe2O4 could be a useful process to remove the benzothiazoles from low dissolved organic carbon waters like urban runoff or polluted groundwater. PMID:27144396

  5. Preparation, thermo-optic property and simulation of optical switch based on azo benzothiazole polymer

    NASA Astrophysics Data System (ADS)

    Cao, Zhijuan; Qiu, Fengxian; Wang, Qing; Cao, Guorong; Guan, Yijun; Zhuang, Lin; Xu, Xiaolong; Wang, Jie; Chen, Qian; Yang, Dongya

    2013-04-01

    An azo chromophore molecule 4-[(benzothiazole-2-yl)diazenyl]phenyl-1,3-diamine (BTPD) was prepared with 2-amino benzothiazole and m-phenylenediamine by diazo-coupling reaction. Then, the chromophore molecule BTPD was polymerized with NJ-210 and isophorone diisocyanate (IPDI) to obtain novel azo benzothiazole polymer (BTPU). The structures of BTPD and BTPU were characterized using the Fourier transform infrared, UV-visible spectroscopy, DSC and TGA. The physical properties of the obtained BTPU were investigated. The refractive index ( n) of BTPU was demonstrated at different temperature and wavelength (532, 650 and 850 nm) using attenuated total reflection technique. The transmission loss and dispersion characteristic of BTPU film were investigated using the CCD digital imaging devices and Sellmeyer equation. A Y-branch and 2 × 2 Mach-Zehnder interferometer (MZI) polymeric thermo-optic switches based on the thermo-optic effect of prepared BTPU were proposed and the performance of switches was simulated. The results indicated that the power consumption of the Y-branch thermo-optic switch could be only 0.6 mW. The Y-branch and MZI switching rising and falling times obtained were 8.0 and 1.8 ms.

  6. Benzothiazole Amphiphiles Ameliorate Amyloid β-Related Cell Toxicity and Oxidative Stress.

    PubMed

    Cifelli, Jessica L; Chung, Tim S; Liu, Haiyan; Prangkio, Panchika; Mayer, Michael; Yang, Jerry

    2016-06-15

    Oxidative stress from the increase of reactive oxygen species in cells is a common part of the normal aging process and is accelerated in patients with Alzheimer's disease (AD). Herein, we report the evaluation of three benzothiazole amphiphiles (BAMs) that exhibit improved biocompatibility without loss of biological activity against amyloid-β induced cell damage compared to a previously reported hexa(ethylene glycol) derivative of benzothiazole aniline (BTA-EG6). The reduced toxicity of these BAM agents compared to BTA-EG6 corresponded with their reduced propensity to induce membrane lysis. In addition, all of the new BAMs were capable of protecting differentiated SH-SY5Y neuroblastoma cells from toxicity and concomitant oxidative stress induced by AD-related aggregated Aβ (1-42) peptides. Binding and microscopy studies support that these BAM agents target Aβ and inhibit the interactions of catalase with Aβ in cells, which, in turn, can account for an observed inhibition of Aβ-induced increases in hydrogen peroxide in cells treated with these compounds. These results support that this family of benzothiazole amphiphiles may have therapeutic potential for treating cellular damage associated with AD and other Aβ-related neurologic diseases. PMID:27055069

  7. Manganese(III) Acetate-Promoted Cross-Coupling Reaction of Benzothiazole/Thiazole Derivatives with Organophosphorus Compounds under Ball-Milling Conditions.

    PubMed

    Li, Liang; Wang, Jun-Jie; Wang, Guan-Wu

    2016-07-01

    The first solvent-free manganese(III) acetate-promoted reaction of benzothiazole/thiazole derivatives with organophosphorus compounds including phosphine oxides, phosphinate ester, and phosphonate diester has been efficiently developed under ball-milling conditions, providing a highly efficient and green protocol to structurally diverse C2-phosphonylated benzothiazole/thiazole derivatives with remarkable functional group tolerance and excellent yields. PMID:27248000

  8. Tautomeric conversion, vibrational spectra, and density functional studies on peripheral sulfur derivatives of benzothiazole and benzothiazoline isomers

    NASA Astrophysics Data System (ADS)

    Altun, Ahmet; Kuliyev, Eziz; Aghatabay, Naz M.

    2016-01-01

    The room temperature structural (tautomerism, dimerization, conformational preference, geometry parameters) and vibrational spectral (IR and Raman) analyses have been performed on benzothiazoline (benzothiazoline-2-thione, 3-methyl-benzothiazoline-2-thione) and benzothiazole [2-mercaptobenzothiazole, 2-methylthiobenzothiazole, and bis(benzothiazole-2-ylthio)ethane] derivatives at the B3LYP/6-311++G∗∗ level of theory. Although the keto to enol transition barriers are too high over the most stable benzothiazoline isomers, vibrational spectral analyses reveal some major bands of benzothiazole isomers in the present room temperature experimental FT-IR and FT-Raman specta. Therefore, benzothiazole isomers exist at rare amounts in the powdered samples that are mainly composed of benzothiazoline isomers. The benzothiazole isomers have two stable conformations due to the orientation of their SH and SCH3 moieties. The energetic and vibrational spectral analyses suggest that the benzothiazoline-2-thione molecules can be stabilized further through the NH⋯S intermolecular hydrogen bonds in solid phase. All observed fundamental vibrational bands of the molecules have been assigned based on the calculated mode frequencies and IR/Raman intensities. The mode assignments have been expressed in terms of internal coordinates and their percent potential energy distributions. The effects of substitution at the nitrogen and peripheral sulfur atoms have been analyzed for the geometries and vibrational bands of the molecules.

  9. Determination of total sulfur compounds and benzothiazole in asphalt fume samples by gas chromatography with sulfur chemiluminescence detection.

    PubMed

    Jaycox, L B; Olsen, L D

    2000-09-01

    As part of a collaborative project between the National Institute for Occupational Safety and Health and the Federal Highway Administration to evaluate asphalt pavers' exposures to asphalt fume and their potential health effects, a method was developed for the determination of total sulfur compounds and benzothiazole in asphalt fume samples. Asphalt fume samples were collected from asphalt mixtures with and without the addition of ground-up rubber tires. The asphalt fume samples were collected with sampling trains that consisted of a Teflon membrane filter and an XAD-2 adsorbent tube. Filter and sampling tube media were extracted with hexane and subsequently analyzed by gas chromatography with a sulfur chemiluminescence detector. Separation was achieved with a 100 percent dimethyl polysiloxane fused silica column. Typical calibration curves had linear correlation coefficients of 0.99 or better with a relative standard deviation (RSD) of 5 percent. Benzothiazole desorption efficiency (DE) determined using spiked sampling tubes ranged from 96.5 percent at 5.0 micrograms to 89.4 percent at 40 micrograms with RSD values from 0.9 to 4.0 percent. Benzothiazole storage recovery determined using sampling tubes spiked at 20 micrograms and refrigerated for 30 days at 4 degrees C was 89.8 percent when corrected for the DE with an RSD of 1.1 percent. The limit of detection for the method determined using spiked sampling tubes was 0.30 microgram. Quantitation for total sulfur compounds and benzothiazole was against benzothiazole standards in hexane. Because of detector selectivity, sample preparation consisted of a simple hexane extraction even when samples had a high background due to hydrocarbon overload. Detector sensitivity provided quantitation in the sub-microgram region. Because of the sample preparation step and because benzothiazole was determined during the same analysis run, this method is straightforward and analytically efficient. The method has been used to

  10. Occurrence, phase distribution, and mass loadings of benzothiazoles in riverine runoff of the Pearl River Delta, China.

    PubMed

    Ni, Hong-Gang; Lu, Feng-Hui; Luo, Xian-lin; Tian, Hui-Yu; Zeng, Eddy Y

    2008-03-15

    A set of six benzothiazoles was determined in riverine runoff samples of the Pearl River Delta (PRD) collected monthly from March 2005 to February 2006. The concentrations of total benzothiazoles ranged from 220 to 611 ng/L, with benzothiazole (BT) being the most prominent (82%), followed by 2-methylthiobenzothiazole (MBT),thianaphthene (TN), and triphenylene (TP). The annual fluxes ofTN, BT, MBT, dibenzothiophene (DBT), 2-(4-morpholinyl)benzothiazole (24MoBT), and TP from the PRD to the coastal ocean were 1.94, 65.1, 10.1,0.63, 0.18, and 0.89 tons/yr, summing to yield an annual flux of 79 tons/yr for total benzothiazoles. In the PRD, approximately 1.1 x 10(5) tons of rubber are estimated to be released into the environment each year. This corresponds to the annual fluxes of 13 tons/yr for BT and 0.4 tons/yr for 24MoBT from tire particles. The annual fluxes of BT from scrap tires from Japan, Korea, Brazil, the European Union, the United States, and China were 99, 21, 36, 270, 328, and 120 tons/yr, respectively. The fluxes of 24MoBT from the same countries were 3.0, 0.5, 1.1, 8.4, 10.3, and 3.8 tons/ yr, respectively. These results indicated that tire-wear particles and scrap tires are the dominant sources of benzothiazoles in the environment. By comparison, Asia may be the major contributor to the global input of benzothiazoles from auto tires in the coming years. Overall, the six benzothiazoles under investigation appeared to be suitable tracers of pollutant inputs to surface runoff within the PRD aquatic system. In addition, 24MoBT seemed more appropriate than BT to trace tire rubber residues and therefore can be a good indicator of economic development and urbanization in a specific region. PMID:18409609

  11. Synthesis, physical properties and simulation of thermo-optic switch based on azo benzothiazole heterocyclic polymer

    NASA Astrophysics Data System (ADS)

    Qiu, Fengxian; Chen, Caihong; Zhou, Qiaolan; Cao, Zhijuan; Cao, Guorong; Guan, Yijun; Yang, Dongya

    2014-05-01

    A chromophore molecule 4-[(benzothiazole-2-yl)diazenyl]phenyl-1,3-diamine (BTPD) was prepared with 2-amino benzothiazole and m-phenylenediamine by diazo-coupling reaction. Then, the BTPD was polymerized with polyether polyol (NJ-220) and isophorone diisocyanate (IPDI) to obtain novel azo benzothiazole polyurethane-urea (BTPUU). The chemical structures of BTPD and BTPUU were characterized by FT-IR and UV-visible spectroscopy. The thermal and mechanical properties of BTPUU film were investigated. The refractive index and transmission loss of BTPUU film were measured at different temperatures and different laser wavelengths (532 nm, 650 nm and 850 nm) by an attenuated total reflection (ATR) technique and CCD digital imaging devices. The thermo-optic coefficients of BTPUU are -4.7086 × 10-4 °C-1 (532 nm), -6.5257 × 10-4 °C-1 (650 nm) and -5.1029 × 10-4 °C-1 (850 nm), respectively. A Y-branch switch and Mach-Zehnder interferometer (MZI) thermo-optic switches based on thermo-optic effect were proposed and the performances of the switches were simulated, respectively. The results show that the power consumption of the Y-branch thermo-optic switch is only 3.28 mW. The response times of Y-branch and MZI switches are 8.0 ms and 2.0 ms, respectively. The results indicate that the prepared BTPUU has high potential for the applications of the Y-branch digital optical switch (DOS), MZI thermo-optic switch, directional coupler (DC) switch and optical modulators.

  12. Synthesis and herbicidal evaluation of novel benzothiazole derivatives as potential inhibitors of D1 protease.

    PubMed

    Huang, Tonghui; Sun, Jie; An, Lin; Zhang, Lixian; Han, Cuiping

    2016-04-01

    D1 protease is a C-terminal processing protease that has been predicted to be an ideal herbicidal target. Three novel series of benzothiazole derivatives were synthesized and evaluated for their herbicidal activities against Brassica napus (rape) and Echinochloa crusgalli (barnyard grass). The preliminary bioassay indicated that most of the synthesized compounds possess promising D1 protease inhibitory activities and considerable herbicidal activities. Molecular docking was performed to position representative compounds into the active site of D1 protease to determine a probable binding model. PMID:26905829

  13. X-ray diffraction investigation of 1-phenyl-3-isopropyl-5-(benzothiazol-2-yl)formazan

    SciTech Connect

    Slepukhin, P. A. Pervova, I. G.; Rezinskikh, Z. G.; Lipunova, G. N.; Gorbatenko, Yu. A.; Lipunov, I. N.

    2008-01-15

    The crystal structure of 1-phenyl-3-isopropyl-5-(benzothiazol-2-yl)formazan is investigated using X-ray diffraction. The compound crystallizes in the form of two crystallographically independent molecules (A and B) in identical conformations that are stabilized by intermolecular hydrogen bonds. The intermolecular hydrogen bonds N-H-N (N-N, 2.892 and 2.939 A) link molecules into AB dimers. Both molecules have a flattened structure, except for the isopropyl fragment. The bonds in the formazan chains are delocalized. Molecules A and B have close geometric characteristics.

  14. Enantioselective Alkynylation of 2-Trifluoroacetyl Imidazoles Catalyzed by Bis-Cyclometalated Rhodium(III) Complexes Containing Pinene-Derived Ligands.

    PubMed

    Zheng, Yu; Harms, Klaus; Zhang, Lilu; Meggers, Eric

    2016-08-16

    Chiral rhodium(III) complexes containing two cyclometalating 2-phenyl-5,6-(S,S)-pinenopyridine ligands and two additional acetonitriles are introduced as excellent catalysts for the highly enantioselective alkynylation of 2-trifluoroacetyl imidazoles. Whereas the ligand-based chirality permits the straightforward synthesis of the complexes in a diastereomerically and enantiomerically pure fashion, the metal-centered chirality is responsible for the asymmetric induction over the course of the catalysis. For comparison, the analogous iridium congeners provide only low enantioselectivity, and previously reported benzoxazole- and benzothiazole-based catalysts do not show any catalytic activity for this reaction under standard reaction conditions. PMID:27312941

  15. Pharmacophore generation of 2-substituted benzothiazoles as AdeABC efflux pump inhibitors in A. baumannii.

    PubMed

    Yilmaz, S; Altinkanat-Gelmez, G; Bolelli, K; Guneser-Merdan, D; Over-Hasdemir, M U; Yildiz, I; Aki-Yalcin, E; Yalcin, I

    2014-01-01

    RND family efflux pumps are important for multidrug resistance in Gram-negative bacteria. To date no efflux pump inhibitors for clinical use have been found, so developing the specific inhibitors of this pump system will be beneficial for the treatment of infections caused by these multidrug-resistant pathogens. A set of BSN-coded 2-substituted benzothiazoles were tested alone and in combination with ciprofloxacin (CIP) against the RND family efflux pump AdeABC overexpressor Acinetobacter baumannii SbMox-2 strain. The results indicated that the BSN compounds did not have antimicrobial activity when tested alone. However, if they were applied in combination with CIP, it was observed that the antibiotic had antimicrobial activity against the tested pathogen, possessing a minimum inhibitory concentration value that could be utilized in clinical treatment. A 3D-common features pharmacophore model was applied by using the HipHop method and the generated pharmacophore hypothesis revealed that the hydrogen bond acceptor property of nitrogen in the thiazole ring and the oxygen of the amide substituted at the second position of the benzothiazole ring system were significant for binding to the target protein. Moreover, three hydrophobic aromatic features were found to be essential for inhibitory activity. PMID:24905472

  16. Benzothiazole, benzotriazole, and their derivates in clothing textiles--a potential source of environmental pollutants and human exposure.

    PubMed

    Avagyan, Rozanna; Luongo, Giovanna; Thorsén, Gunnar; Östman, Conny

    2015-04-01

    Textiles play an important role in our daily life, and textile production is one of the oldest industries. In the manufacturing chain from natural and/or synthetic fibers to the final clothing products, the use of many different chemicals is ubiquitous. A lot of research has focused on chemicals in textile wastewater, but the knowledge of the actual content of harmful chemicals in clothes sold on the retail market is limited. In this paper, we have focused on eight benzothiazole and benzotriazole derivatives, compounds rated as high production volume chemicals. Twenty-six clothing samples of various textile materials and colors manufactured in 14 different countries were analyzed in textile clothing using liquid chromatography tandem mass spectrometry. Among the investigated textile products, 11 clothes were for babies, toddlers, and children. Eight of the 11 compounds included in the investigation were detected in the textiles. Benzothiazole was present in 23 of 26 investigated garments in concentrations ranging from 0.45 to 51 μg/g textile. The garment with the highest concentration of benzothiazole contained a total amount of 8.3 mg of the chemical. The third highest concentration of benzothiazole (22 μg/g) was detected in a baby body made from "organic cotton" equipped with the "Nordic Ecolabel" ("Svanenmärkt"). It was also found that concentrations of benzothiazoles in general were much higher than those for benzotriazoles. This study implicates that clothing textiles can be a possible route for human exposure to harmful chemicals by skin contact, as well as being a potential source of environmental pollutants via laundering and release to household wastewater. PMID:25342452

  17. Benzothiazole Sulfinate: a Water-Soluble and Slow-Releasing Sulfur Dioxide Donor.

    PubMed

    Day, Jacob J; Yang, Zhenhua; Chen, Wei; Pacheco, Armando; Xian, Ming

    2016-06-17

    Sulfur dioxide (SO2) has long been considered a toxic environmental pollutant and byproduct of industrial processing. Recently it has become evident that SO2 may also have regulatory functions in mammalian pulmonary systems. However, the study of these effects has proven to be challenging due to the difficulty in administering SO2 in a reliable manner. In this work, we report the discovery of a new pH-dependent and water-soluble SO2 donor, benzothiazole sulfinate (BTS). We have found BTS to have slow and sustained SO2 release at physiological pH. Additionally, we have explored its vasorelaxation properties as compared to the authentic SO2 gas solutions. The slow release of BTS should make it a useful tool for the study of endogenously generated SO2. PMID:27031093

  18. Hybrid benzothiazole analogs as antiurease agent: Synthesis and molecular docking studies.

    PubMed

    Taha, Muhammad; Ismail, Nor Hadiani; Imran, Syahrul; Wadood, Abdul; Rahim, Fazal; Khan, Khalid Muhammad; Riaz, Muhammad

    2016-06-01

    Benzothiazole analogs (1-20) have been synthesized, characterized by EI-MS and (1)H NMR, and evaluated for urease inhibition activity. All compounds showed excellent urease inhibitory potential varying from 1.4±0.10 to 34.43±2.10μM when compared with standard thiourea (IC50 19.46±1.20μM). Among the series seventeen (17) analogs 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 17, and 18 showed outstanding urease inhibitory potential. Analogs 15 and 19 also showed good urease inhibition activity. When we compare the activity of N-phenylthiourea 20 with all substituted phenyl derivatives (1-18) we found that compound 15 showed less activity than compound 20 having 3-methoxy substituent. The binding interactions of these active analogs were confirmed through molecular docking. PMID:27038849

  19. Synthesis and anticandidal evaluation of new benzothiazole derivatives with hydrazone moiety.

    PubMed

    Yurttaş, Leyla; Kaplancıklı, Zafer Asım; Göger, Gamze; Demirci, Fatih

    2016-10-01

    In this study, we have performed the synthesis of new N'-(arylidene)-4-[(benzothiazol-2-yl)thio]butanoylhydrazide derivatives (3a-s) bearing azole moiety and hydrazone group in a lipophilic structural framework. The target compounds were prepared by a three step synthetic procedure starting from 2-mercaptobenzothiazole. The structures of the target compounds were elucidated by IR, (1)H NMR, (13)C NMR spectra and elemental analysis. The antifungal activity of the obtained compounds has been determined against a number of clinic and fluconazole-resistant Candida strains by using microdilution method. Compounds (3a-3s) exhibited anticandidal activity in different ratios varying between the range of MIC: 50 and 200 µg/mL. PMID:26247354

  20. Synthesis, in vitro protoporphyrinogen oxidase inhibition, and herbicidal activity of N-(benzothiazol-5-yl)hexahydro-1H-isoindole-1,3-diones and N-(benzothiazol-5-yl)hexahydro-1H-isoindol-1-ones.

    PubMed

    Wu, Qiong-You; Jiang, Li-Li; Zuo, Yang; Wang, Zhi-Fang; Xi, Zhen; Yang, Guang-Fu

    2014-10-01

    Protoporphyrinogen oxidase (EC 1.3.3.4) is one of the most significant targets for a large family of herbicides. As part of our continuous efforts to search for novel protoporphyrinogen oxidase-inhibiting herbicides, N-(benzothiazol-5-yl)tetrahydroisoindole-1,3-dione was selected as a lead compound for structural optimization, leading to the syntheses of a series of novel N-(benzothiazol-5-yl)hexahydro-1H-isoindole-1,3-diones (1a-o) and N-(benzothiazol-5-yl)hexahydro-1H-isoindol-1-ones (2a-i). These newly prepared compounds were characterized by elemental analyses, (1) H NMR, and ESI-MS, and the structures of 1h and 2h were further confirmed by X-ray diffraction analyses. The bioassays indicated that some compounds displayed comparable or higher protoporphyrinogen oxidase inhibition activities in comparison with the commercial control. Very promising, compound 2a, ethyl 2-((6-fluoro-5-(4,5,6,7-tetrahydro-1-oxo-1H-isoindol-2(3H)-yl)benzo[d]thiazol-2-yl)-sulfanyl)acetate, was recognized as the most potent candidate with K(i) value of 0.0091 μm. Further greenhouse screening results demonstrated that some compounds exhibited good herbicidal activity against Chenopodium album at the dosage of 150 g/ha. PMID:24803371

  1. One-Pot Synthesis and Evaluation of Antileishmanial Activities of Functionalized S-Alkyl/Aryl Benzothiazole-2-carbothioate Scaffold.

    PubMed

    Dar, Ajaz A; Shadab, M; Khan, Suman; Ali, Nahid; Khan, Abu T

    2016-04-15

    The synthesis of hitherto unreported S-alkyl/aryl benzothiazole-2-carbothioate is reported from thiols, oxalyl chloride, and 2-aminothiophenols using 10 mol % n-tetrabutylammonium iodide (TBAI) as catalyst in acetonitrile through multicomponent reaction (MCR) strategy. The present protocol favored formation of benzothiazoles and thioesters via simultaneous formation of C-N and C-S bonds in good yields with a wide range of substrates. A few of the synthesized derivatives were evaluated for their antimicrobial activity against the protozoan parasite Leishmania donovani, a causative agent of visceral leishmaniasis (VL). Further, these compounds displayed no toxicity toward macrophage RAW 264.7 cells and are therefore nontoxic and effective antileishmanial leads. In silico docking studies were performed to understand the possible binding site interaction with trypanothione reductase (TryR). PMID:26999637

  2. A comparative study between para-aminophenyl and ortho-aminophenyl benzothiazoles using NMR and DFT calculations.

    PubMed

    Pierens, G K; Venkatachalam, T K; Reutens, D

    2014-08-01

    Ortho-substituted and para-substituted aminophenyl benzothiazoles were synthesised and characterised using NMR spectroscopy. A comparison of the proton chemical shift values reveals significant differences in the observed chemical shift values for the NH protons indicating the presence of a hydrogen bond in all ortho-substituted compounds as compared to the para compounds. The presence of intramolecular hydrogen bond in the ortho amino substituted aminophenyl benzothiazole forces the molecule to be planar which may be an additional advantage in developing these compounds as Alzheimer's imaging agent because the binding to amyloid fibrils prefers planar compounds. The splitting pattern of the methylene proton next to the amino group also showed significant coupling to the amino proton consistent with the notion of the existence of slow exchange and hydrogen bond in the ortho-substituted compounds. This is further verified by density functional theory calculations which yielded a near planar low energy conformer for all the o-aminophenyl benzothiazoles and displayed a hydrogen bond from the amine proton to the nitrogen of the thiazole ring. A detailed analysis of the (1)H, (13)C and (15)N NMR chemical shifts and density functional theory calculated structures of the compounds are described. PMID:24890025

  3. A Tetra(Ethylene Glycol) Derivative of Benzothiazole Aniline Enhances Ras-Mediated Spinogenesis

    PubMed Central

    Megill, Andrea; Lee, Taehee; DiBattista, Amanda Marie; Song, Jung Min; Spitzer, Matthew H.; Rubinshtein, Mark; Habib, Lila K.; Capule, Christina C.; Mayer, Michael; Turner, R. Scott; Kirkwood, Alfredo; Yang, Jerry; Pak, Daniel T. S.; Lee, Hey-Kyoung

    2013-01-01

    The tetra(ethylene glycol) derivative of benzothiazole aniline, BTA-EG4, is a novel amyloid-binding small molecule that can penetrate the blood–brain barrier and protect cells from Aβ-induced toxicity. However, the effects of Aβ-targeting molecules on other cellular processes, including those that modulate synaptic plasticity, remain unknown. We report here that BTA-EG4 decreases Aβ levels, alters cell surface expression of amyloid precursor protein (APP), and improves memory in wild-type mice. Interestingly, the BTA-EG4-mediated behavioral improvement is not correlated with LTP, but with increased spinogenesis. The higher dendritic spine density reflects an increase in the number of functional synapses as determined by increased miniature EPSC (mEPSC) frequency without changes in presynaptic parameters or postsynaptic mEPSC amplitude. Additionally, BTA-EG4 requires APP to regulate dendritic spine density through a Ras signaling-dependent mechanism. Thus, BTA-EG4 may provide broad therapeutic benefits for improving neuronal and cognitive function, and may have implications in neurodegenerative disease therapy. PMID:23719799

  4. Benzothiazoles in indoor air from Albany, New York, USA, and its implications for inhalation exposure.

    PubMed

    Wan, Yanjian; Xue, Jingchuan; Kannan, Kurunthachalam

    2016-07-01

    Benzothiazole and its derivatives (collectively referred to BTHs) are used widely in many consumer (e.g., textiles) and industrial (e.g., rubber) products. Very little is known about the occurrence of BTHs in indoor air and the inhalation exposure of humans to these substances. In this study, 81 indoor air samples collected from various locations in Albany, New York, USA, in 2014 were analyzed for BTHs by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). BTHs were found in all indoor air samples, and the overall concentrations in bulk air (vapor plus particulate phases) were in the range of 4.36-2229 ng/m(3) (geometric mean: 32.7 ng/m(3)). The highest concentrations (geometric mean: 148 ng/m(3)) were found in automobiles, followed by homes (49.5)>automobile garages (46.0)>public places, e.g., shopping malls (24.2)>barbershops (18.9) >offices (18.8)>laboratories (15.1). The estimated geometric mean daily intake (EDI) of BTHs for infants, toddlers, children, teenagers, and adults through indoor air inhalation from homes was 27.7, 26.3, 17.9, 10.5, and 7.77 ng/kg-bw/day, respectively. The estimated contribution of indoor air to total BTHs intake was approximately 10%. This is the first study on the occurrence of BTHs in indoor air. PMID:26954474

  5. Synthesis of new spiroindolinones incorporating a benzothiazole moiety as antioxidant agents.

    PubMed

    Karali, Nilgün; Güzel, Ozlen; Ozsoy, Nurten; Ozbey, Süheyla; Salman, Aydin

    2010-03-01

    3H-Spiro[1,3-benzothiazole-2,3'-indol]-2'(1'H)-ones 3a-c and 4a-e were synthesized from treating the 5-substituted 1H-indole-2,3-diones with 2-aminothiophenol in ethanol. The structures were confirmed by elemental analyses, spectrometry (IR, (1)H NMR, (13)C NMR, HSQC-2D and LCMS-APCI) and single crystal X-ray analysis. The new compounds were screened for their antioxidant activities such as the Fe(3+)/ascorbate system induced inhibition of lipid peroxidation (LP) in liposomes, trolox equivalent antioxidant capacity (TEAC), scavenging effect on diphenylpicryl hydrazine (DPPH*), and reducing power. These compounds showed potent scavenging activities against DPPH* and 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS*(+)) radicals, reducing powers, and strong inhibitory capacity on lipid peroxidation. Compound 4a incorporating methyl both at R(1) and R(2) was found to be the most potent antioxidant described in this study. Compounds 3b and 4b were selected as representative compounds by the National Cancer Institute for screening against anticancer activity and these compounds were found to be cytotoxic against CNS cancer cell line SNB-75 in the primary screen. PMID:20045221

  6. DFT simulation, quantum chemical electronic structure, spectroscopic and structure-activity investigations of 2-benzothiazole acetonitrile.

    PubMed

    Arjunan, V; Thillai Govindaraja, S; Jose, Sujin P; Mohan, S

    2014-07-15

    The Fourier transform infrared and FT-Raman spectra of 2-benzothiazole acetonitrile (BTAN) have been recorded in the range 4000-450 and 4000-100 cm(-1) respectively. The conformational analysis of the compound has been carried out to obtain the stable geometry of the compound. The complete vibrational assignment and analysis of the fundamental modes of the compound are carried out using the experimental FTIR and FT-Raman data and quantum chemical studies. The experimental vibrational frequencies are compared with the wavenumbers derived theoretically by B3LYP gradient calculations employing the standard 6-31G(**), high level 6-311++G(**) and cc-pVTZ basis sets. The structural parameters, thermodynamic properties and vibrational frequencies of the normal modes obtained from the B3LYP methods are in good agreement with the experimental data. The (1)H (400 MHz; CDCl3) and (13)C (100 MHz;CDCl3) nuclear magnetic resonance (NMR) spectra are also recorded. The electronic properties, the energies of the highest occupied and lowest unoccupied molecular orbitals are measured by DFT approach. The kinetic stability of the molecule has been determined from the frontier molecular orbital energy gap. The charges of the atoms and the structure-chemical reactivity relations of the compound are determined by its chemical potential, global hardness, global softness, electronegativity, electrophilicity and local reactivity descriptors by conceptual DFT methods. The non-linear optical properties of the compound have been discussed by measuring the polarisability and hyperpolarisability tensors. PMID:24662754

  7. FeF(3) catalyzed cascade C-C and C-N bond formation: synthesis of differentially substituted triheterocyclic benzothiazole functionalities under solvent-free condition.

    PubMed

    Atar, Amol B; Jeong, Yeon Tae

    2014-05-01

    A series of diverse polyfunctionalized triheterocyclic benzothiazoles were easily prepared in excellent yields via the Biginelli reaction of 2-aminobenzothiazole with substituted benzaldehydes and α-methylene ketones using FeF(3) as an expeditious catalyst under solvent-free conditions. The protocol provides a practical and straightforward approach toward highly functionalized triheterocyclic benzothiazole derivatives in excellent yields. The reaction was conveniently promoted by FeF(3) and the catalyst could be recovered easily after the reaction and reused without any loss of its catalytic activity. The advantageous features of this methodology are high atom economy, operational simplicity, shorter reaction time, convergence, and facile automation. PMID:24504377

  8. 2-(4-Amino-3-methylphenyl)-5-fluorobenzothiazole is a ligand and shows species-specific partial agonism of the aryl hydrocarbon receptor

    SciTech Connect

    Bazzi, Rana; Bradshaw, Tracey D.; Rowlands, J. Craig; Stevens, Malcolm F.G.; Bell, David R.

    2009-05-15

    2-(4-Amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203) and related compounds are a series of anti-cancer candidate pharmaceuticals, that have been shown to activate the AhR. We show that these compounds are high-affinity ligands for the rat AhR, but a quantitative assay for their ability to induce CYP1A1 RNA in H4IIEC3 cells, a measure of activation of the AhR, showed a poor relationship between affinity for the AhR and ability to induce CYP1A1 RNA. 5F 203, an agonist with low potency, was able to antagonise the induction of CYP1A1 RNA by TCDD, while IH 445, a potent agonist, did not antagonise the induction of CYP1A1 RNA by TCDD, and Schild analysis confirmed 5F 203 to be a potent antagonist of the induction of CYP1A1 RNA by TCDD in H4IIEC3 cells. In contrast, several benzothiazoles show potent induction of CYP1A1 RNA in human MCF-7 cells, and 5F 203 is unable to detectably antagonise the induction of CYP1A1 RNA in MCF-7 cells, showing a species difference in antagonism. Evaluation of the anti-proliferative activity of benzothiazoles showed that the ability to agonise the AhR correlated with growth inhibition both in H4IIEC3 cells for a variety of benzothiazoles, and between H4IIEC3 and MCF-7 cells for 5F 203, suggesting an important role of agonism of the AhR in the anti-proliferative activity of benzothiazoles.

  9. Characterization of immunoglobulin adsorption on dextran-grafted hydrophobic charge-induction resins: Cross-effects of ligand density and pH/salt concentration.

    PubMed

    Liu, Tao; Lin, Dong-Qiang; Zhang, Qi-Lei; Yao, Shan-Jing

    2015-05-29

    Hydrophobic charge-induction chromatography (HCIC) is a promising technology for antibody purification. New HCIC resins MMI-B-XL with dextran-grafted agarose gel as the matrix and 2-mercapto-1-methyl-imidazole (MMI) as the functional ligand were prepared with different ligand densities. The adsorption behaviors (static adsorption equilibrium and adsorption kinetics) of human immunoglobulin G (hIgG) on series of MMI-B-XL resins at varying pHs and salt concentrations were investigated. The cross-effects of solid phase property (ligand density) and liquid phase conditions (pH and salt concentration) were focused. The results showed that the new resins had typical pH-dependent and salt-tolerant characteristics for hIgG adsorption, but differences were found for the resins with different ligand densities. For MMI-B-XL resins with higher ligand density, an obvious higher saturated adsorption capacity (Qm) and effective pore diffusivity (De) could be obtained, which were less affected at pH 7.0∼8.9 but dropped drastically at pH 5.0. Salt addition had less influence on protein adsorption onto MMI-B-XL with higher ligand density. Qm and De both reached minimum values at 0.2mol/L NaCl for all MMI-B-XL resins tested. The results of dynamic binding in the column demonstrated that MMI-B-XL with higher ligand density had better performance for hIgG adsorption, especially under high linear velocities. The mechanism of the cross-effects of ligand density and pH/salt concentration on IgG adsorption was discussed, which provides new insights into protein adsorption and mass transport for dextran-grafted HCIC resins. PMID:25892639

  10. Synthesis and an angiolytic role of novel piperazine-benzothiazole analogues on neovascularization, a chief tumoral parameter in neoplastic development.

    PubMed

    Al-Ghorbani, Mohammed; Pavankumar, G S; Naveen, P; Thirusangu, Prabhu; Prabhakar, B T; Khanum, Shaukath Ara

    2016-04-01

    A novel series of benzoic acid N'-[2-(4-benzothiazol-2-yl-piperazin-1-yl)-acetyl]-hydrazides 6a-j were synthesized and characterized by IR, (1)H, (13)C NMR, elemental and mass spectral analyses. The in-vitro cytotoxicity and cell viability assay of the synthesized compounds 6a-j were evaluated against Dalton's lymphoma ascites (DLA) cells. Our results showed that compound 6c with a bromo group on phenyl ring has showed promising antiproliferative efficacy. Further investigation of compound 6c on in-vivo treatment model depicts the increased tumor suppression through inhibition of angiogenesis. PMID:26918263

  11. The influence of the various central metals on photophysical and photochemical properties of benzothiazole-substituted phthalocyanines

    NASA Astrophysics Data System (ADS)

    Nas, Asiye; Dilber, Gülsev; Durmuş, Mahmut; Kantekin, Halit

    2015-01-01

    The photophysical (fluorescence quantum yields and lifetimes, fluorescence quenching studies by 1,4-benzoquinone (BQ)) and photochemical (singlet oxygen quantum yields and photodegradation studies under light irradiation) properties of tetra-benzothiazole substituted metal-free (H2Pc, 1), lead (II) (PbPc, 2) and zinc(II) (ZnPc, 3) phthalocyanine compounds were investigated in tetrahydrofuran (THF) solution. All of these compounds did not show any aggregation and they produced good singlet oxygen (especially ZnPc). The influence of the various central metal ions (zinc, lead or without metal) on the photophysical and photochemical parameters was also investigated and compared.

  12. The influence of the various central metals on photophysical and photochemical properties of benzothiazole-substituted phthalocyanines.

    PubMed

    Nas, Asiye; Dilber, Gülsev; Durmuş, Mahmut; Kantekin, Halit

    2015-01-25

    The photophysical (fluorescence quantum yields and lifetimes, fluorescence quenching studies by 1,4-benzoquinone (BQ)) and photochemical (singlet oxygen quantum yields and photodegradation studies under light irradiation) properties of tetra-benzothiazole substituted metal-free (H2Pc, 1), lead (II) (PbPc, 2) and zinc(II) (ZnPc, 3) phthalocyanine compounds were investigated in tetrahydrofuran (THF) solution. All of these compounds did not show any aggregation and they produced good singlet oxygen (especially ZnPc). The influence of the various central metal ions (zinc, lead or without metal) on the photophysical and photochemical parameters was also investigated and compared. PMID:25062049

  13. Synergistic Inhibition Effect of Zinc Acetylacetonate and Benzothiazole in Epoxy Coating on the Corrosion of Mild Steel

    NASA Astrophysics Data System (ADS)

    Amoozadeh, S. M.; Mahdavian, M.

    2015-06-01

    The corrosion inhibition effect of zinc acetylacetonate (ZAA) and benzothiazole (BTH) mixture was evaluated for mild steel in 3.5% NaCl solution. To this end, ZAA:BTH mixtures ranged from 6:1 to 1:6 mol ratios were examined by weight loss and open circuit potential to obtain optimal mole ratio. The optimal mixture of ZAA:BTH at 1:5 mol ratio showed a significant corrosion inhibition efficiency proved by electrochemical impedance spectroscopy and polarization studies. The addition of the optimal mixture of ZAA:BTH to epoxy coating showed a considerable increase of corrosion protection evaluated by salt spray exposure.

  14. Benzothiazole Amphiphiles Promote the Formation of Dendritic Spines in Primary Hippocampal Neurons.

    PubMed

    Cifelli, Jessica L; Dozier, Lara; Chung, Tim S; Patrick, Gentry N; Yang, Jerry

    2016-06-01

    The majority of excitatory synapses in the brain exist on dendritic spines. Accordingly, the regulation of dendritic spine density in the hippocampus is thought to play a central role in learning and memory. The development of novel methods to control spine density could, therefore, have important implications for treatment of a host of neurodegenerative and developmental cognitive disorders. Herein, we report the design and evaluation of a new class of benzothiazole amphiphiles that exhibit a dose-dependent response leading to an increase in dendritic spine density in primary hippocampal neurons. Cell exposure studies reveal that the increase in spine density can persist for days in the presence of these compounds, but returns to normal spine density levels within 24 h when the compounds are removed, demonstrating the capability to reversibly control spinogenic activity. Time-lapse imaging of dissociated hippocampal neuronal cultures shows that these compounds promote a net increase in spine density through the formation of new spines. Biochemical studies support that promotion of spine formation by these compounds is accompanied by Ras activation. These spinogenic molecules were also capable of inhibiting a suspected mechanism for dendritic spine loss induced by Alzheimer-related aggregated amyloid-β peptides in primary neurons. Evaluation of this new group of spinogenic agents reveals that they also exhibit relatively low toxicity at concentrations displaying activity. Collectively, these results suggest that small molecules that promote spine formation could be potentially useful for ameliorating cognitive deficiencies associated with spine loss in neurodegenerative diseases such as Alzheimer disease, and may also find use as general cognitive enhancers. PMID:27022020

  15. Identification of selected microorganisms from activated sludge capable of benzothiazole and benzotriazole transformation.

    PubMed

    Kowalska, Katarzyna; Felis, Ewa

    2015-01-01

    Benzothiazole (BT) and benzotriazole (BTA) are present in the environment - especially in urban and industrial areas, usually as anthropogenic micropollutants. BT and BTA have been found in the municipal and industrial wastewater, rivers, soil, groundwater, sediments and sludge. The origins of those substances' presence in the environment are various industry branches (food, chemical, metallurgical, electrical), households and surface runoff from industrial areas. Increasingly strict regulations on water quality and the fact that the discussed compounds are poorly biodegradable, make them a serious problem in the environment. Considering this, it is important to look for environmentally friendly and socially acceptable ways to remove BT and BTA. The aim of this study was to identify microorganisms capable of BT and BTA transformation or/and degradation in aquatic environment. Selected microorganisms were isolated from activated sludge. The identification of microorganisms capable of BT and BTA removal was possible using molecular biology techniques (PCR, DNA sequencing). Among isolated microorganisms of activated sludge are bacteria potentially capable of BT and BTA biotransformation and/or removal. The most common bacteria capable of BT and BTA transformation were Rhodococcus sp., Enterobacter sp., Arthrobacter sp. They can grow in a medium with BT and BTA as the only carbon source. Microorganisms previously adapted to the presence of the studied substances at a concentration of 10 mg/l, showed a greater rate of growth of colonies on media than microorganisms unconditioned to the presence of such compounds. Results of the biodegradation test suggest that BT was degraded to a greater extent than BTA, 98-100% and 11-19%, respectively. PMID:26641641

  16. Benzotriazole, benzothiazole, and benzophenone compounds in indoor dust from the United States and East Asian countries.

    PubMed

    Wang, Lei; Asimakopoulos, Alexandros G; Moon, Hyo-Bang; Nakata, Haruhiko; Kannan, Kurunthachalam

    2013-05-01

    Organic corrosion inhibitors (OCIs), including ultraviolet light filters, are widely used in plastics, rubbers, colorants, and coatings to increase the performance of products. Derivatives of benzotriazole (BTR), benzothiazole (BTH), and benzophenone (BP) are high-production volume OCIs that have been detected in the environment and human tissues. However, knowledge of their occurrence in indoor environments, as well as human exposure to them, is still lacking. In this study, BTR, BTH, BP and their 12 derivatives were determined in indoor dust for the first time. All three groups of OCIs were found in all 158 indoor dust samples from the U.S. and three East Asian countries (China, Japan, and Korea). The geometric mean (GM) concentration of the sum of six BTRs (GM CΣBTRs) ranged from 20 to 90 ng/g among the four countries studied, with a maximum CΣBTRs of ∼2000 ng/g found in a dust sample from China. Tolyltriazole was the major derivative of BTR measured in dust. GM CΣBTHs in indoor dust from the four countries ranged from 600 to 2000 ng/g. 2-OH-BTH was the predominant BTH in dust from the U.S., Japan, and Korea. GM CΣBPs in dust ranged from 80 to 600 ng/g, with 2-OH-4-MeO-BP and 2,4-2OH-BP, contributing to the majority of ∑BP concentrations. Based on the concentrations of three types of OCIs in indoor dust, human exposure through dust ingestion was calculated. Daily intake of OCIs through dust ingestion was higher for people in the U.S., Japan, and Korea than in China; the residents in urban China are exposed to higher levels of OCIs via dust ingestion than are those in rural China. PMID:23544437

  17. Quantitative investigations of cation complexation of photochromic 8-benzothiazole-substituted benzopyran: towards metal-ion sensors.

    PubMed

    Zakharova, Marianna I; Coudret, Christophe; Pimienta, Véronique; Micheau, Jean Claude; Delbaere, Stéphanie; Vermeersch, Gaston; Metelitsa, Anatoly V; Voloshin, Nikolai; Minkin, Vladimir I

    2010-02-01

    The photochromic, thermochromic and metallochromic behaviour of a series of three spiro[indoline-8-(benzothiazol-2-yl)-benzopyrans] has been investigated. The thermodynamic and kinetic parameters of their thermal equilibrium between the ring-closed (spiro) and ring-opened (merocyanine) isomeric forms have been determined using UV-Vis absorption and (1)H NMR spectroscopies. By adding Co(ii) and Ni(ii) ions in acetonitrile solution, 1 : 1 and 1 : 2 metal : merocyanine complexes are formed simultaneously. Using appropriate numerical methods, the kinetic analysis of the complexation allowed us to determine accurately key thermodynamic and spectroscopic parameters of the metal complexes. Results showed that the complexation strength is very sensitive to the size of the indoline nitrogen substituent. Complexation can be reversed by shining white light on the coloured complexes which regenerates the inactive spiropyran form, and releases the metallic ion; hence, these systems display fully reversible negative photochromism. The Zn(ii) complexes exhibit intense fluorescence in the 600-800 nm wavelength range. All these behaviours make these spiropyrans bearing benzothiazole heterocycles promising building blocks for the future construction of photodynamic chemosensors for transition metal ions. PMID:20126795

  18. Identification of Benzothiazole Derivatives and Polycyclic Aromatic Hydrocarbons as Aryl Hydrocarbon Receptor Agonists Present in Tire Extracts

    PubMed Central

    He, Guochun; Zhao, Bin; Denison, Michael S.

    2012-01-01

    Leachate from rubber tire material contains a complex mixture of chemicals previously shown to produce toxic and biological effects in aquatic organisms. While the ability of these leachates to induce Ah receptor (AhR)-dependent cytochrome P4501A1 expression in fish indicated the presence of AhR active chemicals, the responsible chemical(s) and their direct interaction with the AhR signaling pathway were not examined. Using a combination of AhR-based bioassays, we have demonstrated the ability of tire extract to stimulate both AhR DNA binding and AhR-dependent gene expression and confirmed that the responsible chemical(s) was metabolically labile. The application of CALUX (Chemical-Activated LUciferase gene eXpression) cell bioassay-driven toxicant identification evaluation not only revealed that tire extract contained a variety of known AhR-active polycyclic aromatic hydrocarbons, but also identified 2-methylthiobenzothiazole and 2-mercaptobenzothiazole as AhR agonists. Analysis of a structurally diverse series of benzothiazoles identified many that could directly stimulate AhR DNA binding and transiently activate the AhR signaling pathway and identified benzothiazoles as a new class of AhR agonists. In addition to these compounds, the relatively high AhR agonist activity of a large number of fractions strongly suggests that tire extract contains a large number of physiochemically diverse AhR agonists whose identities and toxicological/biological significances are unknown. PMID:21590714

  19. Identification of benzothiazole derivatives and polycyclic aromatic hydrocarbons as aryl hydrocarbon receptor agonists present in tire extracts.

    PubMed

    He, Guochun; Zhao, Bin; Denison, Michael S

    2011-08-01

    Leachate from rubber tire material contains a complex mixture of chemicals previously shown to produce toxic and biological effects in aquatic organisms. The ability of these leachates to induce Ah receptor (AhR)-dependent cytochrome P4501A1 expression in fish indicated the presence of AhR active chemicals, but the responsible chemicals and their direct interaction with the AhR signaling pathway were not examined. Using a combination of AhR-based bioassays, we have demonstrated the ability of tire extract to stimulate both AhR DNA binding and AhR-dependent gene expression and confirmed that the responsible chemicals were metabolically labile. The application of CALUX (chemical-activated luciferase gene expression) cell bioassay-driven toxicant identification evaluation not only revealed that tire extract contained a variety of known AhR-active polycyclic aromatic hydrocarbons but also identified 2-methylthiobenzothiazole and 2-mercaptobenzothiazole as AhR agonists. Analysis of a structurally diverse series of benzothiazoles identified many that could directly stimulate AhR DNA binding and transiently activate the AhR signaling pathway and identified benzothiazoles as a new class of AhR agonists. In addition to these compounds, the relatively high AhR agonist activity of a large number of fractions strongly suggests that tire extract contains a large number of physiochemically diverse AhR agonists whose identities and toxicological/biological significances are unknown. PMID:21590714

  20. Determination of urinary 2-mercaptobenzothiazole (2-MBT), the main metabolite of 2-(thiocyanomethylthio)benzothiazole (TCMTB) in humans and rats.

    PubMed

    Manninen, A; Auriola, S; Vartiainen, M; Liesivuori, J; Turunen, T; Pasanen, M

    1996-01-01

    A method for biological monitoring of urinary 2-(thiocyanomethylthio)benzothiazole (TCMTB), a wood preservative and an industrial chemical, was developed. Three different doses of TCMTB in olive oil were given to male rats by gavage for 3 weeks. Urine was collected daily and the metabolites were analysed as thioethers by derivatization with pentafluorobenzyl-bromide by gas chromatography-mass spectrometry. The parent chemical was not detected in urine samples, but two metabolites of TCMTB were identified. 2-Mercaptobenzothiazole (2-MBT) was the main metabolite, and its excretion varied according to the dose. The second metabolite was 2-(mercaptomethylthio)benzothiazole. The amount of 2-MBT excreted in rat urine was 66 +/- 12% (SD), 51 +/- 20% and 44 +/- 9% for TCMTB doses of 15, 75 and 150 mg/kg, respectively. Two doses, 75 and 150 mg/kg, caused diuresis in rats during the 1 week of dosing. During the 3-week TCMTB treatment, rat liver microsomal CYP enzyme profile was not significantly changed. Urine samples of sawmill workers exposed to TCMTB were collected after their work shifts for exposure assessment. TCMTB could not be detected in the urine samples of exposed workers. Most concentrations of 2-MBT were below the limit of the detection, 0.12 mumol/l, the concentrations were 0.12-0.15 mumol/l only in few cases. The determination of 2-MBT in urine, when a sample is taken immediately after a work shift, is a suitable indicator of workers' exposure to TCMTB. PMID:8831908

  1. Biodegradation of benzotriazoles and hydroxy-benzothiazole in wastewater by activated sludge and moving bed biofilm reactor systems.

    PubMed

    Mazioti, Aikaterini A; Stasinakis, Athanasios S; Pantazi, Ypapanti; Andersen, Henrik R

    2015-09-01

    Two laboratory scale fully aerated continuous flow wastewater treatment systems were used to compare the removal of five benzotriazoles and one benzothiazole by suspended and attached growth biomass. The activated sludge system was operated under low organic loading conditions. The moving bed biofilm reactor (MBBR) system consisted of two serially connected reactors filled with K3-biocarriers. It was either operated under low or high organic loading conditions. Target compounds were removed partially and with different rates in tested systems. For MBBR, increased loading resulted in significantly lower biodegradation for 4 out of 6 examined compounds. Calculation of specific removal rates (normalized to biomass) revealed that attached biomass had higher biodegradation potential for target compounds comparing to suspended biomass. Clear differences in the biodegradation ability of attached biomass grown in different bioreactors of MBBR systems were also observed. Batch experiments showed that micropollutants biodegradation by both types of biomass is co-metabolic. PMID:26093257

  2. Design and Synthesis of Novel Schiff Base-Benzothiazole Hybrids as Potential Epidermal Growth Factor Receptor (EGFR) Inhibitors.

    PubMed

    Singh, Meenakshi; Singh, Sudhir Kumar; Thakur, Bhushan; Ray, Pritha; Singh, Sushil K

    2016-01-01

    A series of novel Schiff bases -benzothiazole hybrids was designed, synthesized and evaluated for their anticancer activity by MTT assay and western blot method. Antiproliferative screening indicated that compound containing dihydroxy substituents had potent inhibitory activity with IC50 value 34µg/ml against SKOV3, A2780-S and A2780-CR cell lines. It showed more potent cytotoxicity in combination with cisplatin and paclitaxel than alone in the selected cell lines (SKOV3, A2780 and A2780-CR models). The in vitro cytotoxicity of the compounds on IOSE 364 cell line was evaluated to establish the selectivity. Molecular docking study exhibited good binding against epidermal growth factor receptor, which was further ascertained by immunoblot assay using specific antibody against phosphorylated EGFR, and thus unravelling the targeted anticancer mechanism. PMID:26443027

  3. Fast low-pressurized microwave-assisted extraction of benzotriazole, benzothiazole and benezenesulfonamide compounds from soil samples.

    PubMed

    Speltini, Andrea; Sturini, Michela; Maraschi, Federica; Porta, Alessio; Profumo, Antonella

    2016-01-15

    Benzotriazoles (BTRs), benzothiazoles (BTs) and benzenesulfonamides (BSAs), compounds largely used in industrial and household applications, are ubiquitous emerging contaminants. In this work a novel, straightforward procedure for the simultaneous determination of two BTRs (1H-benzotriazole, 5-methyl-1H-benzotriazole), three BTs (benzothiazole, 2-hydroxybenzothiazole, 2-methylthiobenzothiazole) and two BSAs (benzenesulfonamide, toluenesulfonamide) in soil has been developed. The target analytes were extracted from soil by a single low-pressurized microwave-assisted extraction (MAE) cycle (120°C, 10min) and quantified by high-performance liquid chromatography with UV detection. For all the seven analytes, quantitative extraction yields (72-119%, n=4) were observed from recovery tests on soil samples (1g) spiked with 5, 10 and 50mg kg(-1), using 4mL water-methanol (85:15) as extracting solution. For the lower concentrations levels (100, 250 and 500μg kg(-1)), the analytes were extracted from soil samples (2-3g) using 6mL methanol, and the extract was pre-concentrated by evaporation before analysis; recoveries in the range 70-117% were obtained (n=4). Suitable intra-day and inter-day precision were observed, with values of relative standard deviation generally below 6% and 11% (n=4), respectively. Linearity was evaluated in the concentration range 0.5-10mg L(-1) by matrix-matched standards, obtaining r(2)>0.9996. The experimental method quantification limit (MQL) was 100μg kg(-1). The entire procedure has been successfully applied to the analysis of real impacted soil samples. PMID:26592614

  4. A p-Hydroxyphenacyl-Benzothiazole-Chlorambucil Conjugate as a Real-Time-Monitoring Drug-Delivery System Assisted by Excited-State Intramolecular Proton Transfer.

    PubMed

    Barman, Shrabani; Mukhopadhyay, Sourav K; Biswas, Sandipan; Nandi, Surajit; Gangopadhyay, Moumita; Dey, Satyahari; Anoop, Anakuthil; Pradeep Singh, N D

    2016-03-18

    Among the well-known phototriggers, the p-hydroxyphenacyl (pHP) group has consistently enabled the very fast, efficient, and high-conversion release of active molecules. Despite this unique behavior, the pHP group has been ignored as a delivery agent, particularly in the area of theranostics, because of two major limitations: Its excitation wavelength is below 400 nm, and it is nonfluorescent. We have overcome these limitations by incorporating a 2-(2'-hydroxyphenyl)benzothiazole (HBT) appendage capable of rapid excited-state intramolecular proton transfer (ESIPT). The ESIPT effect also provided two unique advantages: It assisted the deprotonation of the pHP group for faster release, and it was accompanied by a distinct fluorescence color change upon photorelease. In vitro studies showed that the p-hydroxyphenacyl-benzothiazole-chlorambucil conjugate presents excellent properties, such as real-time monitoring, photoregulated drug delivery, and biocompatibility. PMID:26919455

  5. Anchoring of Cu(II) onto surface of porous metal-organic framework through post-synthesis modification for the synthesis of benzimidazoles and benzothiazoles

    NASA Astrophysics Data System (ADS)

    Kardanpour, Reihaneh; Tangestaninejad, Shahram; Mirkhani, Valiollah; Moghadam, Majid; Mohammadpoor-Baltork, Iraj; Zadehahmadi, Farnaz

    2016-03-01

    Efficient synthesis of various benzimidazoles and benzothiazoles under mild conditions catalyzed by Cu(II) anchored onto UiO-66-NH2 metal organic framework is reported. In this manner, first, the aminated UiO-66 was modified with thiophene-2-carbaldehyde and then the prepared Schiff base was reacted with CuCl2. The prepared catalyst was characterized by FT-IR, UV-vis, X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), N2 adsorption, inductively coupled plasma atomic emission spectroscopy (ICP-AES) and field emission scanning electron microscopy (FE-SEM). The UiO-66-NH2-TC-Cu was applied as a highly efficient catalyst for synthesis of benzimidazole and benzothiazole derivatives by the reaction of aldehydes with 1,2-diaminobenzene or 2-aminothiophenol. The Cu(II)-containing MOF was reused several times without any appreciable loss of its efficiency.

  6. Evaluating the toxic potential of benzothiazoles with the rainbow trout cell lines, RTgill-W1 and RTL-W1.

    PubMed

    Zeng, Fanxing; Sherry, James P; Bols, Niels C

    2016-07-01

    Benzothiazole (BTHs) are environmental contaminants of emerging concern for which little toxicological information is available. Therefore the toxic potential of twelve BTHs was evaluated with two rainbow trout epithelial cell lines, RTgill-W1 and RTL-W1. The BTHs were benzothiazole (BTH), 3,3'-diethylthia dicarbocyanine iodide (DTDC), C.I. sulphur orange 1 (SO), 2-mercaptobenzothiazole (2MBTH), zinc 2-mercaptobenzothiazole (ZnMBTH), sodium 2-mercaptobenzothiazole (NaMBTH), 2-hydroxy-benzothiazole (OHBTH), 2- aminobenzothiazole (2ABTH), C.I. vat yellow 2 (VY), N,N-dicyclohexyl-2-benzothiazolsulfene amide (NNA), 2,2'-dithiobis (benzothiazole) (DBTH) and 2-(p-aminophenyl)-6-methylbenzothiazole-7-sulfonic acid (MBTHS). All BTHs, except for NNA, DBTH, and MBTHS, caused both cytotoxicity and a transitory elevation in reactive oxygen species (ROS) levels. Yet, neither N-acetyl cysteine (NAC) nor IM-54 inhibited cytotoxicity, suggesting that ROS imbalance did not contribute to cell death. Cell death was not blocked by Necrostatin-1 nor accompanied by DNA laddering, suggesting that neither necroptosis nor apoptosis took place. The comet assay revealed DNA strand breaks after exposures to 2ABTH and OHBTH for 1 day and to BTH for 12 days. In RTL-W1, cytochrome P4501A was induced noticeably by 2ABTH, OHBTH, and MBTHS and weakly by NaMBTH, ZnMBTH, SO, VY, and NNA, suggesting that these BTHs have the potential to alter xenobiotic metabolism and activate the aryl hydrocarbon receptor. In summary, several toxic actions were initiated in vitro by some but not all BTHs, warranting further study of these BTHs in vivo. PMID:27131451

  7. Application of the SOS/umu test and high-content in vitro micronucleus test to determine genotoxicity and cytotoxicity of nine benzothiazoles.

    PubMed

    Ye, Yan; Weiwei, Jiang; Na, Li; Mei, Ma; Kaifeng, Rao; Zijian, Wang

    2014-12-01

    Benzothiazole and benzothiazole derivatives (BTs) have been detected in various environmental matrices as well as in human beings, but little is currently available regarding their toxicities. In our study, genotoxicities of nine BTs (benzothiazole [BT], 2-chlorobenzothiazole [CBT], 2-bromobenzothiazole [BrBT], 2-fluorobenzothiazole [FBT], 2-methylbenzothiazole [MeBT], 2-mercaptobenzothiazole [MBT], 2-aminobenzothiazole [ABT], 2-hydroxy-benzothiazole [OHBT] and 2-methythiobenzothiazole [MTBT]) are comprehensively evaluated by the SOS/umu test using the bacterial Salmonella typhimurium TA1535/pSK1002 for DNA-damaging effect and the high content in vitro micronucleus test using two human carcinoma cells (MGC-803 and A549) for chromosome-damaging effect. The cytotoxicity of BTs on both bacteria and two human cells was also evaluated. Except for the cytotoxic effect of MBT on MGC-803 and A549, the other tested BTs showed more than 50% cytotoxicity at their highest concentrations in a dose-dependent manner, and their LC50s ranged from 19 (MBT in bacteria) to 270 mg l(-1) (CBT in A549). Activation and inactivation were observed for specific BTs after metabolism. On the other hand, no evidence of genotoxicity was obtained for BT, FBT and MBT, and DNA damage was induced by ABT, OHBT, BrBT and MTBT in MGC-803, by MeBT in A549 and by CBT in both cells. Through quantitative structure-activity relationship analysis, two structure alerts for chemical genotoxicity, including heterocyclic amine and hacceptor-path3-hacceptor are present in ABT and OHBT respectively; however, the underlying mechanisms still need further evaluation. PMID:24478133

  8. Synthesis and anti-oomycete activity of novel quinazolin- and benzothiazol-6-yloxyacetamides: Potent aza-analogs and five-ring analogs of quinoline fungicides.

    PubMed

    Beaudegnies, Renaud; Quaranta, Laura; Murphy Kessabi, Fiona; Lamberth, Clemens; Knauf-Beiter, Gertrud; Fraser, Torquil

    2016-02-01

    Novel quinazolin- and benzothiazol-6-yloxyacetamides show excellent in vivo activity against the three economically most important Oomycete pathogens Phytophthora infestans, Plasmopara viticola and Pythium ultimum. They are polar analogs of known quinolin-6-yloxyacetamides, which are not active against the soil-borne damping-off disease caused by Pythium ultimum. The Bogert quinazoline synthesis, an almost forgotten heterocyclization technique, proved to be highly useful for the concise construction of required quinazolin-6-ol building blocks. PMID:26346670

  9. Synthesis, characterization and biological evaluation of benzothiazoles and tetrahydrobenzothiazoles bearing urea or thiourea moieties as vasorelaxants and inhibitors of the insulin releasing process.

    PubMed

    Harrouche, Kamel; Renard, Jean-Francois; Bouider, Nafila; de Tullio, Pascal; Goffin, Eric; Lebrun, Philippe; Faury, Gilles; Pirotte, Bernard; Khelili, Smail

    2016-06-10

    A series of 1,3-benzothiazoles (series I) and 4,5,6,7-tetrahydro-1,3-benzothiazoles (series II) bearing an urea or a thiourea moiety at the 2-position were synthesized and tested as myorelaxants and inhibitors of insulin secretion. Several compounds (i.e. 13u and 13v) from series I showed a marked myorelaxant activity. Benzothiazoles bearing a strong electron withdrawing group (NO2, CN) at the 6-position and an alkyl group linked to the urea or the thiourea function at the 2-position were found to be the most potent compounds. The weak vasorelaxant activity of series II compounds evidenced the necessity of the presence of a complete aromatic heterocyclic system. The myorelaxant activity of some active compounds was reduced when measured on aorta rings precontracted by 80 mM KCl or by 30 mM KCl in the presence of 10 μM glibenclamide, suggesting the involvement of KATP channels in the vasorelaxant effect. Some compounds of series I tested on rat pancreatic islets provoked a marked inhibition of insulin secretion, among which 13a exhibited a clear tissue selectivity for pancreatic β-cells. PMID:27031211

  10. Crystal structure of the salt bis-(tri-ethano-lamine-κ(4) N,O,O',O'')cadmium bis[2-(2-oxo-2,3-di-hydro-1,3-benzo-thia-zol-3-yl)acetate].

    PubMed

    Ashurov, Jamshid Mengnorovich

    2016-04-01

    The reaction of 2-(2-oxo-2,3-di-hydro-1,3-benzo-thia-zol-3-yl)acetic acid (NBTA) and tri-ethano-lamine (TEA) with Cd(CH3OO)2 resulted in the formation of the title salt, [Cd(C6H15NO3)2](C9H6NO3S)2. In its crystal structure, the complex cation [Cd(TEA)2](2+) and two independent NBTA(-) units with essentially similar geometries and conformations are present. In the complex cation, each TEA mol-ecule behaves as an N,O,O',O''-tetra-dentate ligand, giving rise to an eight-coordinate Cd(II) ion with a bicapped trigonal-prismatic configuration. All ethanol groups of each TEA mol-ecule form three five-membered chelate rings around the Cd(II) ion. The Cd-O and Cd-N distances are in the ranges 2.392 (2)-2.478 (2) and 2.465 (2)-2.475 (3) Å, respectively. O-H⋯O hydrogen bonds between the TEA hy-droxy groups and carboxyl-ate O atoms connect cationic and anionic moieties into chains parallel to [110]. Each NBTA(-) anion is additionally linked to a symmetry-related anion through π-π stacking inter-actions between the benzene and thia-zoline rings [minimum centroid-to-centroid separation = 3.604 (2) Å]. Together with additional C-H⋯O inter-actions, these establish a double-layer polymeric network parallel to (001). PMID:27375881

  11. In vitro DNA binding, pBR322 plasmid cleavage and molecular modeling study of chiral benzothiazole Schiff-base-valine Cu(II) and Zn(II) complexes to evaluate their enantiomeric biological disposition for molecular target DNA

    NASA Astrophysics Data System (ADS)

    Alizadeh, Rahman; Afzal, Mohd; Arjmand, Farukh

    2014-10-01

    Bicyclic heterocyclic compounds viz. benzothiazoles are key components of deoxyribonucleic acid (DNA) molecules and participate directly in the encoding of genetic information. Benzothiazoles, therefore, represent a potent and selective class of antitumor compounds. The design and synthesis of chiral antitumor chemotherapeutic agents of Cu(II) and Zn(II), L- and -D benzothiazole Schiff base-valine complexes 1a &b and 2a &b, respectively were carried out and thoroughly characterized by spectroscopic and analytical techniques. Interaction of 1a and b and 2a and b with CT DNA by employing UV-vis, florescence, circular dichroic methods and cleavage studies of 1a with pBR322 plasmid, molecular docking were done in order to demonstrate their enantiomeric disposition toward the molecular drug target DNA. Interestingly, these studies unambiguously demonstrated the greater potency of L-enantiomer in comparison to D-enantiomer.

  12. Study of the retention of benzotriazoles, benzothiazoles and benzenesulfonamides in mixed-mode solid-phase extraction in environmental samples.

    PubMed

    Salas, Daniela; Borrull, Francesc; Marcé, Rosa Maria; Fontanals, Núria

    2016-04-29

    In the present study, the capabilities of strong cation-exchange and strong anion-exchange sorbents for solid-phase extraction (SPE) have been evaluated for the selective retention of benzotriazoles (BTRs), benzothiazoles (BTs) and benzenesulfonamides (BSAs), which are a group of neutral analytes with interesting properties such as high polarity and the capability of delocalizing electron density. The retention of these analytes has been compared in both sorbents for the first time, using a SPE procedure specially designed to promote ionic retention of the analytes with the objective of including a washing step with an organic solvent to eliminate interferences retained by hydrophobic interactions. As a result, ionic interactions between the analytes and both sorbents were observed, which allowed the successful introduction of a washing step using methanol in the SPE procedure even when most of the analytes were in their neutral state under SPE conditions. Consequently, a method was developed and further validated for each sorbent using liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS). Apart from the development of an improved method, special attention was paid to the discussion of the interactions present between the sorbents and each group of analytes to explain how these analytes in their neutral state might develop ionic interactions with the sorbents. At the end, the use of these sorbents helped to simplify previous developed methods where hydrophobic/hydrophilic sorbents were used, obtaining enhanced results when evaluated in river water and effluent and influent wastewaters. PMID:27040512

  13. Synthesis and biological evaluation of benzothiazole derivatives bearing the ortho-hydroxy-N-acylhydrazone moiety as potent antitumor agents.

    PubMed

    Ma, Junjie; Zhang, Guangyan; Han, Xiaoqi; Bao, Guanglong; Wang, Lihui; Zhai, Xin; Gong, Ping

    2014-12-01

    A novel series of benzothiazole derivatives bearing the ortho-hydroxy-N-acylhydrazone moiety were designed, synthesized, and evaluated for their procaspase-3 kinase activation activities and antiproliferative activities against five cancer cell lines (NCI-H226, SK-N-SH, HT29, MKN-45, and MDA-MB-231). Most target compounds showed moderate to excellent cytotoxic activity against all five tested cancer lines. The most promising compound 18e (procaspase-3 EC50  = 0.31 µM) with IC50 values ranging from 0.24 to 0.92µM against all tested cell lines was 4.24-12.2 times more active than PAC-1 (procaspase-3 EC50  = 0.41 µM). Structure-activity relationship studies indicated that the phenyl group on the 2-hydroxyphenyl ring (moiety A) was critical for pharmacological activity in vitro. In addition, introduction of a benzyloxyl group on moiety A and a mono-electron-withdrawing group at the 4-position of the benzyloxyl group were more favorable for antitumor activity. Moreover, reduction of the electron density in the phenyl ring of the benzyloxy group led to a dramatic decrease in the procaspase-3 kinase activation activity. PMID:25230149

  14. Indirect extraction-spectrophotometric determination of 2-(thiocyanomethylthiol)benzothiazole in chrome tanning liquors after its breakdown to 2-mercaptobenzothiazole.

    PubMed

    Hinojosa Reyes, Laura; Wróbel, Katarzyna; Wróbel, Kazimierz

    2002-03-01

    The simple extraction-spectrophotometric procedure is proposed in this work for the determination of 2-(thiocyanomethylthiol)benzothiazole (TCMTB) in chrome tanning liquors after its breakdown to 2-mercaptobenzothiazole (MBT). The sample (50mul) was 4-fold diluted with deionized water and the conversion of TCMTB to MBT was obtained with cysteine (400 mul, 0.1 moll(-1)) in alkaline conditions (pH 10). After acidification to pH 2.5 (100 mul phosphoric acid, 2 moll(-1)), the extraction was carried out with 800 mul of ethyl acetate, containing 0.2% of beta-mercaptoethanol and absorbance was measured at 324 nm with the cut-off filter 295 nm. To avoid possible errors due to MBT presence in the sample, this same sample was taken for blank, but the reagents were added in form of one acid solution (omitting the conversion step). The calibration range was 10-120 mugml(-1) of TCMTB with the regression coefficient 0.9999, the quantitation limit was 2.80 mugml(-1) and the within day precision was 3.34 and 0.20%, respectively, for 10 and for 100 mugml(-1) of TCMTB. The results obtained in the analysis of the three industrial liquor samples by the proposed procedure were in a good agreement with the results obtained using liquid chromatography method. PMID:18968524

  15. Addition Reactions of Me3 SiCN with Aldehydes Catalyzed by Aluminum Complexes Containing in their Coordination Sphere O, S, and N Ligands.

    PubMed

    Yang, Zhi; Yi, Yafei; Zhong, Mingdong; De, Sriman; Mondal, Totan; Koley, Debasis; Ma, Xiaoli; Zhang, Dongxiang; Roesky, Herbert W

    2016-05-10

    The reaction of one equivalent of LAlH2 (1; L=HC(CMeNAr)2 , Ar=2,6-iPr2 C6 H3 , β-diketiminate ligand) with two equivalents of 2-mercapto-4,6-dimethylpyrimidine hydrate resulted in LAl[(μ-S)(m-C4 N2 H)(CH2 )2 ]2 (2) in good yield. Similarly, when N-2-pyridylsalicylideneamine, N-(2,6-diisopropylphenyl)salicylaldimine, and ethyl 3-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylate were used as starting materials, the corresponding products LAl[(μ-O)(o-C6 H4 )CN(C5 NH4 )]2 (3), LAlH[(μ-O)(o-C4 H4 )CN(2,6-iPr2 C6 H3 )] (4), and LAl[(μ-NH)(o-C8 SH8 )(COOC2 H5 )]2 (5) were isolated. Compounds 2-5 were characterized by (1) H and (13) C NMR spectroscopy as well as by single-crystal X-ray structural analysis. Surprisingly, compounds 2-5 exhibit good catalytic activity in addition reactions of aldehydes with trimethylsilyl cyanide (TMSCN). PMID:27062461

  16. Metal-ligand cooperation.

    PubMed

    Khusnutdinova, Julia R; Milstein, David

    2015-10-12

    Metal-ligand cooperation (MLC) has become an important concept in catalysis by transition metal complexes both in synthetic and biological systems. MLC implies that both the metal and the ligand are directly involved in bond activation processes, by contrast to "classical" transition metal catalysis where the ligand (e.g. phosphine) acts as a spectator, while all key transformations occur at the metal center. In this Review, we will discuss examples of MLC in which 1) both the metal and the ligand are chemically modified during bond activation and 2) bond activation results in immediate changes in the 1st coordination sphere involving the cooperating ligand, even if the reactive center at the ligand is not directly bound to the metal (e.g. via tautomerization). The role of MLC in enabling effective catalysis as well as in catalyst deactivation reactions will be discussed. PMID:26436516

  17. Detection and Quantification of Benzothiazoles in Exhaled Breath and Exhaled Breath Condensate by Real-Time Secondary Electrospray Ionization-High-Resolution Mass Spectrometry and Ultra-High Performance Liquid Chromatography.

    PubMed

    García-Gómez, Diego; Bregy, Lukas; Nussbaumer-Ochsner, Yvonne; Gaisl, Thomas; Kohler, Malcolm; Zenobi, Renato

    2015-10-20

    2-Subtituted benzothiazoles are widely used industrial chemicals whose occurrence in environmental samples has been shown to be ubiquitous. However, knowledge about human exposure to these compounds and their excretion route is still scarce. Here, we demonstrate for the first time the detection of benzothiazole derivatives in exhaled breath. Real-time analysis of breath was carried out by means of secondary electrospray ionization coupled to high-resolution mass spectrometry. This coupling allowed not only the detection of these compounds in breath with a sensitivity in the pptv range but also their robust identification by comparing tandem high-resolution mass spectra from breath and standards. For further confirmation, benzothiazoles were also determined in exhaled breath condensate samples by means of ultra high-performance liquid chromatography. This approach strengthened the identification as a result of excellent matches in retention times and also allowed quantification. An estimated total daily exhalation of ca. 20 μg day(-1) was calculated for the six benzothiazole derivatives found in breath. PMID:26390299

  18. Determination of polar 1H-benzotriazoles and benzothiazoles in water by solid-phase extraction and liquid chromatography LTQ FT Orbitrap mass spectrometry

    NASA Astrophysics Data System (ADS)

    van Leerdam, Jan A.; Hogenboom, Ariadne C.; van der Kooi, Margaretha M. E.; de Voogt, Pim

    2009-05-01

    A sensitive, reliable and robust method for the trace determination of six polar 1H-benzotriazoles and four benzothiazoles in drinking and surface water was developed. These compounds were extracted from water by solid-phase extraction and analyzed by Liquid Chromatography-Electrospray Mass Spectrometry using a linear ion trap-Orbitrap hybrid instrument at high resolution of 30,000 FWHM in the full-scan acquisition mode. At least one product ion was simultaneously detected in the linear ion trap at low mass resolution and was used for confirmation of compound identity. The compounds studied are soluble in water, resistant to biodegradation, only partially removed in wastewater treatment and they may pass the water treatment processes in the production of drinking water. The analytes and four internal standards were preconcentrated by solid-phase extraction at low pH. Positive electrospray ionization resulted in protonated molecular ions for all the 1H-benzotriazoles and benzothiazoles. The mass accuracy was between -5 ppm at m/z 120 and -0.1 ppm at m/z 182 and did not change for more than 2 ppm over a sample sequence of 8 days of analysis time. The optimized method allowed quantifying six benzotriazoles and four benzothiazoles in samples of drinking and surface water down to method detection limits of 0.01 [mu]g/L. The recoveries ranged between 45 and 125% in ultrapure, drinking and surface water at a spiking level of 0.2 [mu]g/L; the repeatability was between 2 and 13%. All analytes showed a linear response between 0.01 and 1.0 [mu]g/L. No significant matrix effect was observed in drinking and surface water, except for the compounds 2-aminobenzothiazole (signal enhancement about 50%) and 2-hydroxybenzothiazole (signal suppression about 25%). In Dutch drinking water samples, the compounds 1H-benzotriazole, 4- and 5-methyl-1H-benzotriazole, 5,6-dimethyl-1H-benzotriazole, 5-chloro-1H-benzothiazole and benzothiazole were detected. The concentration levels ranged from

  19. 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.

  20. 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.

  1. Synthesis and evaluation of antimicrobial activity of 4H-pyrimido[2,1-b]benzothiazole, pyrazole and benzylidene derivatives of curcumin.

    PubMed

    Sahu, Pramod K; Sahu, Praveen K; Gupta, S K; Thavaselvam, D; Agarwal, D D

    2012-08-01

    A novel, one-pot, simple, efficient procedure for 4H-pyrimido[2,1-b]benzothiazole (4a-h), pyrazole (6a-d) and benzylidene (7a-d) derivatives of curcumin under solvent and solvent free conditions in microwave with good yield is have been synthesized. The synthesized compounds were evaluated for their antibacterial activity against gram-positive and gram-negative bacteria viz. Staphylococcus aureus, Pseudomonas aeruginosa, Salmonella typhi, Escherichia coli, Bacillus cereus and Providencia rettgeri and antifungal activity against fungi viz Aspergillus niger, Aspergillus fumigates, Aspergillus flavus. Detailed mechanistic study shows reaction proceeds through Knoevenagel type intermediate 3a which has been suggested as key intermediate for reaction (Fig. 3). PMID:22683240

  2. Synthesis of some novel phosphorylated and thiophosphorylated benzimidazoles and benzothiazoles and their evaluation for larvicidal potential to Aedes albopictus and Culex quinquefasciatus.

    PubMed

    Bandyopadhyay, Prabal; Sathe, Manisha; Tikar, Sachin N; Yadav, Ruchi; Sharma, Pratibha; Kumar, Ashok; Kaushik, M P

    2014-07-01

    Series of benzimidazole and benzothiazole linked phosphoramidates and phosphoramidothioates (5a-j) and benzimidazole linked phenylphosphoramidates and phenylphosphoramidothioates (10a-e) were synthesized. The title compounds were preliminary screened for mosquito larvicidal properties against Aedes albopictus and Culex quinquefasciatus at different concentration from 40 to 5 mg/L. Among the screened compounds three compounds revealed potential larvicidal effects with 100% mortality in the order of 10e>5j>5e. Compound 10e was found to be the most toxic compound to Ae. albopictus and Cx. quinquefasciatus. The LC50 of 10e against Ae. albopictus was found to be 6.42 and 5.25 mg/L at 24 and 48 h, respectively, whereas it was 7.01 and 3.88 mg/L, respectively in Cx. quinquefasciatus. Temephos was used as positive control. PMID:24857290

  3. A combined theoretical and experimental investigation on the solvatochromism of ESIPT3-(1,3-benzothiazol-2-yl)-2-hydroxynaphthalene-1-carbaldehyde

    NASA Astrophysics Data System (ADS)

    Satam, Manjaree A.; Telore, Rahul D.; Tathe, Abhinav B.; Gupta, Vinod D.; Sekar, Nagaiyan

    2014-06-01

    Excited state intramolecular proton transfer inspired 3-(1,3-benzothiazol-2-yl)-2-hydroxynaphthalene-1-carbaldehyde, showing solid state fluorescence has been synthesized. Existence of excited state intramolecular proton transfer process between carbonyl group and phenolic sbnd OH group has been theoretically predicted using computational method. Density functional theory and time dependent density functional theory computations have been used to investigate structural parameters and understand the photophysical properties of the synthesized carbaldehyde. The photophysical properties of carbaldehyde were evaluated using UV-Visible and fluorescence spectroscopy and are found to be very sensitive to the microenvironment such as solvent polarity and pH. The experimental absorption-emission a results are correlated with the computed values. The increase in the dipole moment of A2-Keto* than A2-Enol* suggested the presence of keto form in the excited state and which is responsible for the single fluorescence emission with a large Stokes shift in all solvents.

  4. Spectroscopic study of 2-[2-(4-cyclaminophenyl)ethen-1-yl] benzothiazoles and their N-allylbenzothiazolium bromides. Solvent and substituent effects on their ultraviolet-visible and fluorescence spectra

    NASA Astrophysics Data System (ADS)

    Gáplovský, Anton; Donovalová, Jana; Magdolen, Peter; Toma, Štefan; Zahradník, Pavol

    2002-01-01

    UV-vis and fluorescence spectra of 2-[2-(4-cyclaminophenyl)ethen-1-yl] benzothiazoles 1 and their N-allylbenzothiazolium bromides 2 have been measured and interpreted. The substitution and solvent effects on electronic structure and spectra have been investigated. The benzothiazolium salts substituted with saturated cyclamines show strong push-pull character and can be used as potential NLO materials. Formation of aggregated structures was observed at higher concentrations of the benzothiazolium bromides.

  5. Expanding the family of bis-cyclometalated chiral-at-metal rhodium(iii) catalysts with a benzothiazole derivative.

    PubMed

    Ma, Jiajia; Shen, Xiaodong; Harms, Klaus; Meggers, Eric

    2016-05-28

    Synthetic access to previously elusive single enantiomers of an octahedral chiral-at-metal rhodium(iii) complex containing two cyclometalated 2-phenylbenzothiazoles and two acetonitrile ligands is reported. The complex is a superior chiral Lewis acid catalyst compared to its benzoxazole congener which can be rationalized with a higher steric congestion around the coordination sites. PMID:27143346

  6. LigandRNA: computational predictor of RNA–ligand interactions

    PubMed Central

    Philips, Anna; Milanowska, Kaja; Łach, Grzegorz; Bujnicki, Janusz M.

    2013-01-01

    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. PMID:24145824

  7. 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.

  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.

  9. Development of a solid-phase extraction liquid chromatography tandem mass spectrometry method for benzotriazoles and benzothiazoles in wastewater and recycled water.

    PubMed

    Loi, Clara H; Busetti, Francesco; Linge, Kathryn L; Joll, Cynthia A

    2013-07-19

    Two methods employing solid-phase extraction and liquid chromatography tandem mass spectrometry were developed for the analysis of benzotriazoles (BTs) and benzothiazoles (BThs), compounds which are commonly found in a large variety of commercial and household products. The first method was able to detect 7 BTs and 7 BThs, the largest suite of BTs and BThs analysed in a single method to-date, but could not distinguish between the isomers, 4-methylbenzotriazole (4-MeBT) and 5-methylbenzotriazole (5-MeBT). Therefore, a second method was developed to achieve the chromatographic separation of 4-MeBT and 5-MeBT. The methods were validated for ultrapure water and secondary wastewater, and method limits of detection (MLD) for BTs and BThs (for the primary method) ranged from 0.1 to 58ngL(-1) for ultrapure water, and 2 to 322ngL(-1) for secondary wastewater. For the secondary method, MLDs for 4- and 5-MeBT ranged from 8 to 12ngL(-1) for ultrapure water, and 388 to 406ngL(-1) for secondary wastewater. Analysis of secondary wastewater and reverse osmosis (RO) treated water from an advanced water recycling plant in Australia is presented, and represents the first reported data from the analysis of BTs and BThs in recycled water. Some of these compounds were found to persist through wastewater treatment and incompletely removed by RO treatment. Benzotriazole (BT), 4-MeBT, 5-MeBT and 2-(methylthio)benzothiazole were detected in secondary wastewater, however the latter compound was not quantifiable. Concentrations of BT and tolyltriazoles (TTs, i.e. sum of 4- and 5-MeBT, detected with the primary method) in secondary wastewater were 3.3 (±0.02) and 2.8 (±0.04)μgL(-1), respectively. These same compounds were also detected in the post-RO water samples at concentrations of 974 (±28)ngL(-1) for BT and 416(±34)ngL(-1) for TTs. 2-Hydroxybenzothiazole was also detected in the post-RO water samples, however it was not quantifiable. Removal efficiencies for RO treatment were

  10. Degradation rates of benzotriazoles and benzothiazoles under UV-C irradiation and the advanced oxidation process UV/H2O2.

    PubMed

    Bahnmüller, Sabrina; Loi, Clara H; Linge, Kathryn L; Gunten, Urs von; Canonica, Silvio

    2015-05-01

    Benzotriazoles (BTs) and benzothiazoles (BTHs) are extensively used chemicals found in a wide range of household and industrial products. They are chemically stable and are therefore ubiquitous in the aquatic environment. The present study focuses on the potential of ultraviolet (UV) irradiation, alone or in combination with hydrogen peroxide (H2O2), to remove BTs and BTHs from contaminated waters. Six compounds, three out of each chemical class, were investigated using a low-pressure mercury lamp (main emission at 254 nm) as the radiation source. Initially, the direct phototransformation kinetics and quantum yield in dilute aqueous solution was studied over the pH range of 4-12. All BTs and BTHs, except for benzothiazole, exhibited pH-dependent direct phototransformation rate constants and quantum yields in accordance to their acid-base speciation (7.1 < pKa < 8.9). The direct phototransformation quantum yields (9.0 × 10(-4)-3.0 × 10(-2) mol einstein(-1)), as well as the photon fluence-based rate constants (1.2-48 m(2) einstein(-1)) were quite low. This suggests that UV irradiation alone is not an efficient method to remove BTs and BTHs from impacted waters. The second-order rate constants for the reaction of selected BTs and BTHs with the hydroxyl radical were also determined, and found to fall in the range of 5.1-10.8 × 10(9) M(-1) s(-1), which is typical for aromatic contaminants. Finally, the removal of BTs and BTHs was measured in wastewater and river water during application of UV irradiation or the advanced oxidation process UV/H2O2. The latter process provided an efficient removal, mostly due to the effect of the hydroxyl radical, that was comparable to other aromatic aquatic contaminants, in terms of energy requirement or treatment costs. PMID:25725202

  11. The immunomodulation potential of the synthetic derivatives of benzothiazoles: Implications in immune system disorders through in vitro and in silico studies.

    PubMed

    Khan, Khalid Mohammed; Mesaik, Mohammad A; Abdalla, Omer M; Rahim, Fazal; Soomro, Samreen; Halim, Sobia A; Mustafa, Ghulam; Ambreen, Nida; Khalid, Ahmad Shukralla; Taha, Muhammad; Perveen, Shahnaz; Alam, Muhammad Tanveer; Hameed, Abdul; Ul-Haq, Zaheer; Ullah, Hayat; Rehman, Zia Ur; Siddiqui, Rafat Ali; Voelter, Wolfgang

    2016-02-01

    Benzothiazole and its natural or synthetic derivatives have been used as precursors for several pharmacological agents for neuroprotective, anti-bacterial, and anti-allergic activities. The objective of the present study was to evaluate effects of benzothiazole analogs (compounds 1-26) for their immunomodulatory activities. Eight compounds (2, 4, 5, 8-10, 12, and 18) showed potent inhibitory activity on PHA-activated peripheral blood mononuclear cells (PBMCs) with IC50 ranging from 3.7 to 11.9 μM compared to that of the standard drug, prednisolone <1.5 μM. Some compounds (2, 4, 8, and 18) were also found to have potent inhibitory activities on the production of IL-2 on PHA/PMA-stimulated PBMCs with IC50 values ranging between <4.0 and 12.8 μM. The binding interaction of these compounds was performed through silico molecular docking. Compounds 2, 8, 9, and 10 significantly suppressed oxidative burst ROS production in phagocytes with IC50 values between <4.0 and 15.2 μM. The lipopolysaccharide (LPS)-induced nitrites in murine macrophages cell line J774 were found to be inhibited by compounds 4, 8, 9, and 18 at a concentration of 25 μg/mL by 56%, 91%, 58%, and 78%, respectively. Furthermore, compounds 5, 8, 12, and 18 showed significant (P<0.05) suppressive activity on Th-2 cytokine, interleukin 4 (IL-4) with an IC50 range of <4.0 to 40.3 μM. Interestingly compound 4 has shown a selective inhibitory activity on IL-2 and T cell proliferation (naïve T cell proliferation stage) rather than on IL-4 cytokine, while compound 12 displayed an interference with T-cell proliferation and IL-4 generation. Moreover compound 8 and 18 exert non-selective inhibition on both IL-2 and IL-4 cytokines, indicating a better interference with stage leading to humoral immune response and hence possible application in autoimmune diseases. PMID:26637945

  12. Design and syntheses of novel N-(benzothiazol-5-yl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione and N-(benzothiazol-5-yl)isoindoline-1,3-dione as potent protoporphyrinogen oxidase inhibitors.

    PubMed

    Jiang, Li-Li; Zuo, Yang; Wang, Zhi-Fang; Tan, Yin; Wu, Qiong-You; Xi, Zhen; Yang, Guang-Fu

    2011-06-01

    Discovery of protoporphyrinogen oxidase (PPO, EC 1.3.3.4) inhibitors has been one of the hottest research areas in the field of herbicide development for many years. As a continuation of our research work on the development of new PPO-inhibiting herbicides, a series of novel N-(benzothiazol-5-yl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-diones (1a-p) and N-(benzothiazol-5-yl)isoindoline-1,3-diones (2a-h) were designed and synthesized according to the ring-closing strategy of two ortho-substituents. The bioassay results indicated that some newly synthesized compounds exhibited higher PPO inhibition activity than the control of sulfentrazone. Compound 1a, S-(5-(1,3-dioxo-4,5,6,7-tetrahydro-1H-isoindol-2(3H)-yl)-6-fluorobenzothiazol-2-yl) O-methyl carbonothioate, was identified as the most potent inhibitor with k(i) value of 0.08 μM, about 9 times higher than that of sulfentrazone (k(i) = 0.72 μM). Further green house assay showed that compound 1b, methyl 2-((5-(1,3-dioxo-4,5,6,7-tetrahydro-1H-isoindol-2(3H)-yl)-6-fluorobenzothiazol-2-yl)thio)acetate, exhibited herbicidal activity comparable to that of sulfentrazone even at a concentration of 37.5 g ai/ha. In addition, among six tested crops, wheat exhibited high tolerance to compound 1b even at a dosage of 300 g ai/ha. These results indicated that compound 1b might have the potential to be developed as a new herbicide for weed control of wheat field. PMID:21517076

  13. Identification of new aminoacid amides containing the imidazo[2,1-b]benzothiazol-2-ylphenyl moiety as inhibitors of tumorigenesis by oncogenic Met signaling.

    PubMed

    Furlan, Alessandro; Colombo, Francesco; Kover, Andrea; Issaly, Nathalie; Tintori, Cristina; Angeli, Lucilla; Leroux, Vincent; Letard, Sébastien; Amat, Mercedes; Asses, Yasmine; Maigret, Bernard; Dubreuil, Patrice; Botta, Maurizio; Dono, Rosanna; Bosch, Joan; Piccolo, Oreste; Passarella, Daniele; Maina, Flavio

    2012-01-01

    The Met receptor tyrosine kinase is a promising target in anticancer therapies for its role during tumor evolution and resistance to treatment. It is characterized by an unusual structural plasticity as its active site accepts different inhibitor binding modes. Such feature can be exploited to identify distinct agents targeting tumor dependence and/or resistance by oncogenic Met. Here we report the identification of bioactive agents, featuring a new 4-(imidazo[2,1-b]benzothiazol-2-yl)phenyl moiety, targeting cancer cells dependent on oncogenic Met. One of these compounds (7c; Triflorcas) impairs survival, anchorage-independent growth, and in vivo tumorigenesis, without showing side effects. Our medicinal chemistry strategy was based on an in-house Met-focused library of aminoacid-amide derivatives enriched through structure-based computer modeling, taking into account the Met multiple-binding-mode feature. Altogether, our findings show how a rational structure-based drug design approach coupled to cell-based drug evaluation strategies can be applied in medicinal chemistry to identify new agents targeting a given oncogenic-dependency setting. PMID:22138308

  14. Design, synthesis, biological evaluation and preliminary mechanism study of novel benzothiazole derivatives bearing indole-based moiety as potent antitumor agents.

    PubMed

    Ma, Junjie; Bao, Guanglong; Wang, Limei; Li, Wanting; Xu, Boxuan; Du, Baoquan; Lv, Jie; Zhai, Xin; Gong, Ping

    2015-01-01

    Through a structure-based molecular hybridization approach, a series of novel benzothiazole derivatives bearing indole-based moiety were designed, synthesized and screened for in vitro antitumor activity against four cancer cell lines (HT29, H460, A549 and MDA-MB-231). Most of them showed moderate to excellent activity against all the tested cell lines. Among them, compounds 20a-w with substituted benzyl-1H-indole moiety showed better selectivity against HT29 cancer cell line than other compounds. Compound 20d exhibited excellent antitumor activity with IC50 values of 0.024, 0.29, 0.84 and 0.88 μM against HT29, H460, A549 and MDA-MB-231, respectively. Further mechanism studies indicated that the marked pharmacological activity of compound 20d might be ascribed to activation of procaspase-3 (apoptosis-inducing) and cell cycle arrest, which had emerged as a lead for further structural modifications. Furthermore, 3D-QSAR model (training set: q(2) = 0.850, r(2) = 0.987, test set: r(2) = 0.811) was built to provide a comprehensive guide for further structural modification and optimization. PMID:25874341

  15. Contribution of primary and secondary treatment on the removal of benzothiazoles, benzotriazoles, endocrine disruptors, pharmaceuticals and perfluorinated compounds in a sewage treatment plant.

    PubMed

    Stasinakis, Athanasios S; Thomaidis, Nikolaos S; Arvaniti, Olga S; Asimakopoulos, Alexandros G; Samaras, Vasilios G; Ajibola, Akinranti; Mamais, Daniel; Lekkas, Themistokles D

    2013-10-01

    The occurrence and fate of 36 emerging contaminants, belonging to five different classes, (benzotriazoles, BTRs; benzothiazoles, BTHs; perfluorinated compounds, PFCs; non-steroidal anti-inflammatory drugs, NSAIDs and endocrine disruptors, EDCs) were investigated in raw, treated wastewater (both particulate and dissolved phases), and in sludge from a sewage treatment plant (STP) in Athens, Greece. The average concentrations of BTRs, BTHs, NSAIDs and EDCs in raw wastewater ranged between 11 ng L(-1) and 7.27 μg L(-1), while PFCs did not exceed 100 ng L(-1). In dewatered sludge, the average concentrations ranged between 0.8 ng g(-1) dw (perfluorohexanoic acid, PFHxA) and 3895 ng g(-1) dw (nonylphenol, NP). The distribution of emerging contaminants between particulate and dissolved phase was different among the compounds. BTRs and BTHs showed lower solid-liquid distribution coefficients (Kd) than all other compounds. For 9 over the 27 compounds detected in influents, the removal efficiency was higher than 70%, while the others either were removed to a lesser extent or detected at higher concentrations in effluents. Based on this, advanced treatment processes should be applied in the future for achieving adequate emerging contaminants removal in STPs. Regarding removal mechanisms, almost 60% of BTRs and 30 to 75% of BTHs were removed in bioreactors, while the contribution of primary and secondary clarifiers was of minor importance. Sorption to primary sludge was a significant mechanism affecting EDCs fate in STP. PMID:23891999

  16. 2-(4-Hydroxy-3-methoxyphenyl)-benzothiazole suppresses tumor progression and metastatic potential of breast cancer cells by inducing ubiquitin ligase CHIP.

    PubMed

    Hiyoshi, Hiromi; Goto, Natsuka; Tsuchiya, Mai; Iida, Keisuke; Nakajima, Yuka; Hirata, Naoya; Kanda, Yasunari; Nagasawa, Kazuo; Yanagisawa, Junn

    2014-01-01

    Breast cancer is the most common malignancy among women and has poor survival and high recurrence rates for aggressive metastatic disease. Notably, triple-negative breast cancer (TNBC) is a highly aggressive cancer and there is no preferred agent for TNBC therapy. In this study, we show that a novel agent, 2-(4-hydroxy-3-methoxyphenyl)-benzothiazole (YL-109), has ability to inhibit breast cancer cell growth and invasiveness in vitro and in vivo. In addition, YL-109 repressed the sphere-forming ability and the expression of stem cell markers in MDA-MB-231 mammosphere cultures. YL-109 increased the expression of carboxyl terminus of Hsp70-interacting protein (CHIP), which suppresses tumorigenic and metastatic potential of breast cancer cells by inhibiting the oncogenic pathway. YL-109 induced CHIP transcription because of the recruitment of the aryl hydrocarbon receptor (AhR) to upstream of CHIP gene in MDA-MB-231 cells. Consistently, the antitumor effects of YL-109 were depressed by CHIP or AhR knockdown in MDA-MB-231 cells. Taken together, our findings indicate that a novel agent YL-109 inhibits cell growth and metastatic potential by inducing CHIP expression through AhR signaling and reduces cancer stem cell properties in MDA-MB-231 cells. It suggests that YL-109 is a potential candidate for breast cancer therapy. PMID:25403352

  17. Design, synthesis, and structure-activity relationships of novel benzothiazole derivatives bearing the ortho-hydroxy N-carbamoylhydrazone moiety as potent antitumor agents.

    PubMed

    Ma, Junjie; Chen, Dong; Lu, Kuan; Wang, Lihui; Han, Xiaoqi; Zhao, Yanfang; Gong, Ping

    2014-10-30

    A series of novel benzothiazole derivatives bearing the ortho-hydroxy N-carbamoylhydrazone moiety were designed and synthesized and their cytotoxic activities against five cancer cell lines (NCI-H226, SK-N-SH, HT29, MKN45, and MDA-MB-231) were screened in vitro. Most of them showed moderate to excellent activity against all the tested cell lines. Among them, compounds 15g (procaspase-3 EC50 = 1.42 μM) and 16b (procaspase-3 EC50 = 0.25 μM) exhibited excellent antitumor activity with IC50 values ranging from 0.14 μM to 0.98 μM against all cancer cell lines, which were 1.8-8.7 times more active than the first procaspase activating compound (PAC-1) (procaspase-3 EC50 = 4.08 μM). The structure-activity relationship (SAR) analyses indicated that the introduction of a lipophilic group (a benzyloxy or heteroaryloxy group) at the 4-position of the 2-hydroxy phenyl ring was beneficial to antitumor activity, and the presence of substituents containing nitrogen that are positively charged at physiological pH could also improve antitumor activity. It was also confirmed that the steric effect of the 4-position substituent of the benzyloxy group had a significant influence on cytotoxic activity. PMID:25171780

  18. Design and synthesis of cis-restricted benzimidazole and benzothiazole mimics of combretastatin A-4 as antimitotic agents with apoptosis inducing ability.

    PubMed

    Ashraf, Md; Shaik, Thokhir B; Malik, M Shaheer; Syed, Riyaz; Mallipeddi, Prema L; Vardhan, M V P S Vishnu; Kamal, Ahmed

    2016-09-15

    A series of colchicine site binding tubulin inhibitors were designed and synthesized by the modification of the combretastatin A-4 (CA4) pharmacophore. The ring B was replaced by the pharmacologically relevant benzimidazole or benzothiazole scaffolds, and the cis-configuration of the olefinic bond was restricted by the incorporation of a pyridine ring which is envisaged by the structural resemblance to a tubulin inhibitor like E7010. These compounds were evaluated for their antiproliferative activity on selected cancer cell lines and an insight in the structure activity relationship was developed. The most potent compounds (6c and 6l) demonstrated an antiproliferative effect comparable and superior to that of CA4 (GI50 up to 40nM). Mitotic cell cycle arrest in G2/M phase revealed the disruption of microtubule dynamics that was confirmed by tubulin polymerization assays and immunocytochemistry studies at the cellular level. The molecular docking studies suggested that the binding of these mimics at the colchicine site of the tubulin is similar to that of combretastatin A-4. PMID:27515320

  19. Synthesis, DNA/HSA Interaction Spectroscopic Studies and In Vitro Cytotoxicity of a New Mixed Ligand Cu(II) Complex.

    PubMed

    Gan, Qian; Fu, Xiabing; Chen, Weijiang; Xiong, Yahong; Fu, Yinlian; Chen, Shi; Le, Xueyi

    2016-05-01

    A new mixed ligand copper(II)-dipeptide complex with 2-(2'-pyridyl)benzothiazole (pbt), [Cu(Gly-L-leu)(pbt)(H2O)]·ClO4 (Gly-L-leu = Glycyl-L-leucine anion) was synthesized and characterized by various physico-chemical means. The DNA binding and cleavage properties of the complex investigated by viscosity, agarose gel electrophoresis and multi-spectroscopic techniques (UV, circular dichroism (CD) and fluorescence) showed that the complex was bound to CT-DNA through intercalation mode with moderate binding constant (K b = 3.132 × 10(4) M(-1)), and cleaved pBR322 DNA efficiently (~ 5 μM) in the presence of Vc, probably via an oxidative mechanism induced by •OH. Additionally, the interaction of the complex with human serum albumin (HSA) was explored by UV-visible, CD, fluorescence, synchronous fluorescence and 3D fluorescence spectroscopy. The complex exhibits desired affinity to HSA through hydrophobic interaction. Moreover, the cytotoxicity of the complex against three human carcinoma cell lines (HeLa, HepG2 and A549) was evaluated by MTT assay, which showed that the complex had effective cytotoxicity and higher inhibition toward A549 cell lines with IC50 of 38.0 ± 3.2 μM. PMID:26961845

  20. Galanin Receptors and Ligands

    PubMed Central

    Webling, Kristin E. B.; Runesson, Johan; Bartfai, Tamas; Langel, Ülo

    2012-01-01

    The neuropeptide galanin was first discovered 30 years ago. Today, the galanin family consists of galanin, galanin-like peptide (GALP), galanin-message associated peptide (GMAP), and alarin and this family has been shown to be involved in a wide variety of biological and pathological functions. The effect is mediated through three GPCR subtypes, GalR1-3. The limited number of specific ligands to the galanin receptor subtypes has hindered the understanding of the individual effects of each receptor subtype. This review aims to summarize the current data of the importance of the galanin receptor subtypes and receptor subtype specific agonists and antagonists and their involvement in different biological and pathological functions. PMID:23233848

  1. A highly selective fluorescent 'turn-on' chemosensor for Zn(2+) based on a benzothiazole conjugate: their applicability in live cell imaging and use of the resultant complex as a secondary sensor of CN(-).

    PubMed

    Khairnar, Nilesh; Tayade, Kundan; Sahoo, Suban K; Bondhopadhyay, Banashree; Basu, Anupam; Singh, Jasminder; Singh, Narinder; Gite, Vikas; Kuwar, Anil

    2015-02-01

    A benzothiazole derivative linked "off-on" multi-responsive and selective chemosensor has been synthesized and evaluated for cation recognition properties. The receptor shows a high sensitivity and selectivity for Zn(2+) through a 'turn-on' fluorescence response over the other tested cations with a detection limit as low as 0.67 μM. The receptor was successfully applied for the detection of Zn(2+) in live HeLa cells. Then, the Zn(2+) complex of receptor was also used for cyanide detection and recognition. PMID:25482915

  2. 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.

  3. Al(+)-ligand binding energies

    NASA Technical Reports Server (NTRS)

    Sodupe, M.; Bauschlicher, Charles W., Jr.

    1991-01-01

    Ab initio calculations are used to optimize the structure and determine the binding energies of Al(+) to a series of ligands. For Al(+)-CN, the bonding was found to have a large covalent component. For the remaining ligands, the bonding is shown to be electrostatic in origin. The results obtained for Al(+) are compared with those previously reported for Mg(+).

  4. 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

  5. Predicting target-ligand interactions using protein ligand-binding site and ligand substructures

    PubMed Central

    2015-01-01

    Background Cell proliferation, differentiation, Gene expression, metabolism, immunization and signal transduction require the participation of ligands and targets. It is a great challenge to identify rules governing molecular recognition between chemical topological substructures of ligands and the binding sites of the targets. Methods We suppose that the ligand-target interactions are determined by ligand substructures as well as the physical-chemical properties of the binding sites. Therefore, we propose a fragment interaction model (FIM) to describe the interactions between ligands and targets, with the purpose of facilitating the chemical interpretation of ligand-target binding. First we extract target-ligand complexes from sc-PDB database, based on which, we get the target binding sites and the ligands. Then we represent each binding site as a fragment vector based on a target fragment dictionary that is composed of 199 clusters (denoted as fragements in this work) obtained by clustering 4200 trimers according to their physical-chemical properties. And then, we represent each ligand as a substructure vector based on a dictionary containing 747 substructures. Finally, we build the FIM by generating the interaction matrix M (representing the fragment interaction network), and the FIM can later be used for predicting unknown ligand-target interactions as well as providing the binding details of the interactions. Results The five-fold cross validation results show that the proposed model can get higher AUC score (92%) than three prevalence algorithms CS-PD (80%), BLM-NII (85%) and RF (85%), demonstrating the remarkable predictive ability of FIM. We also show that the ligand binding sites (local information) overweight the sequence similarities (global information) in ligand-target binding, and introducing too much global information would be harmful to the predictive ability. Moreover, The derived fragment interaction network can provide the chemical insights on

  6. A novel water-soluble benzothiazole derivative BD926 inhibits human activated T cell proliferation by down-regulating the STAT5 activation.

    PubMed

    Liu, Yang; Lai, Yi; Li, Hua; Liu, Jin; Luo, Xing-Yan; Li, Min-Hui; Yang, Tai; Wang, Yan-Tang; Yang, Shu-Xia; Li, Li-Mei; Zou, Qiang; Chen, Zheng-Liang

    2015-08-15

    Immunosuppressants are widely used for treatment of T cell-mediated autoimmune diseases and allogeneic graft rejection. However, because of the toxicity and tolerance of these drugs, novel immunosuppressants are urgently needed. We synthesized a series of novel water-soluble benzothiazole derivatives and found that BD926 [sodium 2-(benzo[d]thiazol-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-olate] had potent immunosuppressive activity. Treatment with BD926 significantly inhibited anti-CD3/anti-CD28 and alloantigen-induced human T cell proliferation as well as IL2-stimulated activated T cell proliferation in a dose-dependent manner in vitro. BD926 had no obvious cytotoxicity against human resting T cells, IL-4 treated activated T cells and fibroblast-like synoviocytes in our experimental conditions. Furthermore, BD926 induced cell cycle arrest at G0/G1 phase and inhibited the cyclin D3 and CDK 6 expression in activated T cells. BD926 inhibited the STAT5, but not Akt and p70S6K, phosphorylation in a dose-dependent manner in the IL-2-treated activated T cells. Interestingly, BD926 inhibited IFN-γ, IL-6 and IL-17, but not IL-2, IL-4 and IL-10, production in activated T cells. Finally, treatment with BD926 reduced delayed-type hypersensitivity in mice in a dose-dependent manner. Collectively, these data suggest that BD926 may be a lead compound for the design and development of new immunosuppressants for the intervention of allograft rejection and autoimmune diseases. PMID:25935419

  7. Design and synthesis of 1-(benzothiazol-5-yl)-1H-1,2,4-triazol-5-ones as protoporphyrinogen oxidase inhibitors.

    PubMed

    Zuo, Yang; Yang, Sheng-Gang; Luo, Yan-Ping; Tan, Ying; Hao, Ge-Fei; Wu, Qiong-You; Xi, Zhen; Yang, Guang-Fu

    2013-06-01

    Protoporphyrinogen oxidase (PPO, E.C. 1.3.3.4) is the action target for several structurally diverse herbicides. A series of novel 4-(difluoromethyl)-1-(6-halo-2-substituted-benzothiazol-5-yl)-3-methyl-1H-1,2,4-triazol-5(4H)-ones 2a-z were designed and synthesized via the ring-closure of two ortho-substituents. The in vitro bioassay results indicated that the 26 newly synthesized compounds exhibited good PPO inhibition effects with K(i) values ranging from 0.06 to 17.79 μM. Compound 2e, ethyl 2-{[5-(4-(difluoromethyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-6-fluorobenzo-thiazol-2-yl]thio}acetate, was the most potent inhibitor with K(i) value of 0.06 μM against mtPPO, comparable to (K(i)=0.03 μM) sulfentrazone. Further green house assays showed that compound 2f (K(i)=0.24 μM, mtPPO), ethyl 2-{[5-(4-(difluoromethyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-6-fluorobenzothiazol-2-yl]thio}propanoate, showed the most promising post-emergence herbicidal activity with broad spectrum even at concentrations as low as 37.5 gai/ha. Soybean exhibited tolerance to compound 2f at the dosages of 150 gai/ha, whereas they are susceptible to sulfentrazone even at 75 gai/ha. Thus, compound 2f might be a potential candidate as a new herbicide for soybean fields. PMID:23623257

  8. Hit to lead optimization of a series of N-[4-(1,3-benzothiazol-2-yl)phenyl]acetamides as monoacylglycerol lipase inhibitors with potential anticancer activity.

    PubMed

    Afzal, Obaid; Akhtar, Md Sayeed; Kumar, Suresh; Ali, Md Rahmat; Jaggi, Manu; Bawa, Sandhya

    2016-10-01

    A total of thirty five new N-[4-(1,3-benzothiazol-2-yl)phenyl]acetamide derivatives were synthesized and structures of all the compounds were confirmed on the basis of elemental analysis and collective use of IR, (1)H NMR, (13)C NMR and mass spectral data. Compounds were tested for their ability to inhibit human monoacylglycerol lipase (hMAGL) enzyme. Eight compounds 4, 19-21, 24-26, and 34 reduced the hMAGL activity less than 50% at 100 nM concentrations. The halogen substituted aniline derivatives 20, 21 and 24-26 were found to be most active among all the synthesized compounds having IC50 value in the range of 6.5-9 nM. Twenty five compounds were selected by NCI, USA for one dose anticancer screening. Compound 21 (NSC: 780167) and 24 (NSC: 780168) fulfilled prearranged doorstep growth inhibition criteria and further selected for NCI full panel five dose assay at 10-fold dilutions of five different concentrations (0.01, 0.1, 1, 10 and 100 μM). Both the compounds 21 and 24 were found to be most active against MCF7 and MDA-MB-468 breast cancer cell lines. The GI50 value of 32.5 nM (MCF7) and 23.8 nM (MDA-MB-468) was observed for compound 21. Compound 24 showed GI50 values of 37.1 nM against MCF7 breast cancer cell line and 25.1 nM against MDA-MB-468 breast cancer cell line. PMID:27267002

  9. Simultaneous determination of benzothiazoles, benzotriazoles and benzosulfonamides by solid phase microextraction-gas chromatography-triple quadrupole mass spectrometry in environmental aqueous matrices and human urine.

    PubMed

    Naccarato, Attilio; Gionfriddo, Emanuela; Sindona, Giovanni; Tagarelli, Antonio

    2014-04-18

    This work proposes a new approach for the simultaneous determination of benzothiazoles, benzotriazoles and benzosulfonamides in different environmental matrices and human urine, using solid-phase microextraction coupled with gas-chromatography-triple quadrupole mass spectrometry (SPME-GC-QqQMS). The analytes object of this investigation have been classified as toxic to aquatic organisms and their presence in human urine was reported to occur as result of human exposure to contaminated environment. In this work many of the challenges related to the chemical diversity and polarity of the analytes selected were overcame conducting a multivariate optimization of the working conditions by using the approach of "Experimental design". Tests performed to assess the performances of five SPME coatings in direct immersion mode revealed the polyacrylate coating to be the most suitable for the extraction of the probe analytes. A central composite design (CCD) was employed to determine the optimal conditions for four factors affecting the solid-phase microextraction process: extraction time, extraction temperature, pH and percentage of sodium chloride. The optimal working condition determined by using Derringer's desirability function were 40min as extraction time, pH 7.1 and 6.0% of NaCl. Since the extraction temperature do not significantly affects the responses for all the analytes considered, analyses were performed at room temperature. A careful evaluation of the matrix effect for all the matrices tested was carried out. The results obtained showed that the proposed method did not significantly influenced by matrix effects in most of the cases tested, and thus allows the use of simplified calibration procedure. Satisfactory values of accuracy and precision were also obtained for all the matrices considered. PMID:24636758

  10. Crystal structure of the salt bis-(tri-ethano-lamine-κ(3) N,O,O')cobalt(II) bis-[2-(2-oxo-2,3-di-hydro-1,3-benzo-thia-zol-3-yl)acetate].

    PubMed

    Ashurov, Jamshid M; Obidova, Nodira J; Abdireymov, Hudaybergen B; Ibragimov, Bakhtiyar T

    2016-03-01

    The reaction of 2-(2-oxo-2,3-di-hydro-1,3-benzo-thia-zol-3-yl)acetic acid (NBTA) and tri-ethano-lamine (TEA) with Co(NO3)2 results in the formation of the title complex, [Co(C6H15NO3)2](C9H6NO3S)2, which is formed as a result of the association of bis-(tri-ethano-lamine)-cobalt(II) and 2-(2-oxo-2,3-di-hydro-1,3-benzo-thia-zol-3-yl)acetate units. It crystallizes in the monoclinic centrosymmetric space group P21/c, with the Co(II) ion situated on an inversion centre. In the complex cation, the Co(II) ion is octa-hedrally coordinated by two N,O,O'-tridentate TEA mol-ecules with a facial distribution and the N atoms in a trans arrangement. Two ethanol groups of each TEA mol-ecule form two five-membered chelate rings around the Co(II) ion, while the third ethanol group does not coordinate to the metal. The free and coordinating hy-droxy groups of the TEA mol-ecules are involved in hydrogen bonding with the O atoms of NBTA anions, forming an infinite two-dimensional network extending parallel to the bc plane. PMID:27006821

  11. Hydrogen and halogen bonding patterns and π-π aromatic interactions of some 6,7-disubstituted 1,3-benzothiazoles studied by X-ray diffraction and DFT calculations

    NASA Astrophysics Data System (ADS)

    Čičak, Helena; Đaković, Marijana; Mihalić, Zlatko; Pavlović, Gordana; Racané, Livio; Tralić-Kulenović, Vesna

    2010-06-01

    The structures of five 6,7-disubstituted 1,3-benzothiazole (1,3-benzothiazole = bta) derivatives: 6-chloro-7-nitro-bta ( 3), 6-iodo-7-nitro-bta ( 5), 6-amino-7-iodo-bta ( 6), 6-acetylamino-7-iodo-bta ( 7) and 6-amino-7-bromo-bta ( 8) are reported and investigated by X-ray crystallography and DFT calculations. The crystal structures of 3 and 5- 8 are characterized by: (i) relatively weak C sbnd H⋯O/N/Br and N sbnd H⋯O/N/S hydrogen bonds, (ii) C sbnd Cl⋯O and C sbnd I⋯O/N halogen bonds and Br⋯Br interactions and (iii) π-π interactions. DFT optimized structures of 3, 5, 6 and 8 are in a good agreement with the corresponding X-ray molecular data. Calculated structure of 7 deviates from the experimental geometry because of more favourable intermolecular hydrogen bonding in crystal phase compared to the weak intramolecular hydrogen bond in the gas phase. The molecular electrostatic potential maps were used for predicting possible hydrogen and halogen bonding sites in structures of 3, 5, 6 and 8, and AIM analysis in order to characterize the nature and strength of intermolecular interactions in all of the examined crystal structures. Experimental results agree well with AIM analysis suggesting that the detected hydrogen and halogen bonds are weak and mostly of electrostatic origin.

  12. Design and synthesis of new potent anticancer benzothiazole amides and ureas featuring pyridylamide moiety and possessing dual B-Raf(V600E) and C-Raf kinase inhibitory activities.

    PubMed

    El-Damasy, Ashraf Kareem; Lee, Ju-Hyeon; Seo, Seon Hee; Cho, Nam-Chul; Pae, Ae Nim; Keum, Gyochang

    2016-06-10

    A new series of benzothiazole amide and urea derivatives tethered with the privileged pyridylamide moiety by ether linkage at the 6-position of benzothiazole (22 final compounds) has been designed and synthesized as potent anticancer sorafenib analogs. A selected group of twelve derivatives was appraised for its antiproliferative activity over a panel of 60 human cancer cell lines at a single dose concentration of 10 μM at National Cancer Institute (NCI, USA). Compounds 4b, 5a, 5b and 5d exhibited promising growth inhibitions and thus were further tested in advanced 5-dose testing assay to determine their GI50 values. The cellular based assay results revealed that 3,5-bis-trifluoromethylphenyl (5b) urea member is the best derivative with superior potency and efficacy compared to sorafenib as well as notable extended spectrum activity covering 57 human cancer cell lines. Kinase screening of compound 5b showed its kinase inhibitory effect against both B-Raf(V600E) and C-Raf. Moreover, the most potent derivatives in cells were investigated for their RAF inhibitory activities, and the results were rationalized with the molecular docking study. Profiling of CYP450 and hERG channel inhibitory effects for the active compounds revealed their low possibilities to exhibit undesirable drug-drug interactions and cardiac side effects. PMID:27017549

  13. C-H arylation of azaheterocycles: a direct ligand-free and Cu-catalyzed approach using diaryliodonium salts.

    PubMed

    Kumar, Dalip; Pilania, Meenakshi; Arun, V; Pooniya, Savita

    2014-09-01

    An efficient and high yielding Cu-catalyzed direct C-H arylation of azaheterocycles including oxadiazoles, thiadiazoles, benzoxazoles and benzothiazoles has been achieved by employing easily accessible diaryliodonium salts. PMID:25017573

  14. 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

  15. What are Nuclear Receptor Ligands?

    PubMed Central

    Sladek, Frances M.

    2010-01-01

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

  16. 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.

  17. Fluorescent Ligands for Adenosine Receptors

    PubMed Central

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

    2012-01-01

    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. PMID:23200243

  18. 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.

  19. 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.

  20. New cyclometallated precursors of unsubstituted N-phenylpyrazole [{Pd(phpz)(μ-X)}2] (X = AcO or OH) and study of their reactivity towards selected ligands.

    PubMed

    Serrano, José Luis; García, Luis; Pérez, José; Pérez, Eduardo; Galiana, José Miguel; García, Joaquín; Martínez, Marina; Sánchez, Gregorio; da Silva, Ivan

    2011-01-01

    A new acetate-bridged dinuclear palladacycle with unsubstituted N-phenylpyrazole [{Pd(phpz)(μ-AcO)}(2)] 1 has been isolated and characterised, including an X-ray diffraction study. A survey of the Cambridge Structural Database (CSD) v. 5.31 looking for analogous dimeric C^N cyclopalladated complexes has been done, exploring the incidence of cisoid/transoid arrangements, the preferred conformation of the eight-membered ring formed in the double bridge, the Pd-Pd distance and the main factors that affect it. The reaction of 1 with NBu(4)OH yielded [{Pd(phpz)(μ-OH)}(2)] 2 that has shown to be a complementary precursor of 1 in terms of acid/base reactivity. In this sense, both 1 and 2 are also well differentiated from halide precursors available to date. The preparation of selected complexes with potential applications in several fields, [Pd(phpz)(O^N)] O^N = N-p-chlorophenylsalycilaldiminate (N-pClsal) 3, picolinic acid (pic) 4; 8-hydroxiquinolinate (oxin) 5; 2-pyrrole-carboxaldeydate (2-pcal) 6, [Pd(phpz)(O^O)] O^O = salycilaldehydate (sal) 7 acetylacetonate (acac) 8, [{Pd(phpz)(μ-N^S)}(2)] N^S = 2-mercapto-1-methylimidazolate (SMeimz) 11; [{Pd(phpz)(μ-N^O)}(2)] N^O = succinimidate (succ) 12; [{Pd(phpz)(μ-N^N)}(2)] (N^N = pyrazolate (pz) 13, has been achieved using 1 or 2 as starting materials in acid/base reactions. Dithiocarbamate [Pd(phpz)(S(2)CNEt(2))] 9 and dithiophosphate [Pd(phpz){S(S)P(OEt)(2)}] 10 derivatives have been synthesised in related reactions, and the reactivity of 1 against neutral phosphine ligands has also been tested with the preparation of [Pd(phpz)(AcO)(PPh(3))] 14. The crystal structures of compounds 7, 9, 11, 12 and 13 (this one obtained from a powder sample using synchrotron radiation) have also been established, and together with 1 are the first examples of complexes containing unsubstituted N-phenylpyrazole as cyclometallated backbone that have been deposited to date on the Cambridge Structural Database. PMID:21060953

  1. 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

  2. Efficient pseudo-enantiomeric carbohydrate olefin ligands.

    PubMed

    Grugel, Holger; Albrecht, Fabian; Minuth, Tobias; Boysen, Mike M K

    2012-07-20

    Highly efficient pseudo-enantiomeric olefin ligands were designed from D-glucose and D-galactose. These ligands yield consistently excellent levels of enantioselectivity in Rh(I)-catalyzed 1,4-additions of aryl- and alkenylboronic acids to achiral enones and high diastereoselectivity with chiral substrates. Contrary to established olefin ligands, they are obtained enantiomerically pure via short syntheses without racemic resolution steps, making them a valuable addition to the arsenal of chiral ligands with olefinic donor sites. PMID:22780685

  3. Glyconanomaterials: Synthesis, Characterization, and Ligand Presentation

    PubMed Central

    Wang, Xin

    2010-01-01

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

  4. Combining quantum mechanical ligand conformation analysis and protein modeling to elucidate GPCR-ligand binding modes.

    PubMed

    Schultes, Sabine; Engelhardt, Harald; Roumen, Luc; Zuiderveld, Obbe P; Haaksma, Eric E J; de Esch, Iwan J P; Leurs, Rob; de Graaf, Chris

    2013-01-01

    SAR beyond protein-ligand interactions: By combining structure-affinity relationships, protein-ligand modeling studies, and quantum mechanical calculations, we show that ligand conformational energies and basicity play critical roles in ligand binding to the histamine H4 receptor, a GPCR that plays a key role in inflammation. PMID:23161844

  5. Ligand chain length conveys thermochromism.

    PubMed

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

    2014-08-14

    Thermochromic properties of a series of non-ionic copper compounds have been reported. Herein, we demonstrate that Cu(II) ion with straight-chain primary amine (A) and alpha-linolenic (fatty acid, AL) co-jointly exhibit thermochromic properties. In the current case, we determined that thermochromism becomes ligand chain length-dependent and at least one of the ligands (A or AL) must be long chain. Thermochromism is attributed to a balanced competition between the fatty acids and amines for the copper(II) centre. The structure-property relationship of the non-ionic copper compounds Cu(AL)2(A)2 has been substantiated by various physical measurements along with detailed theoretical studies based on time-dependent density functional theory. It is presumed from our results that the compound would be a useful material for temperature-sensor applications. PMID:24943491

  6. Mg(+)-ligand binding energies

    NASA Technical Reports Server (NTRS)

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

    1991-01-01

    Ab initio calculations are used to optimize the structures and determine the binding energies of Mg(+) to a series of ligands. Mg(+) bonds electrostatically with benzene, acetone, H2, CO, and NH3 and a self-consistent-field treatment gives a good description of the bonding. The bonding in MgCN(+) and MgCH3(+) is largely covalent and a correlated treatment is required.

  7. 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.

  8. Presentation of Ligands on Hydroxylapatite

    NASA Technical Reports Server (NTRS)

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

    1997-01-01

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

  9. 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

  10. Bifunctional crosslinking ligands for transthyretin

    PubMed Central

    Mangione, P. Patrizia; Deroo, Stéphanie; Ellmerich, Stephan; Bellotti, Vittorio; Kolstoe, Simon; Wood, Stephen P.; Robinson, Carol V.; Smith, Martin D.; Tennent, Glenys A.; Broadbridge, Robert J.; Council, Claire E.; Thurston, Joanne R.; Steadman, Victoria A.; Vong, Antonio K.; Swain, Christopher J.; Pepys, Mark B.; Taylor, Graham W.

    2015-01-01

    Wild-type and variant forms of transthyretin (TTR), a normal plasma protein, are amyloidogenic and can be deposited in the tissues as amyloid fibrils causing acquired and hereditary systemic TTR amyloidosis, a debilitating and usually fatal disease. Reduction in the abundance of amyloid fibril precursor proteins arrests amyloid deposition and halts disease progression in all forms of amyloidosis including TTR type. Our previous demonstration that circulating serum amyloid P component (SAP) is efficiently depleted by administration of a specific small molecule ligand compound, that non-covalently crosslinks pairs of SAP molecules, suggested that TTR may be also amenable to this approach. We first confirmed that chemically crosslinked human TTR is rapidly cleared from the circulation in mice. In order to crosslink pairs of TTR molecules, promote their accelerated clearance and thus therapeutically deplete plasma TTR, we prepared a range of bivalent specific ligands for the thyroxine binding sites of TTR. Non-covalently bound human TTR–ligand complexes were formed that were stable in vitro and in vivo, but they were not cleared from the plasma of mice in vivo more rapidly than native uncomplexed TTR. Therapeutic depletion of circulating TTR will require additional mechanisms. PMID:26400472

  11. Tumor Targeting via Integrin Ligands

    PubMed Central

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

    2013-01-01

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

  12. 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.

  13. NKG2D ligands as therapeutic targets

    PubMed Central

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

    2013-01-01

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

  14. 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

  15. 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

  16. 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

  17. 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. PMID:25335915

  18. Ligand-targeted liposomes for cancer treatment.

    PubMed

    Sapra, Puja; Tyagi, Pradeep; Allen, Theresa M

    2005-10-01

    Selective targeting of ligand-targeted liposomes containing anticancer drugs or therapeutic genes to cell surface receptors expressed on cancer cells is a recognized strategy for improving the therapeutic effectiveness of conventional chemotherapeutics or gene therapeutics. Some recent advances in the field of ligand-targeted liposomes for the treatment of cancer are summarized including: selection criteria for the receptors to be targeted, choice of targeting ligands and choice of encapsulated therapeutics. Targeting of liposomes to solid tumors, versus angiogenic endothelial cells versus vascular targets is discussed. Ligand-targeted liposomes have shown considerable promise in preclinical xenograft models and are poised for clinical development. PMID:16305440

  19. Chemical monitoring and occurrence of alkylphenols, alkylphenol ethoxylates, alcohol ethoxylates, phthalates and benzothiazoles in sewage treatment plants and receiving waters along the Ter River basin (Catalonia, N. E. Spain).

    PubMed

    Céspedes, Raquel; Lacorte, Sílvia; Ginebreda, Antonio; Barceló, Damià

    2006-07-01

    This study presents a quantitative estimation of the analysis and fate of several emerging pollutants, some of them endocrine-disrupting compounds, in surface water samples collected at several locations along the Ter River and two of its tributaries. Influent and effluent waters and particulate matter from five sewage treatment plants (STP) that discharge into these rivers were also studied. The target compounds analyzed were: nonylphenol ethoxylates (NPEO), nonylphenol (NP), octylphenol (OP), bisphenol A (BPA), phthalates, alcohol ethoxylates (AEO) and benzothiazoles. Chemical analysis by liquid chromatography-mass spectrometry using an electrospray interface (LC-ESI-MS) revealed the presence of low amounts (between 0.06 and 17.5 microg L(-1)) of the target compounds NPE(1+2)O and NP, which were detected in 100% and 84% of the samples respectively. Maximum concentrations occurred in the STPs associated with the municipalities of Vic and Girona. From the fate and behavior data obtained for the various compounds analyzed in the STP influent and effluent, we can conclude that the STPs are effective at removing large amounts (more than 70%) of the compounds studied from the water. PMID:16794817

  20. Synthesis, structural characterization, docking, lipophilicity and cytotoxicity of 1-[(1R)-1-(6-fluoro-1,3-benzothiazol-2-yl)ethyl]-3-alkyl carbamates, novel acetylcholinesterase and butyrylcholinesterase pseudo-irreversible inhibitors.

    PubMed

    Pejchal, Vladimír; Štěpánková, Šárka; Pejchalová, Marcela; Královec, Karel; Havelek, Radim; Růžičková, Zdeňka; Ajani, Haresh; Lo, Rabindranath; Lepšík, Martin

    2016-04-01

    In the current study, sixteen novel derivatives of (R)-1-(6-fluorobenzo[d]thiazol-2-yl)ethanamine were synthesized as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. Chemical structures together with purity of the synthesized compounds were substantiated by IR, (1)H, (13)C, (19)F NMR, high resolution mass spectrometry and elemental analysis. The optical activities were confirmed by optical rotation measurements. The synthesized compounds were evaluated for their AChE and BChE inhibitory activities. In addition, the cytotoxicity of the most active compounds was investigated against human cell lines employing XTT tetrazolium salt reduction assay and xCELLigence system allowing a label-free assessment of the cells proliferation. Our results demonstrated that the inhibitory mechanism was confirmed to be pseudo-irreversible, in line with previous studies on carbamates. Compounds indicated as 3b, 3d, 3l and 3n showed the best AChE inhibitory activity of all the evaluated compounds and were up to tenfold more potent than standard drug rivastigmine. The binding mode was determined using state-of-the-art covalent docking and scoring methodology. The obtained data clearly demonstrated that 3b, 3d, 3l and 3n benzothiazole carbamates possess high inhibitory activity against AChE and BChE and concurrently negligible cytotoxicity. In conclusion, our results indicate, that these derivatives could be promising in an effective therapeutic intervention for Alzheimer's disease. PMID:26947959

  1. Allosterism at muscarinic receptors: ligands and mechanisms.

    PubMed

    Birdsall, N J M; Lazareno, S

    2005-06-01

    The evaluation of allosteric ligands at muscarinic receptors is discussed in terms of the ability of the experimental data to be interpreted by the allosteric ternary complex model. The compilation of useful SAR information of allosteric ligands is not simple, especially for muscarinic receptors, where there are multiple allosteric sites and complex interactions. PMID:15974931

  2. Autocrine signal transmission with extracellular ligand degradation

    NASA Astrophysics Data System (ADS)

    Muratov, C B; Posta, F; Shvartsman, S Y

    2009-03-01

    Traveling waves of cell signaling in epithelial layers orchestrate a number of important processes in developing and adult tissues. These waves can be mediated by positive feedback autocrine loops, a mode of cell signaling where binding of a diffusible extracellular ligand to a cell surface receptor can lead to further ligand release. We formulate and analyze a biophysical model that accounts for ligand-induced ligand release, extracellular ligand diffusion and ligand-receptor interaction. We focus on the case when the main mode for ligand degradation is extracellular and analyze the problem with the sharp threshold positive feedback nonlinearity. We derive expressions that link the speed of propagation and other characteristics of traveling waves to the parameters of the biophysical processes, such as diffusion rates, receptor expression level, etc. Analyzing the derived expressions we found that traveling waves in such systems can exhibit a number of unusual properties, e.g. non-monotonic dependence of the speed of propagation on ligand diffusivity. Our results for the fully developed traveling fronts can be used to analyze wave initiation from localized perturbations, a scenario that frequently arises in the in vitro models of epithelial wound healing, and guide future modeling studies of cell communication in epithelial layers.

  3. Protein-ligand-based pharmacophores: generation and utility assessment in computational ligand profiling.

    PubMed

    Meslamani, Jamel; Li, Jiabo; Sutter, Jon; Stevens, Adrian; Bertrand, Hugues-Olivier; Rognan, Didier

    2012-04-23

    Ligand profiling is an emerging computational method for predicting the most likely targets of a bioactive compound and therefore anticipating adverse reactions, side effects and drug repurposing. A few encouraging successes have already been reported using ligand 2-D similarity searches and protein-ligand docking. The current study describes the use of receptor-ligand-derived pharmacophore searches as a tool to link ligands to putative targets. A database of 68,056 pharmacophores was first derived from 8,166 high-resolution protein-ligand complexes. In order to limit the number of queries, a maximum of 10 pharmacophores was generated for each complex according to their predicted selectivity. Pharmacophore search was compared to ligand-centric (2-D and 3-D similarity searches) and docking methods in profiling a set of 157 diverse ligands against a panel of 2,556 unique targets of known X-ray structure. As expected, ligand-based methods outperformed, in most of the cases, structure-based approaches in ranking the true targets among the top 1% scoring entries. However, we could identify ligands for which only a single method was successful. Receptor-ligand-based pharmacophore search is notably a fast and reliable alternative to docking when few ligand information is available for some targets. Overall, the present study suggests that a workflow using the best profiling method according to the protein-ligand context is the best strategy to follow. We notably present concrete guidelines for selecting the optimal computational method according to simple ligand and binding site properties. PMID:22480372

  4. The chemical biology of Cu(II) complexes with imidazole or thiazole containing ligands: Synthesis, crystal structures and comparative biological activity.

    PubMed

    Lewis, Adam; McDonald, Molly; Scharbach, Stephanie; Hamaway, Stefan; Plooster, Melissa; Peters, Kyle; Fox, Kristin M; Cassimeris, Lynne; Tanski, Joseph M; Tyler, Laurie A

    2016-04-01

    The synthesis and characterization of two copper(II) complexes containing 2-(2-pyridyl)benzimidazole (PyBIm) are reported with the biological activity of these two complexes and a third Cu(II) complex containing 2-(2-pyridyl)benzothiazole (PyBTh). Complex 1, [Cu(PyBIm)(NO3)(H2O)](NO3), is a four coordinate, distorted square planar species with one ligand (N,N), nitrate and water bound to Cu(II). The [Cu(PyBIm)3](BF4)2 complex (2) has distorted octahedral geometry with a 3:1 Py(BIm) ligand to metal ratio. The distorted trigonal bi-pyramidal geometry of compound 3, [Cu(PyBTh)2(H2O)](BF4)2, is comprised of two PyBTh ligands and one water. Biological activity of 1-3 has been assessed by analyzing DNA interaction, nuclease ability, cytotoxic activity and antibacterial properties. Complex 3 exhibits potent concentration dependent SC-DNA cleavage forming single- and double-nicked DNA in contrast to the weak activity of complexes 1 and 2. Mechanistic studies indicate that all complexes utilize an oxidative mechanism however 1 and 2 employ O2(-) as the principal reactive oxygen species while the highly active 3 utilizes (1)O2. The interaction between 1-3 and DNA was investigated using fluorescence emission spectroscopy and revealed all complexes strongly intercalate DNA with Kapp values of 2.65×10(6), 1.85×10(6) and 2.72×10(6)M(-1), respectively. Cytotoxic effects of 1-3 were examined using HeLa and K562 cells and show cell death in the micromolar range with the activity of 1≈2 and were slightly higher than 3. Similar reactivity was observed in the antibacterial studies with E. coli and S. aureus. A detailed comparative analysis of the three complexes is presented. PMID:26828284

  5. Fine tuning of emission color of iridium(III) complexes from yellow to red via substituent effect on 2-phenylbenzothiazole ligands: synthesis, photophysical, electrochemical and DFT study.

    PubMed

    Li, Ming; Zeng, Hui; Meng, Yanyan; Sun, Huiqin; Liu, Song; Lu, Zhiyun; Huang, Yan; Pu, Xuemei

    2011-07-21

    Four novel iridium(III) complexes bearing biphenyl (7a-7c) or fluorenyl (7d) modified benzothiazole cyclometallate ligands are synthesized. In comparison with the yellow parent complex, bis(2-phenylbenzothiozolato-N,C(2')) iridium(III) (acetylacetonate) [(pbt)(2)Ir(acac)] (λ(PLmax) = 557 nm, φ(PL) = 0.26), 7a-7d show 20-43 nm bathochromic shifted orange or red phosphorescence in solution, with maximum photoluminescence (PL) quantum yield of 0.62, and PL lifetime of 1.8-2.0 μs. Meanwhile, the resulting complexes also exhibit intense orange or red phosphorescence of λ(PLmax) = 588-611 nm in solid films. The complex 7c with two tert-butyl substituents possesses the highest phosphorescent efficiency both in dilute solution and thin solid films, therefore may be a prospective candidate for both doping and host emitting electrophosphorescent material. Furthermore, despite the observation of severe oxygen quenching for 7a-7d in solution, 7a and 7c even show efficient emission intensity quenching by oxygen in their solid state due to the existence of void channels in crystals; consequently, they are promising molecular oxygen sensor reagents. Electrochemical measurement and DFT calculation results suggest that all these chelates own declined LUMOs of 0.1 eV relative to that of (pbt)(2)Ir(acac) owing to the contribution of the phenyl substituents; whereas only 7d shows a more destabilized HOMO (∼0.1 eV) compared with the parent chelate. PMID:21666891

  6. Improving protein-ligand docking with flexible interfacial water molecules using SWRosettaLigand.

    PubMed

    Li, Linqing; Xu, Weiwei; Lü, Qiang

    2015-11-01

    Computational protein-ligand docking is of great importance in drug discovery and design. Conformational changes greatly affect the results of protein-ligand docking, especially when water molecules take part in mediating protein ligand interactions or when large conformational changes are observed in the receptor backbone interface. We have developed an improved protocol, SWRosettaLigand, based on the RosettaLigand protocol. This approach incorporates the flexibility of interfacial water molecules and modeling of the interface of the receptor into the original RosettaLigand. In a coarse sampling step, SWRosettaLigand pre-optimizes the initial position of the water molecules, docks the ligand to the receptor with explicit water molecules, and minimizes the predicted structure with water molecules. The receptor backbone interface is treated as a loop and perturbed and refined by kinematic closure, or cyclic coordinate descent algorithm, with the presence of the ligand. In two cross-docking test sets, it was identified that for 8 out of 14, and 16 out of 22, test instances, the top-ranked structures by SWRosettaLigand achieved better accuracy than other protocols. PMID:26515196

  7. Ultrafast dynamics of ligands within heme proteins.

    PubMed

    Vos, Marten H

    2008-01-01

    Physiological bond formation and bond breaking events between proteins and ligands and their immediate consequences are difficult to synchronize and study in general. However, diatomic ligands can be photodissociated from heme, and thus in heme proteins ligand release and rebinding dynamics and trajectories have been studied on timescales of the internal vibrations of the protein that drive many biochemical reactions, and longer. The rapidly expanding number of characterized heme proteins involved in a large variety of functions allows comparative dynamics-structure-function studies. In this review, an overview is given of recent progress in this field, and in particular on initial sensing processes in signaling proteins, and on ligand and electron transfer dynamics in oxidases and cytochromes. PMID:17996720

  8. 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

  9. Bioisosteric matrices for ligands of serotonin receptors.

    PubMed

    Warszycki, Dawid; Mordalski, Stefan; Staroń, Jakub; Bojarski, Andrzej J

    2015-04-01

    The concept of bioisosteric replacement matrices is applied to explore the chemical space of serotonin receptor ligands, aiming to determine the most efficient ways of manipulating the affinity for all 5-HT receptor subtypes. Analysis of a collection of over 1 million bioisosteres of compounds with measured activity towards serotonin receptors revealed that an average of 31 % of the ligands for each target are mutual bioisosteres. In addition, the collected dataset allowed the development of bioisosteric matrices-qualitative and quantitative descriptions of the biological effects of each predefined type of bioisosteric substitution, providing favored paths of modifying the compounds. The concept exemplified here for serotonin receptor ligands can likely be more broadly applied to other target classes, thus representing a useful guide for medicinal chemists designing novel ligands. PMID:25772514

  10. 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.

  11. Glutamate receptor ligands as anxiolytics.

    PubMed

    Chojnacka-Wójcik, E; Kłodzinska, A; Pilc, A

    2001-08-01

    The glutamatergic system has received considerable attention over recent years as a potential target for anxiolytic drugs. In spite of the pronounced anxiolytic-like effects of competitive and non-competitive antagonists of NMDA receptors in animal models of anxiety, these substances can not be regarded as potential anxiolytic drugs, mainly due to their side-effect profiles (eg, ataxia, myorelaxation, impairment of learning and memory processes and psychotomimetic effects). Antagonists and partial agonists of the glycine, receptor inhibit function of the NMDA receptor complex and evoke in animals an anxiolytic-like response. Although data concerning anti-anxiety-like effects of glycine, receptor antagonists are not very promising, studies are underway to develop new, brain-penetrating agents devoid of side effects. Further developments are necessary to more fully elucidate the possible involvement of AMPA/kainate receptors in anxiety. The recent discovery of metabotropic glutamate receptors, which modulate the function of the glutamatergic system, offers new hope for discovery of a new generation of anxiolytics. MPEP, a highly selective, brain penetrable, noncompetitive mGlu5 receptor antagonist, evokes anxiolytic-like effects in several animal models of anxiety, remaining remarkably free of side effects. LY-354740, a selective brain-penetrable group II mGlu receptor agonist, evokes marked anxiolytic-like effects in animal models of anxiety. LY-354740 causes mild sedation in mice, does not disturb motor coordination and has no potential to cause dependence. Therefore mGlu receptor ligands may become the anxiolytics of the future, free from the side effects characteristic of benzodiazepines. PMID:11892923

  12. PLIC: protein-ligand interaction clusters.

    PubMed

    Anand, Praveen; Nagarajan, Deepesh; Mukherjee, Sumanta; Chandra, Nagasuma

    2014-01-01

    Most of the biological processes are governed through specific protein-ligand interactions. Discerning different components that contribute toward a favorable protein- ligand interaction could contribute significantly toward better understanding protein function, rationalizing drug design and obtaining design principles for protein engineering. The Protein Data Bank (PDB) currently hosts the structure of ∼68 000 protein-ligand complexes. Although several databases exist that classify proteins according to sequence and structure, a mere handful of them annotate and classify protein-ligand interactions and provide information on different attributes of molecular recognition. In this study, an exhaustive comparison of all the biologically relevant ligand-binding sites (84 846 sites) has been conducted using PocketMatch: a rapid, parallel, in-house algorithm. PocketMatch quantifies the similarity between binding sites based on structural descriptors and residue attributes. A similarity network was constructed using binding sites whose PocketMatch scores exceeded a high similarity threshold (0.80). The binding site similarity network was clustered into discrete sets of similar sites using the Markov clustering (MCL) algorithm. Furthermore, various computational tools have been used to study different attributes of interactions within the individual clusters. The attributes can be roughly divided into (i) binding site characteristics including pocket shape, nature of residues and interaction profiles with different kinds of atomic probes, (ii) atomic contacts consisting of various types of polar, hydrophobic and aromatic contacts along with binding site water molecules that could play crucial roles in protein-ligand interactions and (iii) binding energetics involved in interactions derived from scoring functions developed for docking. For each ligand-binding site in each protein in the PDB, site similarity information, clusters they belong to and description of

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

    PubMed Central

    DeLuca, Samuel; Khar, Karen; Meiler, Jens

    2015-01-01

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

  14. Ethylene glycol modified 2-(2‧-aminophenyl)benzothiazoles at the amino site: the excited-state N-H proton transfer reactions in aqueous solution, micelles and potential application in live-cell imaging

    NASA Astrophysics Data System (ADS)

    Liu, Bo-Qing; Chen, Yi-Ting; Chen, Yu-Wei; Chung, Kun-You; Tsai, Yi-Hsuan; Li, Yi-Jhen; Chao, Chi-Min; Liu, Kuan-Miao; Tseng, Huan-Wei; Chou, Pi-Tai

    2016-03-01

    Triethylene glycol monomethyl ether and poly(ethylene glycol) monomethyl ether modified 2-(2‧-aminophenyl)benzothiazoles, namely ABT-P3EG, ABT-P7EG and ABT-P12EG varied by different chain length of poly(ethylene glycol) at the amino site, were synthesized to probe their photophysical and bio-imaging properties. In polar, aprotic solvents such as CH2Cl2 ultrafast excited-state intramolecular proton transfer (ESIPT) takes place, resulting in a large Stokes shifted tautomer emission in the green-yellow (550 nm) region. In neutral water, ABT-P12EG forms micelles with diameters of 15  ±  3 nm under a critical micelle concentration (CMC) of ~80 μM, in which the tautomer emission is greatly enhanced free from water perturbation. Cytotoxicity experiments showed that all ABT-PnEGs have negligible cytotoxicity against HeLa cells even at doses as high as 1 mM. Live-cell imaging experiments were also performed, the results indicate that all ABT-PnEGs are able to enter HeLa cells. While the two-photon excitation emission of ABT-P3EG in cells cytoplasm shows concentration independence and is dominated by the anion blue fluorescence, ABT-P7EG and ABT-P12EG exhibit prominent green tautomer emission at  >  CMC and in part penetrate to the nuclei, adding an additional advantage for the cell imaging.

  15. DNA Binding, Cleavage and Antibacterial Activity of Mononuclear Cu(II), Ni(II) and Co(II) Complexes Derived from Novel Benzothiazole Schiff Bases.

    PubMed

    Vamsikrishna, Narendrula; Kumar, Marri Pradeep; Tejaswi, Somapangu; Rambabu, Aveli; Shivaraj

    2016-07-01

    A series of novel bivalent metal complexes M(L1)2 and M(L2)2 where M = Cu(II), Ni(II), Co(II) and L1 = 2-((benzo [d] thiazol-6-ylimino)methyl)-4-bromophenol [BTEMBP], L2 = 1-((benzo [d] thiazol-6-ylimino)methyl) naphthalen-2-ol [BTEMNAPP] were synthesized. All the compounds have been characterized by elemental analysis, SEM, Mass, (1)H NMR, (13)C NMR, UV-Vis, IR, ESR, spectral data and magnetic susceptibility measurements. Based on the analytical and spectral data four-coordinated square planar geometry is assigned to all the complexes. DNA binding properties of these complexes have been investigated by electronic absorption spectroscopy, fluorescence and viscosity measurements. It is observed that these binary complexes strongly bind to calf thymus DNA by an intercalation mode. DNA cleavage efficacy of these complexes was tested in presence of H2O2 and UV light by gel electrophoresis and found that all the complexes showed better nuclease activity. Finally the compounds were screened for antibacterial activity against few pathogens and found that the complexes have potent biocidal activity than their free ligands. PMID:27165038

  16. 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…

  17. Synthesis and characterization of mixed ligand chiral nanoclusters.

    PubMed

    Guven, Zekiye P; Ustbas, Burcin; Harkness, Kellen M; Coskun, Hikmet; Joshi, Chakra P; Besong, Tabot M D; Stellacci, Francesco; Bakr, Osman M; Akbulut, Ozge

    2016-07-28

    Chiral mixed ligand silver nanoclusters were synthesized in the presence of a chiral and an achiral ligand. While the chiral ligand led mostly to the formation of nanoparticles, the presence of the achiral ligand drastically increased the yield of nanoclusters with enhanced chiral properties. PMID:27362744

  18. Synthesis of rhodium(III) complexes with tris/tetrakis-benzimidazoles and benzothiazoles--quick identification of cyclometallation by nuclear magnetic resonance spectroscopy.

    PubMed

    Chandrashekhar, N; Gayathri, V; Nanje Gowda, N M

    2009-08-01

    Reactions of rhodium(III) halides with multidentate N,S-heterocycles, (LH3) 1,3,5-tris(benzimidazolyl)benzene (L1H3; 1), 1,3,5-tris(N-methylbenzimidazolyl) benzene (L2H3; 2) and 1,3,5-tris(benzothiazolyl)benzene (L3H3; 3), in the molar ratio 1:1 in methanol-chloroform produced mononuclear cyclometallated products of the composition [RhX2(LH2)(H2O)] (X = Cl, Br, I; LH2 = L1H2, L2H2, L3H2). When the metal to ligand (1-3 or 1,2,4,5-tetrakis(benzothiazolyl)benzene [L4H2; 4]) molar ratio was 2:1, the reactions yielded binuclear complexes of the compositions [Rh2Cl5(LH2)(H2O)3] (LH2 = L1H2, L2H2, L3H2) and [Rh2X4(L4)(H2O)2] (X = Cl, Br, I). Elemental analysis, IR and 1H nuclear magnetic resonance (NMR) chemical shifts supported the binuclear nature of the complexes. Cyclometallation was detected by conventional 13C NMR spectra that showed a doublet around approximately 190 ppm. Cyclometallation was also detected by gradient-enhanced heteronuclear multiple bond correlation (g-HMBC) experiment that showed cross-peaks between the cyclometallated carbon and the central benzene ring protons of 1-3. Cyclometallation was substantiated by two-dimensional 1H-1H correlated experiments (gradient-correlation spectroscopy and rotating frame Overhauser effect spectroscopy) and 1H-13C single bond correlated two-dimensional NMR experiments (gradient-enhanced heteronuclear single quantum coherence). The 1H-15N g-HMBC experiment suggested the coordination of the heterocycles to the metal ion via tertiary nitrogen. PMID:19444858

  19. 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.

  20. 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

  1. 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.

  2. 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

  3. 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

  4. Dockomatic - automated ligand creation and docking

    PubMed Central

    2010-01-01

    Background The application of computational modeling to rationally design drugs and characterize macro biomolecular receptors has proven increasingly useful due to the accessibility of computing clusters and clouds. AutoDock is a well-known and powerful software program used to model ligand to receptor binding interactions. In its current version, AutoDock requires significant amounts of user time to setup and run jobs, and collect results. This paper presents DockoMatic, a user friendly Graphical User Interface (GUI) application that eases and automates the creation and management of AutoDock jobs for high throughput screening of ligand to receptor interactions. Results DockoMatic allows the user to invoke and manage AutoDock jobs on a single computer or cluster, including jobs for evaluating secondary ligand interactions. It also automates the process of collecting, summarizing, and viewing results. In addition, DockoMatic automates creation of peptide ligand .pdb files from strings of single-letter amino acid abbreviations. Conclusions DockoMatic significantly reduces the complexity of managing multiple AutoDock jobs by facilitating ligand and AutoDock job creation and management. PMID:21059259

  5. 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

  6. 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. PMID:15366904

  7. 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.

  8. Characteristic molecular vibrations of adenosine receptor ligands.

    PubMed

    Chee, Hyun Keun; Yang, Jin-San; Joung, Je-Gun; Zhang, Byoung-Tak; Oh, S June

    2015-02-13

    Although the regulation of membrane receptor activation is known to be crucial for molecular signal transduction, the molecular mechanism underlying receptor activation is not fully elucidated. Here we study the physicochemical nature of membrane receptor behavior by investigating the characteristic molecular vibrations of receptor ligands using computational chemistry and informatics methods. By using information gain, t-tests, and support vector machines, we have identified highly informative features of adenosine receptor (AdoR) ligand and corresponding functional amino acid residues such as Asn (6.55) of AdoR that has informative significance and is indispensable for ligand recognition of AdoRs. These findings may provide new perspectives and insights into the fundamental mechanism of class A G protein-coupled receptor activation. PMID:25622891

  9. Lanthanide clusters with azide capping ligands.

    PubMed

    Moore, Brian F; Emge, Thomas J; Brennan, John G

    2013-05-20

    Weakly binding azide ligands have been used as surface caps in the synthesis of lanthanide oxo and selenido clusters. Addition of NaN3 and Na2O to in situ prepared solutions of Ln(SePh)3 in pyridine results in the formation of (py)18Sm6Na2O2(N3)16 or (py)10Ln6O2(N3)12(SePh)2 (Ln = Ho, Er), with the Sm and Er compounds characterized by low temperature single crystal X-ray diffraction. Attempts to prepare chalcogenido derivatives by ligand-based redox reactions using elemental Se were successful in the preparation of (py)10Er6O2(SeSe)2(N3)10, a diselenido cluster having crystallographic disorder due to some site sharing of both SeSe and N3 ligands. These compounds all detonate when heated. PMID:23639142

  10. 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

  11. 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.

  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. Determination of Ligand Pathways in Globins

    PubMed Central

    Salter, Mallory D.; Blouin, George C.; Soman, Jayashree; Singleton, Eileen W.; Dewilde, Sylvia; Moens, Luc; Pesce, Alessandra; Nardini, Marco; Bolognesi, Martino; Olson, John S.

    2012-01-01

    Although molecular dynamics simulations suggest multiple interior pathways for O2 entry into and exit from globins, most experiments indicate well defined single pathways. In 2001, we highlighted the effects of large-to-small amino acid replacements on rates for ligand entry and exit onto the three-dimensional structure of sperm whale myoglobin. The resultant map argued strongly for ligand movement through a short channel from the heme iron to solvent that is gated by the distal histidine (His-64(E7)) near the solvent edge of the porphyrin ring. In this work, we have applied the same mutagenesis mapping strategy to the neuronal mini-hemoglobin from Cerebratulus lacteus (CerHb), which has a large internal tunnel from the heme iron to the C-terminal ends of the E and H helices, a direction that is 180° opposite to the E7 channel. Detailed comparisons of the new CerHb map with expanded results for Mb show unambiguously that the dominant (>90%) ligand pathway in CerHb is through the internal tunnel, and the major (>75%) ligand pathway in Mb is through the E7 gate. These results demonstrate that: 1) mutagenesis mapping can identify internal pathways when they exist; 2) molecular dynamics simulations need to be refined to address discrepancies with experimental observations; and 3) alternative pathways have evolved in globins to meet specific physiological demands. PMID:22859299

  15. MOESSBAUER EFFECT IN HEMOGLOBIN WITH DIFFERENT LIGANDS.

    PubMed

    GONSER, U; GRANT, R W; KREGZDE, J

    1964-02-14

    Recoil-free nuclear gamma-ray resonance adsorption was observed in the iron-57 of blood. The spectral parameters are dependent on the ligand bound to the iron atoms in hemoglobin. The results are interpreted in terms of isomeric shifts and quad rupole splittings. PMID:14081237

  16. Identification of ligands for bacterial sensor proteins.

    PubMed

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

    2016-02-01

    Bacteria have evolved a variety of different signal transduction mechanisms. However, the cognate signal molecule for the very large amount of corresponding sensor proteins is unknown and their functional annotation represents a major bottleneck in the field of signal transduction. The knowledge of the signal molecule is an essential prerequisite to understand the signalling mechanisms. Recently, the identification of signal molecules by the high-throughput protein screening of commercially available ligand collections using differential scanning fluorimetry has shown promise to resolve this bottleneck. Based on the analysis of a significant number of different ligand binding domains (LBDs) in our laboratory, we identified two issues that need to be taken into account in the experimental design. Since a number of LBDs require the dimeric state for ligand recognition, it has to be assured that the protein analysed is indeed in the dimeric form. A number of other examples demonstrate that purified LBDs can contain bound ligand which prevents further binding. In such cases, the apo-form can be generated by denaturation and subsequent refolding. We are convinced that this approach will accelerate the functional annotation of sensor proteins which will help to understand regulatory circuits in bacteria. PMID:26511375

  17. 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

  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. PMID:24927668

  19. Ligand configurational entropy and protein binding.

    PubMed

    Chang, Chia-en A; Chen, Wei; Gilson, Michael K

    2007-01-30

    The restriction of a small molecule's motion on binding to a protein causes a loss of configurational entropy, and thus a penalty in binding affinity. Some energy models used in computer-aided ligand design neglect this entropic penalty, whereas others account for it based on an expected drop in the number of accessible rotamers upon binding. However, the validity of the physical assumptions underlying the various approaches is largely unexamined. The present study addresses this issue by using Mining Minima calculations to analyze the association of amprenavir with HIV protease. The computed loss in ligand configurational entropy is large, contributing approximately 25 kcal/mol (4.184 kJ/kcal) to DeltaG degrees. Most of this loss results from narrower energy wells in the bound state, rather than a drop in the number of accessible rotamers. Coupling among rotation/translation and internal degrees of freedom complicates the decomposition of the entropy change into additive terms. The results highlight the potential to gain affinity by designing conformationally restricted ligands and have implications for the formulation of energy models for ligand scoring. PMID:17242351

  20. 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.

  1. Ligand configurational entropy and protein binding

    PubMed Central

    Chang, Chia-en A.; Chen, Wei; Gilson, Michael K.

    2007-01-01

    The restriction of a small molecule's motion on binding to a protein causes a loss of configurational entropy, and thus a penalty in binding affinity. Some energy models used in computer-aided ligand design neglect this entropic penalty, whereas others account for it based on an expected drop in the number of accessible rotamers upon binding. However, the validity of the physical assumptions underlying the various approaches is largely unexamined. The present study addresses this issue by using Mining Minima calculations to analyze the association of amprenavir with HIV protease. The computed loss in ligand configurational entropy is large, contributing ∼25 kcal/mol (4.184 kJ/kcal) to ΔG°. Most of this loss results from narrower energy wells in the bound state, rather than a drop in the number of accessible rotamers. Coupling among rotation/translation and internal degrees of freedom complicates the decomposition of the entropy change into additive terms. The results highlight the potential to gain affinity by designing conformationally restricted ligands and have implications for the formulation of energy models for ligand scoring. PMID:17242351

  2. 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.

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

    PubMed

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

    2011-07-01

    Bioinspired hydrogenation of N(2) 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 H(2) remains difficult. In analogy to the heterogeneously catalysed Haber-Bosch process, such a reaction is conceivable via metal-centred N(2) 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 H(2) 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. PMID:21697873

  4. 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

  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. PMID:26796765

  6. 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

  7. Affinity thermoprecipitatin: Contribution of the efficiency of ligand-protein interaction and access of the ligand.

    PubMed

    Galaev, I Y; Mattiasson, B

    1993-05-01

    Conjugates to two thermoprecipitating polymers, poly(N-vinyl caprolactam) and poly(N-isopropylacrylmide), with soybean trypsin inhibitor, Cibacron Blue 3GA, Cu-iminodiacetic acid, and p-aminobenzamidine were synthesized. The interaction of these conjugates with trypsin and lactate dehydrogenase was studied. Coupling of the ligand to a polymer resulted in a 100-1000-fold decrease in enzyme-affinity. Rough theoretical estimates revealed that a successful affinity precipitation required that the binding of a target protein and a ligand coupled to a polymer have binding constants on the order of 10(-7)-10(-8) M. Such strong affinity of low molecular weight ligands that can provide binding constants of 10(-9)-10(-11) M or alternatively multipoint attachment of the target protein molecule. The ligand in the ligand-polymer conjugate is still accessible to the protein after thermoprecipitation, and the latter can bind with the particle of the dispersion of thermoprecipitated ligand-polymer precipitate may result in stripping of enzyme molecules from the surface of the particles. PMID:18601296

  8. 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

  9. Amino Acids in Nine Ligand-Prefer Ramachandran Regions

    PubMed Central

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

    2015-01-01

    Several secondary structures, such as π-helix and left-handed helix, have been frequently identified at protein ligand-binding sites. A secondary structure is considered to be constrained to a specific region of dihedral angles. However, a comprehensive analysis of the correlation between main chain dihedral angles and ligand-binding sites has not been performed. We undertook an extensive analysis of the relationship between dihedral angles in proteins and their distance to ligand-binding sites, frequency of occurrence, molecular potential energy, amino acid composition, van der Waals contacts, and hydrogen bonds with ligands. The results showed that the values of dihedral angles have a strong preference for ligand-binding sites at certain regions in the Ramachandran plot. We discovered that amino acids preceding the ligand-prefer ϕ/ψ box residues are exposed more to solvents, whereas amino acids following ligand-prefer ϕ/ψ box residues form more hydrogen bonds and van der Waals contacts with ligands. Our method exhibited a similar performance compared with the program Ligsite-csc for both ligand-bound structures and ligand-free structures when just one ligand-binding site was predicted. These results should be useful for the prediction of protein ligand-binding sites and for analysing the relationship between structure and function. PMID:26491686

  10. Protein Ligand Complex Guided Approach for Virtual Screening.

    PubMed

    Karthikeyan, Muthukumarasamy; Pandit, Deepak; Vyas, Renu

    2015-01-01

    The target ligand association data is a rich source of information which is not exploited enough for drug design efforts in virtual screening. A java based open-source toolkit for Protein Ligand Network Extraction (J-ProLiNE) focused on protein-ligand complex analysis with several features integrated in a distributed computing network has been developed. Sequence alignment and similarity search components have been automated to yield local, global alignment scores along with similarity and distance scores. 10000 proteins with co-crystallized ligands from pdb and MOAD databases were extracted and analyzed for revealing relationships between targets, ligands and scaffolds. Through this analysis, we could generate a protein ligand network to identify the promiscuous and selective scaffolds for multiple classes of proteins targets. Using J-ProLiNE we created a 507 x 507 matrix of protein targets and native ligands belonging to six enzyme classes and analyzed the results to elucidate the protein-protein, protein-ligand and ligand-ligand interactions. In yet another application of the J-ProLiNE software, we were able to process kinase related information stored in US patents to construct disease-gene-ligand-scaffold networks. It is hoped that the studies presented here will enable target ligand knowledge based virtual screening for inhibitor design. PMID:26138572

  11. 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. PMID:26551690

  12. 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

  13. [Opioid receptors and their selective ligands].

    PubMed

    Piestrzeniewicz, Mariola Katarzyna; Fichna, Jakub; Michna, Jakub; Janecka, Anna

    2006-01-01

    Opioid receptors (micro, delta, and kappa) belong to a large family of G protein-coupled receptors and play an important physiological role. Stimulation of these receptors triggers analgesic effects and affects the function of gastrointestinal tract. The discovery of opioid peptides, which are endogenous ligands of opioid receptors, including delta-selective enkephalins, kappa-selective dynorphins, and micro-selective endomorphins, initiated their structure-activity relationship studies. For the last 30 years, hundreds of analogs of opioid peptides have been synthesized in an effort to obtain the compounds more active, selective, and resistant to biodegradation than the endogenous ligands. Different unnatural amino acids, as well as cyclisation procedures, leading to conformationaly restricted analogs, were employed. All these modifications resulted in obtaining very selective agonists and antagonists with high affinity at micro-, dlta-, and kappa-opioid receptors, which are extremely useful tools in further studies on the pharmacology of opioid receptors in a mammalian organism. PMID:17201067

  14. Enhanced ligand sampling for relative protein-ligand binding free energy calculations.

    PubMed

    Kaus, Joseph W; McCammon, J Andrew

    2015-05-21

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

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

    PubMed Central

    2016-01-01

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

  16. Container molecules based on imine type ligands.

    PubMed

    Schulze, A Carina; Oppel, Iris M

    2012-01-01

    This chapter will give a short overview about container molecules, their synthesis and possible applications. The main focus is on those which are based on imine type ligands. These containers can be used for example for guest exchange, gas separation, as chemical sensors or for the stabilisation of white phosphorus under water. The described cages have wide openings or tightly closed ones. For one cage the reversible opening and closing is also described. PMID:22076078

  17. Inhaled innate immune ligands to prevent pneumonia

    PubMed Central

    Evans, Scott E; Tuvim, Michael J; Fox, Cory J; Sachdev, Nidhi; Gibiansky, Leonid; Dickey, Burton F

    2011-01-01

    Epithelial surfaces throughout the body continuously sample and respond to environmental stimuli. The accessibility of lung epithelium to inhaled therapies makes it possible to stimulate local antimicrobial defences with aerosolized innate immune ligands. This strategy has been shown to be effective in preclinical models, as delivery of innate immune ligands to the lungs of laboratory animals results in protection from subsequent challenge with microbial pathogens. Survival of the animal host in this setting correlates directly with killing of pathogens within the lungs, indicating the induction of a resistance mechanism. Resistance appears to be mediated primarily by activated epithelial cells rather than recruited leucocytes. Resistance reaches a peak within hours and persists for several days. Innate immune ligands can interact synergistically under some circumstances, and synergistic combinations of innate ligands delivered by aerosol are capable of inducing a high level of broad host resistance to bacteria, fungi and viruses. The induction of innate antimicrobial resistance within the lungs could have clinical applications in the prevention of lower respiratory tract infection in subjects transiently at high risk. These include cancer patients undergoing myeloablative chemotherapy, intubated patients being mechanically ventilated, vulnerable individuals during seasonal influenza epidemics, asthmatic subjects experiencing a respiratory viral infection, and healthy subjects exposed to virulent pathogens from a bioterror attack or emergent pandemic. In summary, stimulation of the lung epithelium to induce localized resistance to infection is a novel strategy whose clinical utility will be assessed in the near future. LINKED ARTICLES This article is part of a themed issue on Respiratory Pharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.163.issue-1 PMID:21250981

  18. 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

  19. 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

  20. Targeting Selectins and Their Ligands in Cancer.

    PubMed

    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. 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.

  2. 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.

  3. Ligand binding and hexacoordination in synechocystis hemoglobin.

    PubMed

    Hvitved, A N; Trent, J T; Premer, S A; Hargrove, M S

    2001-09-14

    A large and phylogenetically diverse group of organisms contain truncated hemoglobins, including the unicellular cyanobacterium Synechocystis (Pesce, A., Couture, M., Dewilde, S., Guertin, M., Yamauchi, K., Ascenzi, P., Moens, L., and Bolognesi, M. (2000) EMBO J. 19, 2424-2434). Synechocystis hemoglobin is also hexacoordinate, with a heme pocket histidine that reversibly coordinates the ligand binding site. Hexacoordinate hemoglobins are ubiquitous in plants and are now being identified in a diverse array of organisms including humans (Arredondo-Peter, R., Hargrove, M. S., Moran, J. F., Sarath, G., and Klucas, R. V. (1998) Plant Physiol. 118, 1121-1125; Trent, J. T., III, Watts, R. A., and Hargrove, M. S. (2001) J. Biol. Chem. 276, 30106-30110). Rate constants for association and dissociation of the hexacoordinating amino acid side chain in Synechocystis hemoglobin have been measured along with bimolecular rate constants for association of oxygen and carbon monoxide following laser flash photolysis. These values were compared with ligand binding initiated by rapid mixing. Site-directed mutagenesis was used to determine the roles of several heme pocket amino acids in facilitating hexacoordination and stabilizing bound oxygen. It is demonstrated that Synechocystis hemoglobin contains a very reactive binding site and that ligand migration through the protein is rapid. Rate constants for hexacoordination by His(46) are also large and facilitated by other heme pocket amino acids including Gln(43). PMID:11438545

  4. Assessment of automatic ligand building in ARP/wARP

    SciTech Connect

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

    2007-01-01

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

  5. A Annealing Algorithm for Designing Ligands from Receptor Structures.

    NASA Astrophysics Data System (ADS)

    Zielinski, Peter J.

    DEenspace NOVO, a simulated annealing method for designing ligands is described. At a given temperature, ligand fragments are randomly selected and randomly placed within the given receptor cavity, often replacing existing ligand fragments. For each new ligand fragment combination, bonded, nonbonded, polarization and solvation energies of the new ligand-receptor system are compared to the previous system. Acceptance or rejection of the new system is decided using the Boltzmann distribution. Thus, energetically unfavorable fragment switches are sometimes accepted, sacrificing immediate energy gains in the interest of finding the system with the globally minimum energy. By lowering the temperature, the rate of unfavorable switches decreases and energetically favorable combinations become difficult to change. The process is halted when the frequency of switches becomes too small. As a test of the method, DEenspace NOVO predicted the positions of important ligand fragments for neuraminidase that are in accord with the natural ligand, sialic acid.

  6. Monovalent indium in a sulfur-rich coordination environment: synthesis, structure and reactivity of tris(2-mercapto-1-tert-butylimidazolyl)hydroborato indium, [TmBut]In.

    PubMed

    Yurkerwich, Kevin; Buccella, Daniela; Melnick, Jonathan G; Parkin, Gerard

    2008-07-28

    [Tm(Bu(t))]In, the first structurally-characterized monovalent indium compound that features a sulfur-rich coordination environment, has been synthesized via treatment of InCl with [Tm(Bu(t))]K; in contrast to the thallium counterpart, the lone pair of [Tm(Bu(t))]In is a site of reactivity, thereby allowing formation of [Tm(Bu(t))]In-->B(C(6)F(5))(3) and [Tm(Bu(t))]In(kappa(2)-S(4)) upon treatment with B(C(6)F(5))(3) and S(8), respectively. PMID:18622452

  7. Synthesis, anti-inflammatory, analgesic, COX-1/2 inhibitory activities and molecular docking studies of substituted 2-mercapto-4(3H)-quinazolinones.

    PubMed

    Abdel-Aziz, Alaa A-M; Abou-Zeid, Laila A; ElTahir, Kamal Eldin H; Ayyad, Rezk R; El-Sayed, Magda A-A; El-Azab, Adel S

    2016-10-01

    A new series of 2-substituted mercapto-4(3H)-quinazolinone 1-26 were synthesized and assessed for in vivo anti-inflammatory and analgesic activities and in vitro inhibition of cyclooxygenase COX-1/COX-2. A new series of 2-substituted mercapto-4(3H)-quinazolinone 1-26 were synthesized and assessed for in vivo anti-inflammatory and analgesic activities. The potent anti-inflammatory compounds were subjected to in vitro cyclooxygenase COX-1/COX-2 inhibition assays. Compounds 1, 3, 5, 11, 12, 13, 15, 17, and 25 exhibited potent anti-inflammatory effects, with half-maximal effective dose (ED50) values of 65.7-102.4 mg/kg, (0.16-0.36 mmol/kg), and strong analgesic activities, with ED50 values of 33.3-104.6 mg/kg, (0.07-0.34 mmol/kg). These values were compared with those of diclofenac sodium [ED50 values: 112.2 and 100.4 mg/kg, (0.35 and 0.31 mmol/kg)], and celecoxib [ED50 values: 84.3 and 71.6 mg/kg (0.22 and 0.19 mmol/kg)], respectively as reference drugs. Compounds 1, 11, 12, 13, 15, 17, and 25 exhibited effective COX-2 inhibitory activity, with half-maximal inhibitor concentration (IC50) values of 0.70-2.0 μM and selectivity index (SI) values of more than 50-142.9 compared with celecoxib as reference drugs (IC50 = 0.30 μM and COX-2 SI: >333). Potent COX-2 inhibitors, i.e., compounds 15, 11, and 17 were docked into the binding site pockets of COX-1 and COX-2. These compounds exhibited strong interactions at the COX-2 binding site and poor interactions at COX-1 active site pocket. PMID:27318118

  8. 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

  9. 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

  10. Quantification of ligand bias for clinically relevant β2-adrenergic receptor ligands: implications for drug taxonomy.

    PubMed

    van der Westhuizen, Emma T; Breton, Billy; Christopoulos, Arthur; Bouvier, Michel

    2014-03-01

    The concepts of functional selectivity and ligand bias are becoming increasingly appreciated in modern drug discovery programs, necessitating more informed approaches to compound classification and, ultimately, therapeutic candidate selection. Using the β2-adrenergic receptor as a model, we present a proof of concept study that assessed the bias of 19 β-adrenergic ligands, including many clinically used compounds, across four pathways [cAMP production, extracellular signal-regulated kinase 1/2 (ERK1/2) activation, calcium mobilization, and receptor endocytosis] in the same cell background (human embryonic kidney 293S cells). Efficacy-based clustering placed the ligands into five distinct groups with respect to signaling signatures. In some cases, apparent functional selectivity originated from off-target effects on other endogenously expressed adrenergic receptors, highlighting the importance of thoroughly assessing selectivity of the responses before concluding receptor-specific ligand-biased signaling. Eliminating the nonselective compounds did not change the clustering of the 10 remaining compounds. Some ligands exhibited large differences in potency for the different pathways, suggesting that the nature of the receptor-effector complexes influences the relative affinity of the compounds for specific receptor conformations. Calculation of relative effectiveness (within pathway) and bias factors (between pathways) for each of the compounds, using an operational model of agonism, revealed a global signaling signature for all of the compounds relative to isoproterenol. Most compounds were biased toward ERK1/2 activation over the other pathways, consistent with the notion that many proximal effectors converge on this pathway. Overall, we demonstrate a higher level of ligand texture than previously anticipated, opening perspectives for the establishment of pluridimensional correlations between signaling profiles, drug classification, therapeutic efficacy, and

  11. p-Tolylimido rhenium(v) complexes with phenolate-based ligands: synthesis, X-ray studies and catalytic activity in oxidation with tert-butylhydroperoxide.

    PubMed

    Gryca, Izabela; Machura, Barbara; Małecki, Jan Grzegorz; Kusz, Joachim; Shul'pina, Lidia S; Ikonnikov, Nikolay S; Shul'pin, Georgiy B

    2016-01-01

    The reactions of mer-[Re(p-NTol)X3(PPh3)2] (X = Cl, Br) with chelating phenolate-based ligands (2-(2-hydroxy-5-methylphenyl)benzotriazole (HL(1)), 2-(2-hydroxyphenyl)benzothiazole (HL(2)) or 2-(2-hydroxyphenyl)benzoxazole (HL(3))) afforded a series of p-tolylimido rhenium(v) complexes cis- or trans-(X,X)-[Re(p-NTol)X2(L)(PPh3)]·yMeCN (where X = Cl, Br; L = L(1), L(2), L(3) and y = 0-2) and [Re(p-NTol)X(L)(PPh3)2]Z·pPPh3 (where X = Cl, Br; Z = ReO4, PF6; L = L(1), L(2), L(3) and p = 0 or 1). The reported compounds were characterized by elemental analysis, FT-IR, NMR ((1)H, (13)C and (31)P) and X-ray crystallography. Interestingly, the halide ions of [Re(p-NTol)Cl2(L(1))(PPh3)]·MeCN (1) and [Re(p-NTol)Cl2(L(2))(PPh3)]·2MeCN (3) are in cis relative dispositions, whereas the complexes [Re(p-NTol)Br2(L)(PPh3)] (L(1) for 2, L(2) for 4 and L(3) for 6) and [Re(p-NTol)Cl2(L(3))(PPh3)] (5) were found to be trans-(X,X) isomers. The compounds [Re(p-NTol)X(L)(PPh3)2](PF6) (X = Cl, Br; L = L(1) and L(2)) and [Re(p-NTol)X(L(3))(PPh3)2](PF6)·PPh3 (X = Cl, Br) have been tested in oxidative catalysis. A few compounds exhibited very good catalytic properties in oxidation of alcohols with tert-BuOOH (TBHP) in acetonitrile solution at moderate temperatures. Complex [Re(p-NTol)Cl(L(2))(PPh3)2]PF6 (13) is the catalyst of choice for oxidation of 1-phenylethanol to acetophenone (in 80% yield; turnover number attained 290 after 30 h) and cyclooctanol to cyclooctanone (in 88% yield). Notably lower activity has been found in the oxidation of alkanes with TBHP. Product distribution in the oxidation of methylcyclohexane indicates some steric hindrance around the reaction center. PMID:26618894

  12. Synthesis and Photophysical Studies of Iridium Complexes Having Different Ligands

    NASA Astrophysics Data System (ADS)

    Rho, Hyeon Hee; Park, Gui Youn; Ha, Yunkyoung; Kim, Young Sik

    2006-01-01

    The synthesis and photophysical study of efficient phosphorescent iridium(III) complexes having two different (C∧N) ligands are reported. In order to improve the luminescence efficiency by avoiding triplet-triplet (T-T) annihilation, the iridium complexes, Ir(ppy)2(piq) and Ir(ppy)2(piq-F), are designed and prepared where ppy, piq and piq-F represent 2-phenylpyridine, 1-(phenyl)isoquinoline and 2-(4'-fluorophenyl)isoquinoline, respectively. Two ppy ligands and a piq derivative act as a source of energy supply and a piq derivative acts as a chromophore. Since Ir(ppy)3, Ir(piq)3 and Ir(piq-F)3 can be placed in the metal-to-ligand charge transfer (MLCT) excited state, they absorb light effectively. When Ir(ppy)2(piq-F) is placed in excited state, the excitation energy is neither quenched nor deactivated but quickly intramolecular transferred from two ppy ligands to one luminescent piq-F ligand. This can occure because the triplet energy level of ppy is higher than that of piq-F and light is emitted from piq-F ligand in the end. Thus, Ir(ppy)2(piq-F) shows strong photoluminescence originated from piq-F ligand because piq-F ligand is known to have a shorter lifetime than that of ppy ligand. To analyze luminescent mechanism, we calculated these complexes having two different ligand sets theoretically by using computational method.

  13. Including Ligand Induced Protein Flexibility into Protein Tunnel Prediction

    PubMed Central

    Kingsley, Laura J.; Lill, Markus A.

    2014-01-01

    In proteins with buried active sites, understanding how ligands migrate through the tunnels that connect the exterior of the protein to the active site can shed light on substrate specificity and enzyme function. A growing body of evidence highlights the importance of protein flexibility in the binding site upon ligand binding; however, the influence of protein flexibility throughout the body of the protein during ligand entry and egress is much less characterized. We have developed a novel tunnel prediction and evaluation method named IterTunnel, which includes the influence of ligand-induced protein flexibility, guarantees ligand egress, and provides detailed free energy information as the ligand proceeds along the egress route. IterTunnel combines geometric tunnel prediction with steered MD in an iterative process to identify tunnels that open as a result of ligand migration and calculates the potential of mean force (PMF) of ligand egress through a given tunnel. Applying this new method to cytochrome P450 2B6 (CYP2B6), we demonstrate the influence of protein flexibility on the shape and accessibility of tunnels. More importantly, we demonstrate that the ligand itself, while traversing through a tunnel, can reshape tunnels due to its interaction with the protein. This process results in the exposure of new tunnels and the closure of pre-existing tunnels as the ligand migrates from the active site. PMID:25043499

  14. 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

  15. (Ligand intermediates in metal-catalyzed reactions)

    SciTech Connect

    Not Available

    1992-01-01

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

  16. Transmutable nanoparticles with reconfigurable surface ligands.

    PubMed

    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. PMID:26912697

  17. Helix-helix interfaces and ligand binding.

    PubMed

    Kurochkina, Natalya; Choekyi, Tsering

    2011-08-21

    Helix-helix parallel interfaces can be characterized by certain combinations of amino acids, which repeatedly occur at core positions a and d (leucine zipper nomenclature) in homologous and nonhomologous proteins and influence interhelical angles. Applied for the prediction of interhelical angles in glutathione S-transferase, intracellular chloride channel and annexin molecules from various sources, correct results were achieved in 58 out of 62 proteins. Interhelical angles are found to correlate with the conformation of the glutathione S-transferase ligands glutathione, s-hexylglutathione, glutathione sulfonic acid, and glutathione-s-dinitrobenzene. PMID:21620863

  18. 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.

  19. New ligands for the asymmetric dihydroxylation

    SciTech Connect

    Becker, H.; King, S.B.; Richardson, P.

    1995-12-31

    The asymmetric dibydroxylation of olefins in the presence of cinchona alkaloid derivatives (the AD reaction) has proven to be a reliable method in organic syntheses. For most olefins, the enantioselectivities using the {open_quotes}standard{close_quotes} phathalazine ligands are excellent; however, facial selectivity is still moderate for some olefins. 2,3-Diphenyl pyrazinopyridazine (DPP) and anthraquinone (AQN) as spacers for the {open_quotes}pseudo enantiomeric{close_quotes} alkaloids dihydroquinidine (DHQD) or dihydroquinine (DHQ) give superior enantioselectivities for almost all olefins.

  20. 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

  1. Is cyanide really a strong-field ligand?

    PubMed

    Nakamura, Mikio

    2009-01-01

    Iron man or weakling? Ligand-field strengths are conveniently expressed by the empirical spectrochemical series. Although cyanide has been deeply entrenched as a strong-field ligand, a couple of recent examples cast doubt toward the position of this ligand, namely the high-spin (S = 2) states of [Cr(II)(CN)(5)](3-) and [Fe(II)(tpp)(CN)](-). tpp = meso-tetraphenylporphinate. PMID:19222066

  2. 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.

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

    SciTech Connect

    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.

  4. 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

  5. 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

  6. The first nitro-substituted heteroscorpionate ligand.

    PubMed

    Pellei, Maura; Benetollo, Franco; Lobbia, Giancarlo Gioia; Alidori, Simone; Santini, Carlo

    2005-02-21

    The new dihydridobis(3-nitro-1,2,4-triazolyl)borate ligand, [H2B(tzNO2)2]-, has been synthesized in dimethylacetamide solution, using 3-nitro-1,2,4-triazole and KBH4 through careful temperature control, and characterized as its potassium salt. The zinc(II) and cadmium(II) complexes, {M[H2B(tzNO2)2]Cl(H2O)2}, have been prepared by metathesis of [H2B(tzNO2)2]K with ZnCl2 and CdCl2, respectively. The complexes likely contain a metal core in which the ligand is coordinated to the metal ions in the K2-N,N' or K4-N,N',O,O' fashion. A single-crystal structural characterization is reported for the potassium dihydrobis(3-nitro-1,2,4-triazolyl)borate. The potassium salt is polymeric and shows several K...N and K...O interactions. PMID:15859260

  7. 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

  8. 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.

  9. 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

  10. 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

  11. 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.

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

    SciTech Connect

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

    2009-01-01

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

  13. 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

  14. 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.

  15. Synthesis, crystal structures and characterization of late first row transition metal complexes derived from benzothiazole core: anti-tuberculosis activity and special emphasis on DNA binding and cleavage property.

    PubMed

    Netalkar, Priya P; Netalkar, Sandeep P; Budagumpi, Srinivasa; Revankar, Vidyanand K

    2014-05-22

    Air and moisture stable coordination compounds of late first row transition metals, viz. Co(II), Ni(II), Cu(II) and Zn(II), with a newly designed ligand, 2-(2-benzo[d]thiazol-2-yl)hydrazono)propan-1-ol (LH), were prepared and successfully characterized using various spectro-analytical techniques. The molecular structures of the ligand and nickel complex were unambiguously determined by single-crystal X-ray diffraction method. The [Ni(LH)2]Cl2.3H2O complex is stabilized by intermolecular CH⋯π stacking interactions between the methyl hydrogen and the C18 atom of the phenyl ring (C11-H11B⋯C18) forming 1D zig-zag chain structure. Both, the ligand and its copper complex, were electrochemically active in the working potential range, showing quasi-reversible redox system. The interactions of all the compounds with calf thymus DNA have been comprehensively investigated using electronic absorption spectroscopy, viscosity, electrochemistry and thermal denaturation studies. The cleavage reaction on pBR322 DNA has been monitored by agarose gel electrophoresis. The results showed that the ligand can bind to CT-DNA through partial intercalation, whereas the complexes bind electrostatically. Further, [Ni(LH)2]Cl2.3H2O and [CuLCl(H2O)2] complexes in the series have high binding and cleavage affinity towards pBR322 DNA. Additionally, all the compounds were screened for anti-tuberculosis activity. All the complexes revealed an MIC value of 0.8 μg/mL, which is almost 8 times active than standard used (Streptomycin, 6.25 μg/mL). PMID:24721314

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

    PubMed

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

    2016-03-01

    The ligand capping of phosphonic acid functionalized CdSe/ZnS core-shell quantum dots (QDs) was investigated with a combination of solution and solid-state (31) P nuclear magnetic resonance (NMR) spectroscopy. Two phosphonic acid ligands were used in the synthesis of the QDs, tetradecylphosphonic acid and ethylphosphonic acid. Both alkyl phosphonic acids showed broad liquid and solid-state (31) P NMR resonances for the bound ligands, indicative of heterogeneous binding to the QD surface. In order to quantify the two ligand populations on the surface, ligand exchange facilitated by phenylphosphonic acid resulted in the displacement of the ethylphosphonic acid and tetradecylphosphonic acid and allowed for quantification of the free ligands using (31) P liquid-state NMR. After washing away the free ligand, two broad resonances were observed in the liquids' (31) P NMR corresponding to the alkyl and aromatic phosphonic acids. The washed samples were analyzed via solid-state (31) P NMR, which confirmed the ligand populations on the surface following the ligand exchange process. Copyright © 2015 John Wiley & Sons, Ltd. PMID:26639792

  17. 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

  18. 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

  19. Pathways of ligand clearance in acetylcholinesterase by multiple copy sampling.

    PubMed

    Van Belle, D; De Maria, L; Iurcu, G; Wodak, S J

    2000-05-12

    The clearance of seven different ligands from the deeply buried active-site of Torpedo californica acetylcholinesterase is investigated by combining multiple copy sampling molecular dynamics simulations, with the analysis of protein-ligand interactions, protein motion and the electrostatic potential sampled by the ligand copies along their journey outwards. The considered ligands are the cations ammonium, methylammonium, and tetramethylammonium, the hydrophobic methane and neopentane, and the anionic product acetate and its neutral form, acetic acid. We find that the pathways explored by the different ligands vary with ligand size and chemical properties. Very small ligands, such as ammonium and methane, exit through several routes. One involves the main exit through the mouth of the enzyme gorge, another is through the so-called back door near Trp84, and a third uses a side door at a direction of approximately 45 degrees to the main exit. The larger polar ligands, methylammonium and acetic acid, leave through the main exit, but the bulkiest, tetramethylammonium and neopentane, as well as the smaller acetate ion, remain trapped in the enzyme gorge during the time of the simulations. The pattern of protein-ligand contacts during the diffusion process is highly non-random and differs for different ligands. A majority is made with aromatic side-chains, but classical H-bonds are also formed. In the case of acetate, but not acetic acid, the anionic and neutral form, respectively, of one of the reaction products, specific electrostatic interactions with protein groups, seem to slow ligand motion and interfere with protein flexibility; protonation of the acetate ion is therefore suggested to facilitate clearance. The Poisson-Boltzmann formalism is used to compute the electrostatic potential of the thermally fluctuating acetylcholinesterase protein at positions actually visited by the diffusing ligand copies. Ligands of different charge and size are shown to sample

  20. 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

  1. 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

  2. Rational design of class I MHC ligands

    NASA Astrophysics Data System (ADS)

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

    1995-04-01

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

  3. 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. PMID:25443729

  4. 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.

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

    PubMed

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

    2016-06-23

    Small molecules are powerful tools for investigating protein function and can serve as leads for new therapeutics. Most human proteins, however, lack small-molecule ligands, and entire protein classes are considered 'undruggable'. Fragment-based ligand discovery can identify small-molecule probes for proteins that have proven difficult to target using high-throughput screening of complex compound libraries. Although reversibly binding ligands are commonly pursued, covalent fragments provide an alternative route to small-molecule probes, including those that can access regions of proteins that are difficult to target through binding affinity alone. Here we report a quantitative analysis of cysteine-reactive small-molecule fragments screened against thousands of proteins in human proteomes and cells. Covalent ligands were identified for >700 cysteines found in both druggable proteins and proteins deficient in chemical probes, including transcription factors, adaptor/scaffolding proteins, and uncharacterized proteins. Among the atypical ligand-protein interactions discovered were compounds that react preferentially with pro- (inactive) caspases. We used these ligands to distinguish extrinsic apoptosis pathways in human cell lines versus primary human T cells, showing that the former is largely mediated by caspase-8 while the latter depends on both caspase-8 and -10. Fragment-based covalent ligand discovery provides a greatly expanded portrait of the ligandable proteome and furnishes compounds that can illuminate protein functions in native biological systems. PMID:27309814

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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

  12. 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.

  13. DE NOVO DESIGN OF LIGANDS FOR METAL SEPARATION

    EPA Science Inventory

    This application focuses on the development of appropriate computation tools and parameters for the de novo design of selective metal ligands. We have developed a successful suite of tools for computer-aided design of ligands for receptors of known three-dimensional structure (st...

  14. A three-coordinate iron-silylene complex stabilized by ligand-ligand dispersion forces.

    PubMed

    Hänninen, Mikko M; Pal, Kuntal; Day, Benjamin M; Pugh, Thomas; Layfield, Richard A

    2016-07-28

    The structural and bonding properties of a three-coordinate N-heterocyclic silyene (NHSi) complex of the iron(ii) amide [Fe{N(SiMe3)2}2] are reported. Computational studies reveal that dispersion forces between the amido SiMe3 substituents and the isopropyl substituents on the NHSi ligand significantly enhance the stability of the complex, along with Fe-to-Si π-backbonding. PMID:27362948

  15. Enhancement of surface ligand display on PLGA nanoparticles with amphiphilic ligand conjugates

    PubMed Central

    Park, Jason; Mattessich, Thomas; Jay, Steven M.; Agawu, Atu; Saltzman, W. Mark; Fahmy, Tarek M.

    2013-01-01

    Biodegradable polymeric nanoparticles are widely recognized as efficacious drug delivery vehicles, yet the rational engineering of nanoparticle surfaces in order to improve biodistribution, reduce clearance, and/or improve targeting remains a significant challenge. We have previously demonstrated that an amphiphilic conjugate of avidin and palmitic acid can be used to modify poly(lactic-co-glycolic acid) (PLGA) particle surfaces to display functional avidin groups, allowing for the facile attachment of biotinylated ligands for targeting or steric stabilization. Here, we hypothesized that the incorporation, density, and stability of surface-presented avidin could be modulated through varying the lipophilicity of its fatty acid conjugate partner. We tested this hypothesis by generating a set of novel conjugates incorporating avidin and common fatty acids. We found that conjugation to linoleic acid resulted in a ∼60% increase in the incorporation of avidin on the nanoparticle surface compared to avidin–palmitic acid, which exhibited the highest avidin incorporation in previous studies. Further, the linoleic acid–avidin conjugate yielded nanoparticles with enhanced ability to bind biotinylated ligands compared to the previous method; nanoparticles modified with avidin–linoleic acid bound ∼170% more biotin–HRP than those made with avidin–palmitic acid and ∼1300% more than particles made without conjugated avidin. Most critically, increased ligand density on anti-CD4-targeted nanoparticles formulated with the linoleic acid–avidin conjugate resulted in a 5% increase in binding of CD4+ T cells. Thus we conclude that the novel avidin–linoleic acid conjugate facilitates enhanced ligand density on PLGA nanoparticles, resulting in functional enhancement of cellular targeting. PMID:21723893

  16. 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

  17. 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. PMID:25801825

  18. 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

  19. 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.

  20. 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

  1. 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

  2. Metrical oxidation states of 2-amidophenoxide and catecholate ligands: structural signatures of metal-ligand π bonding in potentially noninnocent ligands.

    PubMed

    Brown, Seth N

    2012-02-01

    Catecholates and 2-amidophenoxides are prototypical "noninnocent" ligands which can form metal complexes where the ligands are best described as being in the monoanionic (imino)semiquinone or neutral (imino)quinone oxidation state instead of their closed-shell dianionic form. Through a comprehensive analysis of structural data available for compounds with these ligands in unambiguous oxidation states (109 amidophenolates, 259 catecholates), the well-known structural changes in the ligands with oxidation state can be quantified. Using these correlations, an empirical "metrical oxidation state" (MOS) which gives a continuous measure of the apparent oxidation state of the ligand can be determined based on least-squares fitting of its C-C, C-O, and C-N bond lengths to this single parameter (a simple procedure for doing so is provided via a spreadsheet in the Supporting Information). High-valent d(0) metal complexes, particularly those of vanadium(V) and molybdenum(VI), have ligands with unexpectedly positive, and generally nonintegral, MOS values. The structural effects in these complexes are attributed not to electron transfer, but rather to amidophenoxide- or catecholate-to-metal π bonding, an interpretation supported by the systematic variation of the MOS values as a function of the degree of competition with the other π-donating groups in the structures. PMID:22260321

  3. 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

  4. 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.

  5. 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.

  6. Metal-ligand cooperation in H2 activation with iron complexes bearing hemilabile bis(diphenylphosphino)amine ligands.

    PubMed

    Frank, Nicolas; Hanau, Katharina; Langer, Robert

    2014-10-20

    The octahedral transition-metal complex [(dppa)Fe(Ph2P-N-PPh2)2] (1) [dppa = bis(diphenylphosphino)amine] with homofunctional bidentate ligands is described. The ligand exhibits hemilability due to its small bite angle and the steric repulsion of the coordinated donor groups. As the {Ph2P-N-PPh2}(-) ligand can act as an internal base, heterolytic cleavage of dihydrogen by complex 1 leads to the formation of the hydride complex [(dppa)(Ph2P-N-PPh2)Fe(H)(κ(1)-Ph2P-NH-PPh2)2] (2), representing an example of cooperative bond activation with a homofunctional hemilabile ligand. This study demonstrates that hemilability of homofunctionalized ligands can be affected by careful adjustment of geometric parameters. PMID:25290535

  7. Development and validation of a novel protein-ligand fingerprint to mine chemogenomic space: application to G protein-coupled receptors and their ligands.

    PubMed

    Weill, Nathanael; Rognan, Didier

    2009-04-01

    The present study introduces a novel low-dimensionality fingerprint encoding both ligand and target properties which is suitable to mine protein-ligand chemogenomic space. Whereas ligand properties have been represented by standard descriptors, protein cavities are encoded by a fixed length bit string describing pharmacophoric properties of a definite number of binding site residues. In order to simplify the cavity fingerprint, the concept was applied here to a unique family of targets (G protein-coupled receptors) with a homogeneous cavity description. Particular attention was given to set up data sets of really diverse protein-ligand pairs covering as exhaustively as possible both ligand and target spaces. Several machine learning classification algorithms were trained on two sets of roughly 200000 receptor-ligand fingerprints with a different definition of inactive decoys. Cross-validated models show excellent precision (>0.9) in distinguishing true from false pairs with a particular preference for support vector machine classifiers. When applied to two external test sets of GPCR ligands, the most predictive models were not those performing the best in the previous cross-validation. The ability to recover true GPCR ligands (ligand prediction mode) or true GPCRs (receptor prediction mode) depends on multiple parameters: the molecular complexity of the ligands, the chemical space from which ligand decoys are selected to generate false protein-ligand pairs, and the target space under consideration. In most cases, predicting ligands is easier than predicting receptors. Although receptor profiling is possible, it probably requires a more detailed description of the ligand-binding site. Noteworthy, protein-ligand fingerprints outperform the corresponding ligand fingerprints in mining the GPCR-ligand space. Since they can be applied to a much larger number of receptors than ligand-based fingerprints, protein-ligand fingerprints represent a novel and promising way to

  8. 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.

  9. 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

  10. 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

  11. 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.

  12. 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

  13. 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

  14. 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

  15. Serum concentrations of Flt-3 ligand in rheumatic diseases.

    PubMed

    Nakamura, Kayo; Nakatsuka, Noriko; Jinnin, Masatoshi; Makino, Takamitsu; Kajihara, Ikko; Makino, Katsunari; Honda, Noritoshi; Inoue, Kuniko; Fukushima, Satoshi; Ihn, Hironobu

    2015-10-01

    Fms-like tyrosine kinase 3 (Flt-3) is a cytokine receptor expressed on the surface of bone-marrow progenitor of hematopoietic cells. Flt-3 ligands are produced by peripheral blood mononuclear cells, and found in various human body fluids. Flt-3 signal is involved in the regulation of vessel formation as well as B cell differentiation, suggesting that Flt-3 signal contributes to the pathogenesis of vascular abnormalities and immune dysregulation in rheumatic diseases. The aim of the present study is to examine serum Flt-3 ligand levels in patients with various rheumatic diseases, and to evaluate the possibility that serum Flt-3 ligand levels can be a useful disease marker. Sera were obtained from 20 dermatomyositis (DM) patients, 36 systemic sclerosis (SSc) patients, 10 systemic lupus erythematosus (SLE) patients, 10 scleroderma spectrum disorder (SSD) patients, 4 mixed connective tissue disease (MCTD) patients, and 12 normal subjects. Flt-3 ligand levels were determined with ELISA. Serum Flt-3 ligand levels were significantly elevated in patients with DM, SSc, SSD and MCTD compared to those in normal subjects. DM patients with elevated Flt-3 ligand levels were accompanied with significantly increased CRP levels and increased frequency of heliotrope rash than those with normal levels. In addition, SSc patients with elevated Flt-3 ligand levels showed significantly reduced frequency of nailfold bleeding. Serum Flt-3 ligand levels can be a marker of cutaneous manifestation in DM and a marker of microangiopathy in SSc. Clarifying the role of Flt-3 ligand in rheumatic diseases may lead to further understanding of these diseases and new therapeutic approaches. PMID:26559027

  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. The Death Ligand TRAIL in Diabetic Nephropathy

    PubMed Central

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

    2008-01-01

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

  18. 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

  19. 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

  20. Ligand migration in nonsymbiotic hemoglobin AHb1 from Arabidopsis thaliana.

    PubMed

    Abbruzzetti, Stefania; Grandi, Elena; Bruno, Stefano; Faggiano, Serena; Spyrakis, Francesca; Mozzarelli, Andrea; Cacciatori, Elena; Dominici, Paola; Viappiani, Cristiano

    2007-11-01

    AHb1 is a hexacoordinated type 1 nonsymbiotic hemoglobin recently discovered in Arabidopsis thaliana. To gain insight into the ligand migration inside the protein, we studied the CO rebinding kinetics of AHb1 encapsulated in silica gels, in the presence of glycerol. The CO rebinding kinetics after nanosecond laser flash photolysis exhibits complex ligand migration patterns, consistent with the existence of discrete docking sites in which ligands can temporarily be stored before rebinding to the heme at different times. This finding may be of relevance to the physiological NO dioxygenase activity of this protein, which requires sequential binding of two substrates, NO and O2, to the heme. PMID:17924689

  1. 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.

  2. Control and recognition of anionic ligands in myoglobin.

    PubMed

    Cutruzzolà, F; Allocatelli, C T; Ascenzi, P; Bolognesi, M; Sligar, S G; Brunori, M

    1991-05-01

    Equilibrium and kinetic experiments on site-directed mutants of a synthetic sperm whale myoglobin (Mb) gene have been performed. Results on the reactivity on both ferric and ferrous wild type and mutants Mb's are presented. Analysis of ligand binding to His (E7) Val and His (E7) Val-Thr (E10) Arg mutants compared to wild-type sperm whale, horse and Aplysia limacina Mb's, shows that the introduction of an arginyl residue at the topological position E10 greatly enhances the stability of the various Mg:heme ligand adducts. Alternative mechanisms of ligand stabilization may therefore be operative in Mb's lacking the distal histidine. PMID:2037047

  3. Highly Active Multidentate Ligand-Based Alkyne Metathesis Catalysts.

    PubMed

    Du, Ya; Yang, Haishen; Zhu, Chengpu; Ortiz, Michael; Okochi, Kenji D; Shoemaker, Richard; Jin, Yinghua; Zhang, Wei

    2016-06-01

    Alkyne metathesis catalysts composed of molybdenum(VI) propylidyne and multidentate tris(2-hydroxylbenzyl)methane ligands have been developed, which exhibit excellent stability (remains active in solution for months at room temperature), high activity, and broad functional-group tolerance. The homodimerization and cyclooligomerization of monopropynyl or dipropynyl substrates, including challenging heterocycle substrates (e.g., pyridine), proceed efficiently at 40-55 °C in a closed system. The ligand structure and catalytic activity relationship has been investigated, which shows that the ortho groups of the multidentate phenol ligands are critical to the stability and activity of such a catalyst system. PMID:27113640

  4. LIGAND-INDUCED CHANGES IN T BOX ANTITERMINATOR RNA STABILITY

    PubMed Central

    Zhou, S.; Acquaah-Harrison, G.; Jack, K.D.; Bergmeier, S.C.; Hines, J.V.

    2012-01-01

    The T box antiterminator RNA element is an important component of the T box riboswitch that controls the transcription of vital genes in many Gram-positive bacteria. A series of 1,4-disubstituted 1,2,3-triazoles was screened in a fluorescence-monitored thermal denaturation assay to identify ligands that altered the stability of antiterminator model RNA. Several ligands were identified that significantly increased or decreased the melting temperature (Tm) of the RNA. The results indicate that this series of triazole ligands can alter the stability of antiterminator model RNA in a structure-dependent manner. PMID:22117759

  5. 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

  6. Quantum chemical exploration of the intramolecular hydrogen bond interaction in 2-thiazol-2-yl-phenol and 2-benzothiazol-2-yl-phenol in the context of excited-state intramolecular proton transfer: A focus on the covalency in hydrogen bond

    NASA Astrophysics Data System (ADS)

    Paul, Bijan Kumar; Ganguly, Aniruddha; Guchhait, Nikhil

    2014-10-01

    The present work demonstrates a computational exploration of the intramolecular H-bond (IMHB) interaction in two model heterocyclic compounds - 2-thiazol-2-yl-phenol (2T2YP) and 2-benzothiazol-2-yl-phenol (2B2YP) by meticulous application of various quantum chemical tools. Major emphasis is rendered on the analysis of IMHB interaction by calculation of electron density ρ(r) and Laplacian ∇2ρ(r) at the bond critical point using the Atoms-In-Molecule methodology. Topological features based on ρ(r) suggest that at equilibrium geometry the IMHB interaction develops certain characteristics typical of a covalent interaction. The interplay between aromaticity and Resonance-Assisted H-Bond (RAHB) has also been discussed using both geometrical and magnetic criteria. The occurrence of IMHB interaction in 2T2YP and 2B2YP has also been criticized under the provision of the Natural Bond Orbital (NBO) analysis. The ESIPT phenomenon in the molecular systems is also critically addressed on the lexicon of potential energy surface (PES) analysis.

  7. Oxidative Stress Promotes Ligand-independent and Enhanced Ligand-dependent Tumor Necrosis Factor Receptor Signaling*

    PubMed Central

    Ozsoy, Hatice Z.; Sivasubramanian, Natarajan; Wieder, Eric D.; Pedersen, Steen; Mann, Douglas L.

    2008-01-01

    Tumor necrosis factor (TNF) receptor 1 (TNFR1, p55) and 2 (TNFR2, p75) are characterized by several cysteine-rich modules in the extracellular domain, raising the possibility that redox-induced modifications of these cysteine residues might alter TNFR function. To test this possibility, we examined fluorescence resonance energy transfer (FRET) in 293T cells transfected with CFP- and YFP-tagged TNFRs exposed to the thiol oxidant diamide. Treatment with high concentrations of diamide (1 mm) resulted in an increase in the FRET signal that was sensitive to inhibition with the reducing agent dithiothreitol, suggesting that oxidative stress resulted in TNFR self-association. Treatment of cells with low concentrations of diamide (1 μm) that was not sufficient to provoke TNFR self-association resulted in increased TNF-induced FRET signals relative to the untreated cells, suggesting that oxidative stress enhanced ligand-dependent TNFR signaling. Similar findings were obtained when the TNFR1- and TNFR2-transfected cells were pretreated with a cell-impermeable oxidase, DsbA, that catalyzes disulfide bond formation between thiol groups on cysteine residues. The changes in TNFR self-association were functionally significant, because pretreating the HeLa cells and 293T cells resulted in increased TNF-induced NF-κB activation and TNF-induced expression of IκB and syndecan-4 mRNA levels. Although pretreatment with DsbA did not result in an increase in TNF binding to TNFRs, it resulted in increased TNF-induced activation of NF-κB, consistent with an allosteric modification of the TNFRs. Taken together, these results suggest that oxidative stress promotes TNFR receptor self-interaction and ligand-independent and enhanced ligand-dependent TNF signaling. PMID:18544535

  8. 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.

  9. 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

  10. HybridDock: A Hybrid Protein-Ligand Docking Protocol Integrating Protein- and Ligand-Based Approaches.

    PubMed

    Huang, Sheng-You; Li, Min; Wang, Jianxin; Pan, Yi

    2016-06-27

    Structure-based molecular docking and ligand-based similarity search are two commonly used computational methods in computer-aided drug design. Structure-based docking tries to utilize the structural information on a drug target like protein, and ligand-based screening takes advantage of the information on known ligands for a target. Given their different advantages, it would be desirable to use both protein- and ligand-based approaches in drug discovery when information for both the protein and known ligands is available. Here, we have presented a general hybrid docking protocol, referred to as HybridDock, to utilize both the protein structures and known ligands by combining the molecular docking program MDock and the ligand-based similarity search method SHAFTS, and evaluated our hybrid docking protocol on the CSAR 2013 and 2014 exercises. The results showed that overall our hybrid docking protocol significantly improved the performance in both binding affinity and binding mode predictions, compared to the sole MDock program. The efficacy of the hybrid docking protocol was further confirmed using the combination of DOCK and SHAFTS, suggesting an alternative docking approach for modern drug design/discovery. PMID:26317502

  11. Investigation of the enantioselectivity of tetramethylammonium L-hydroxyproline ionic liquid as a novel chiral ligand in ligand-exchange CE and ligand-exchange MEKC.

    PubMed

    Liu, Ruijuan; Du, Yingxiang; Chen, Jiaquan; Zhang, Qi; Du, Shuaijing; Feng, Zijie

    2015-01-01

    Chiral ionic liquids (ILs) have drawn more and more attention in separation science; however, only a few papers focused on the application of chiral ILs as chiral ligands in LE-CE. In this article, a novel amino acid ionic liquid (AAIL), tetramethylammonium L-hydroxyproline ([TMA][L-OH-Pro]), was first applied as a chiral ligand to evaluate its enantioselectivity towards several aromatic amino acids in ligand-exchange capillary electrophoresis (LE-CE) and ligand-exchange micellar electrokinetic capillary chromatography (LE-MEKC). In the LE-CE system, excellent separations were achieved for tryptophan (Rs = 3.03) and 3, 4-dihydroxyphenylalanine (DOPA) (Rs = 4.35). Several parameters affecting the enantioseparation were systematically investigated, including AAIL concentration, type and concentration of central metal ion, buffer pH, as well as applied voltage. The optimum separation was obtained with 60 mM AAIL containing 30 mM Cu (II) at pH 4.5. Additionally, an LE-MEKC system was established to further study the enantioselectivity of [TMA][L-OH-Pro] towards selected analytes. As observed, the separations of the enantiomers of tryptophan, phenylalanine, and histidine were all improved compared to the LE-CE system. The results indicated that the application of AAILs as chiral ligands is a promising method in chiral separation science. PMID:25399872

  12. Ligand-based reactivity of a platinum bisdithiolene: double diene addition yields a new C2-chiral chelate ligand.

    PubMed

    Kerr, Mitchell J; Harrison, Daniel J; Lough, Alan J; Fekl, Ulrich

    2009-10-01

    The reaction of Pt(tfd)(2) [tfd = S(2)C(2)(CF(3))(2)] with excess 2,3-dimethyl-1,3-butadiene initially yields the expected 1:1 adduct, in which the diene has added across two sulfur atoms on separate tfd ligands. However, within 1 day at 50 degrees C, this kinetic product quantitatively converts into a thermodynamic product where two dienes have added to one tfd ligand via unprecedented addition across the dithiolene CS bonds. The new reaction is highly selective for the C(2)-symmetric diastereomer. A new chiral bisthioether chelate ligand has formed in the product, which has been characterized crystallographically. PMID:19634863

  13. Regulation of the extracellular ligand binding activity of integrins.

    PubMed

    Fernandez, C; Clark, K; Burrows, L; Schofield, N R; Humphries, M J

    1998-07-01

    Integrins are a large heterodimeric family of cell surface adhesion receptors that bind extracellular matrix and cell surface ligands. The extracellular ligand binding activity of integrins is a dynamic and highly regulated event involving the induction of conformational changes within the integrin structure. The adhesive properties of integrins can be controlled by altering the activation state of the integrin, either through conformational change or receptor clustering, using mechanisms that are regulated by intracellular proteins. In this review, we will discuss what is currently known about integrin structure and the ligand binding sites present within the receptor. In addition, the mechanisms by which the ligand binding event is regulated through conformational change will be addressed, and the potential role of intracellular cytoplasmic proteins will be discussed. PMID:9637803

  14. Investigation of protein-ligand interactions by mass spectrometry.

    PubMed

    Sinz, Andrea

    2007-04-01

    The rate of drug discovery is greatly dependent on the development and improvement of rapid and reliable analytical methods that allow screening for protein-ligand interactions. The solution-based methods for investigating protein-ligand interactions by mass spectrometry (MS), which are discussed in this paper, are hydrogen/deuterium exchange of protein backbone amide hydrogens, and photoaffinity labeling. Moreover, MS analysis of intact noncovalent protein-ligand complexes is described. Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS) with its ultra-high resolution and excellent mass accuracy is also considered herein as it is gaining increasing popularity for a mass spectrometric investigation of protein-ligand interactions. PMID:17299828

  15. An Endogenous Mammalian Retinoid X Receptor Ligand, At Last!

    PubMed

    de Lera, Ángel R; Krezel, Wojciech; Rühl, Ralph

    2016-05-19

    9-cis-Retinoic acid was identified and claimed to be the endogenous ligand of the retinoid X receptors (RXRs) in 1992. Since then, the endogenous presence of this compound has never been rigorously confirmed. Instead, concerns have been raised by other groups that have reported that 9-cis-retinoic acid is undetectable or that its presence occurs at very low levels. Furthermore, these low levels could not satisfactorily explain the physiological activation of RXR. Alternative ligands, among them various lipids, have also been identified, but also did not fulfill criteria for rigorous endogenous relevance, and their consideration as bona fide endogenous mammalian RXR ligand has likewise been questioned. Recently, novel studies claim that the saturated analogue 9-cis-13,14-dihydroretinoic acid functions as an endogenous physiologically relevant mammalian RXR ligand. PMID:27151148

  16. 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)

  17. 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

  18. A new fullerene complexation ligand: N-pyridylfulleropyrrolidine.

    PubMed

    Tat, Fatma T; Zhou, Zhiguo; MacMahon, Shaun; Song, Fayi; Rheingold, Arnold L; Echegoyen, Luis; Schuster, David I; Wilson, Stephen R

    2004-07-01

    The subject of this paper is a new fullerene building block design with the potential for defined geometry and good electronic communication. The synthesis and characterization of a new pyridinofullerene ligand capable of forming axially symmetric complexes with metalloporphyrins is reported. X-ray structural and molecular modeling studies, (1)H NMR, UV-vis spectroscopy, electrochemistry studies, and fluorescence quenching data support the formation of a strong complex between the new ligand and the metal center of ZnTPP. On the basis of computational studies, the highest occupied molecular orbital (HOMO) of this ligand is significantly different from a model compound with insulating carbons between the pyridine and the fullerene. The N-pyridinium fulleropyrrolidine salts of the new ligand and model compound were also prepared and their spectral and electrochemical properties are reported. PMID:15230581

  19. Fluorescent ligand for human progesterone receptor imaging in live cells.

    PubMed

    Weinstain, Roy; Kanter, Joan; Friedman, Beth; Ellies, Lesley G; Baker, Michael E; Tsien, Roger Y

    2013-05-15

    We employed molecular modeling to design and then synthesize fluorescent ligands for the human progesterone receptor. Boron dipyrromethene (BODIPY) or tetramethylrhodamine were conjugated to the progesterone receptor antagonist RU486 (Mifepristone) through an extended hydrophilic linker. The fluorescent ligands demonstrated comparable bioactivity to the parent antagonist in live cells and triggered nuclear translocation of the receptor in a specific manner. The BODIPY labeled ligand was applied to investigate the dependency of progesterone receptor nuclear translocation on partner proteins and to show that functional heat shock protein 90 but not immunophilin FKBP52 activity is essential. A tissue distribution study indicated that the fluorescent ligand preferentially accumulates in tissues that express high levels of the receptor in vivo. The design and properties of the BODIPY-labeled RU486 make it a potential candidate for in vivo imaging of PR by positron emission tomography through incorporation of (18)F into the BODIPY core. PMID:23600997

  20. A Correlation between Protein Function and Ligand Binding Profiles

    PubMed Central

    Shortridge, Matthew D.; Bokemper, Michael; Copeland, Jennifer C.; Stark, Jaime L.; Powers, Robert

    2011-01-01

    We report that proteins with the same function bind the same set of small molecules from a standardized chemical library. This observation led to a quantifiable and rapidly adaptable method for protein functional analysis using experimentally-derived ligand binding profiles. Ligand binding is measured using a high-throughput NMR ligand affinity screen with a structurally diverse chemical library. The method was demonstrated using a set of 19 proteins with a range of functions. A statistically significant similarity in ligand binding profiles was only observed between the two functionally identical albumins and between the five functionally similar amylases. This new approach is independent of sequence, structure or evolutionary information, and therefore, extends our ability to analyze and functionally annotate novel genes. PMID:21366353

  1. 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

  2. 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.

  3. 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

  4. 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

  5. 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

  6. Follitropin receptors contain cryptic ligand binding sites.

    PubMed

    Lin, Win; Bernard, Michael P; Cao, Donghui; Myers, Rebecca V; Kerrigan, John E; Moyle, William R

    2007-01-01

    Human choriogonadotropin (hCG) and follitropin (hFSH) have been shown to contact different regions of the extracellular domains of G-protein coupled lutropin (LHR) and follitropin (FSHR) receptors. We report here that hCG and hFSH analogs interact with different regions of an FSHR/LHR chimera having only two unique LHR residues and that binds both hormones with high affinity. hCG and hFSH analogs dock with this receptor chimera in a manner similar to that in which they bind LHR and FSHR, respectively. This shows that although the FSHR does not normally bind hCG, it contains a cryptic lutropin binding site that has the potential to recognize hCG in a manner similar to the LHR. The presence of this cryptic site may explain why equine lutropins bind many mammalian FSHR and why mutations in the transmembrane domain distant from the extracellular domain enable the FSHR to bind hCG. The leucine-rich repeat domain (LRD) of the FSHR also appears to contain a cryptic FSH binding site that is obscured by other parts of the extracellular domain. This will explain why contacts seen in crystals of hFSH complexed with an LRD fragment of the human FSHR are hard to reconcile with the abilities of FSH analogs to interact with membrane G-protein coupled FSHR. We speculate that cryptic lutropin binding sites in the FSHR, which are also likely to be present in thyrotropin receptors (TSHR), permit the physiological regulation of ligand binding specificity. Cryptic FSH binding sites in the LRD may enable alternate spliced forms of the FSHR to interact with FSH. PMID:17059863

  7. 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

  8. 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.

  9. Reaction chemistry and ligand exchange at cadmium selenide nanocrystal surfaces

    SciTech Connect

    Owen, Jonathan; Park, Jungwon; Trudeau, Paul-Emile; Alivisatos, A. Paul

    2008-12-02

    Chemical modification of nanocrystal surfaces is fundamentally important to their assembly, their implementation in biology and medicine, and greatly impacts their electrical and optical properties. However, it remains a major challenge owing to a lack of analytical tools to directly determine nanoparticle surface structure. Early nuclear magnetic resonance (NMR) and X-ray photoelectron spectroscopy (XPS) studies of CdSe nanocrystals prepared in tri-n-octylphosphine oxide (1) and tri-n-octylphosphine (2), suggested these coordinating solvents are datively bound to the particle surface. However, assigning the broad NMR resonances of surface-bound ligands is complicated by significant concentrations of phosphorus-containing impurities in commercial sources of 1, and XPS provides only limited information about the nature of the phosphorus containing molecules in the sample. More recent reports have shown the surface ligands of CdSe nanocrystals prepared in technical grade 1, and in the presence of alkylphosphonic acids, include phosphonic and phosphinic acids. These studies do not, however, distinguish whether these ligands are bound datively, as neutral, L-type ligands, or by X-type interaction of an anionic phosphonate/phosphinate moiety with a surface Cd{sup 2+} ion. Answering this question would help clarify why ligand exchange with such particles does not proceed generally as expected based on a L-type ligand model. By using reagents with reactive silicon-chalcogen and silicon-chlorine bonds to cleave the ligands from the nanocrystal surface, we show that our CdSe and CdSe/ZnS core-shell nanocrystal surfaces are likely terminated by X-type binding of alkylphosphonate ligands to a layer of Cd{sup 2+}/Zn{sup 2+} ions, rather than by dative interactions. Further, we provide spectroscopic evidence that 1 and 2 are not coordinated to our purified nanocrystals.

  10. 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

  11. 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…

  12. 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.

  13. Application of BRET to monitor ligand binding to GPCRs

    PubMed Central

    Stoddart, Leigh A; Johnstone, Elizabeth K M; Wheal, Amanda J; Goulding, Joëlle; Robers, Matthew B; Machleidt, Thomas; Wood, Keith V

    2015-01-01

    Bioluminescence resonance energy transfer (BRET) is a well-established method for investigating protein-protein interactions. Here we present a novel BRET approach to monitor ligand binding to G protein-coupled receptors (GPCRs) on the surface of living cells made possible by the use of fluorescent ligands in combination with a novel bioluminescent protein (NanoLuc) that can be readily expressed on the N-terminus of GPCRs. PMID:26030448

  14. Application of BRET to monitor ligand binding to GPCRs.

    PubMed

    Stoddart, Leigh A; Johnstone, Elizabeth K M; Wheal, Amanda J; Goulding, Joëlle; Robers, Matthew B; Machleidt, Thomas; Wood, Keith V; Hill, Stephen J; Pfleger, Kevin D G

    2015-07-01

    Bioluminescence resonance energy transfer (BRET) is a well-established method for investigating protein-protein interactions. Here we present a BRET approach to monitor ligand binding to G protein-coupled receptors (GPCRs) on the surface of living cells made possible by the use of fluorescent ligands in combination with a bioluminescent protein (NanoLuc) that can be readily expressed on the N terminus of GPCRs. PMID:26030448

  15. 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

  16. 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.

  17. 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

  18. 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

  19. Phage Selection of Chemically Stabilized α-Helical Peptide Ligands.

    PubMed

    Diderich, Philippe; Bertoldo, Davide; Dessen, Pierre; Khan, Maola M; Pizzitola, Irene; Held, Werner; Huelsken, Joerg; Heinis, Christian

    2016-05-20

    Short α-helical peptides stabilized by linkages between constituent amino acids offer an attractive format for ligand development. In recent years, a range of excellent ligands based on stabilized α-helices were generated by rational design using α-helical peptides of natural proteins as templates. Herein, we developed a method to engineer chemically stabilized α-helical ligands in a combinatorial fashion. In brief, peptides containing cysteines in position i and i + 4 are genetically encoded by phage display, the cysteines are modified with chemical bridges to impose α-helical conformations, and binders are isolated by affinity selection. We applied the strategy to affinity mature an α-helical peptide binding β-catenin. We succeeded in developing ligands with Kd's as low as 5.2 nM, having >200-fold improved affinity. The strategy is generally applicable for affinity maturation of any α-helical peptide. Compared to hydrocarbon stapled peptides, the herein evolved thioether-bridged peptide ligands can be synthesized more easily, as no unnatural amino acids are required and the cyclization reaction is more efficient and yields no stereoisomers. A further advantage of the thioether-bridged peptide ligands is that they can be expressed recombinantly as fusion proteins. PMID:26929989

  20. Extracellular interactions and ligand degradation shape the nodal morphogen gradient

    PubMed Central

    Wang, Yin; Wang, Xi; Wohland, Thorsten; Sampath, Karuna

    2016-01-01

    The correct distribution and activity of secreted signaling proteins called morphogens is required for many developmental processes. Nodal morphogens play critical roles in embryonic axis formation in many organisms. Models proposed to generate the Nodal gradient include diffusivity, ligand processing, and a temporal activation window. But how the Nodal morphogen gradient forms in vivo remains unclear. Here, we have measured in vivo for the first time, the binding affinity of Nodal ligands to their major cell surface receptor, Acvr2b, and to the Nodal inhibitor, Lefty, by fluorescence cross-correlation spectroscopy. We examined the diffusion coefficient of Nodal ligands and Lefty inhibitors in live zebrafish embryos by fluorescence correlation spectroscopy. We also investigated the contribution of ligand degradation to the Nodal gradient. We show that ligand clearance via degradation shapes the Nodal gradient and correlates with its signaling range. By computational simulations of gradient formation, we demonstrate that diffusivity, extra-cellular interactions, and selective ligand destruction collectively shape the Nodal morphogen gradient. DOI: http://dx.doi.org/10.7554/eLife.13879.001 PMID:27101364

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

    PubMed

    Chang, Chenbei

    2016-01-01

    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. PMID:27413100

  2. 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. PMID:25735755

  3. Porphyrin-based design of bioinspired multitarget quadruplex ligands.

    PubMed

    Laguerre, Aurélien; Desbois, Nicolas; Stefan, Loic; Richard, Philippe; Gros, Claude P; Monchaud, David

    2014-09-01

    Secondary nucleic acid structures, such as DNA and RNA quadruplexes, are potential targets for cancer therapies. Ligands that interact with these targets could thus find application as anticancer agents. Synthetic G-quartets have recently found numerous applications, including use as bioinspired G-quadruplex ligands. Herein, the design, synthesis and preliminary biophysical evaluation of a new prototype multitarget G-quadruplex ligand, (PNA)PorphySQ, are reported, where peptidic nucleic acid guanine ((PNA)G) was incorporated in the porphyrin-templated synthetic G-quartet (PorphySQ). Using fluorescence resonance energy transfer (FRET)-melting experiments, PorphySQ was shown to possess enhanced quadruplex-interacting properties thanks to the presence of four positively charged (PNA)G residues that improve its electrostatic interactions with the binding site of both DNA and RNA quadruplexes (i.e., their negatively charged and accessible G-quartets), thereby making (PNA)PorphySQ an interesting prototype of a multitarget ligand. Both the chemical stability and water solubility of (PNA)PorphySQ are improved over the non-PNA derivative (PorphySQ), which are desirable properties for drug development, and while improvements remain to be made, this ligand is a promising lead for the further development of multitarget G-quadruplex ligands. PMID:24678052

  4. Database of Ligand-Receptor Partners, a DIP subset

    DOE Data Explorer

    Graeber, Thomas G.; Eisenberg, David

    The Database of Ligand-Receptor Partners (DLRP) is a subset of DIP (Database of Interacting Proteins). The DLRP is a database of protein ligand and protein receptor pairs that are known to interact with each other. By interact we mean that the ligand and receptor are members of a ligand-receptor complex and, unless otherwise noted, transduce a signal. In some instances the ligand and/or receptor may form a heterocomplex with other ligands/receptors in order to be functional. We have entered the majority of interactions in DLRP as full DIP entries, with links to references and additional information (see the DIP User's Guide). DLRP is a web supplement for: Thomas G. Graeber and David Eisenberg. Bioinformatic identification of potential autocrine signaling loops in cancers from gene expression profiles. Nature Genetics, 29(3):295-300 (November 2001). [Quoted from the DLRP homepage at http://dip.doe-mbi.ucla.edu/dip/DLRP.cgi] Also available from this page is the DLRP chemokine subset.

  5. Ligand and interfacial dynamics in a homodimeric hemoglobin

    PubMed Central

    Gupta, Prashant Kumar; Meuwly, Markus

    2016-01-01

    The structural dynamics of dimeric hemoglobin (HbI) from Scapharca inaequivalvis in different ligand-binding states is studied from atomistic simulations on the μs time scale. The intermediates are between the fully ligand-bound (R) and ligand-free (T) states. Tertiary structural changes, such as rotation of the side chain of Phe97, breaking of the Lys96–heme salt bridge, and the Fe–Fe separation, are characterized and the water dynamics along the R-T transition is analyzed. All these properties for the intermediates are bracketed by those determined experimentally for the fully ligand-bound and ligand-free proteins, respectively. The dynamics of the two monomers is asymmetric on the 100 ns timescale. Several spontaneous rotations of the Phe97 side chain are observed which suggest a typical time scale of 50–100 ns for this process. Ligand migration pathways include regions between the B/G and C/G helices and, if observed, take place in the 100 ns time scale. PMID:26958581

  6. Discovery of GPCR ligands for probing signal transduction pathways

    PubMed Central

    Brogi, Simone; Tafi, Andrea; Désaubry, Laurent; Nebigil, Canan G.

    2014-01-01

    G protein-coupled receptors (GPCRs) are seven integral transmembrane proteins that are the primary targets of almost 30% of approved drugs and continue to represent a major focus of pharmaceutical research. All of GPCR targeted medicines were discovered by classical medicinal chemistry approaches. After the first GPCR crystal structures were determined, the docking screens using these structures lead to discovery of more novel and potent ligands. There are over 360 pharmaceutically relevant GPCRs in the human genome and to date about only 30 of structures have been determined. For these reasons, computational techniques such as homology modeling and molecular dynamics simulations have proven their usefulness to explore the structure and function of GPCRs. Furthermore, structure-based drug design and in silico screening (High Throughput Docking) are still the most common computational procedures in GPCRs drug discovery. Moreover, ligand-based methods such as three-dimensional quantitative structure–selectivity relationships, are the ideal molecular modeling approaches to rationalize the activity of tested GPCR ligands and identify novel GPCR ligands. In this review, we discuss the most recent advances for the computational approaches to effectively guide selectivity and affinity of ligands. We also describe novel approaches in medicinal chemistry, such as the development of biased agonists, allosteric modulators, and bivalent ligands for class A GPCRs. Furthermore, we highlight some knockout mice models in discovering biased signaling selectivity. PMID:25506327

  7. 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.

  8. Riboswitch structure in the ligand-free state.

    PubMed

    Liberman, Joseph A; Wedekind, Joseph E

    2012-01-01

    Molecular investigations of riboswitches bound to small-molecule effectors have produced a wealth of information on how these molecules achieve high affinity and specificity for a target ligand. X-ray crystal structures have been determined for the ligand-free state for representatives of the preQ₁-I, S-adenosylmethionine I, lysine, and glycine aptamer classes. These structures in conjunction with complimentary techniques, such as in-line probing, NMR spectroscopy, Förster resonance energy transfer, small-angle scattering, and computational simulations, have demonstrated that riboswitches adopt multiple conformations in the absence of ligand. Despite a number of investigations that support ligand-dependent folding, mounting evidence suggests that free-state riboswitches interact with their effectors in the sub-populations of largely prefolded states as embodied by the principle of conformational selection, which has been documented extensively for protein-mediated ligand interactions. Fundamental riboswitch investigations of the bound and free states have advanced our understanding of RNA folding, ligand recognition, and how these factors culminate in communication between an aptamer and its expression platform. An understanding of these topics is essential to comprehend riboswitch gene regulation at the molecular level, which has already provided a basis to understand the mechanism of action of natural antimicrobials. PMID:21957061

  9. 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. PMID:25252174

  10. Narrow escape for a stochastically gated Brownian ligand.

    PubMed

    Reingruber, Jürgen; Holcman, David

    2010-02-17

    Molecular activation in cellular microdomains is usually characterized by a forward binding rate, which is the reciprocal of the arrival time of a ligand to a key target. Upon chemical interactions or conformational changes, a Brownian ligand may randomly switch between different states, and when target activation is possible in a specific state only, switching can significantly alter the activation process. The main goal of this paper is to study the mean time for a switching ligand to activate a small substrate, modelled as the time to exit a microdomain through a small absorbing window on the surface. We present the equations for the mean sojourn times the ligand spends in each state, and study the escape process with switching between two states in dimension one and three. When the ligand can exit in only one of the two states, we find that switching always decreases its sojourn time in the state where it can exit. Moreover, the fastest exit is obtained when the ligand diffuses most of the time in the state with the maximal diffusion coefficient, although this may imply that it spends most of the time 'hidden' in the state where it cannot exit. We discuss the physical mechanisms responsible for this apparent paradox. In dimension three we confirm our results with Brownian simulations. Finally, we suggest possible applications in cellular biology. PMID:21389363

  11. 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

  12. 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. PMID:27154268

  13. 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. PMID:20939791

  14. 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.

  15. A novel silver iodide metalo-drug: experimental and computational modelling assessment of its interaction with intracellular DNA, lipoxygenase and glutathione.

    PubMed

    Banti, C N; Kyros, L; Geromichalos, G D; Kourkoumelis, N; Kubicki, M; Hadjikakou, S K

    2014-04-22

    The new mixed ligand silver(I) complex of formula [AgI(TPP)2(MBZT)] (1) was obtained by reacting 2-mercapto-benzothiazole (MBZT) with triphenylphosphine (TPP). The complex was characterized by m.p., vibrational spectroscopy (FT-IR), (1)H NMR, UV-vis, ESI-MS spectroscopic techniques and its structure was confirmed by X-ray crystallography. Mixed ligand complexes of silver(I) iodide with thiones and phosphines are very rare in the literature and to the best of our knowledge compound 1 is the first of this kind exhibiting significant biological effects. Complex 1 was evaluated for its in vitro cytotoxic activity (cell viability) under irradiation with UV light and without irradiation against human cancer cell lines: MCF-7 (breast, ER positive), MDA-MB-231 (breast, ER negative), Caki-1 (renal), A549 (lung), OAW-42 (ovarian), HeLa (cervical) and additionally against the normal human lung cell line MRC-5 (normal human fetal lung fibroblast cells) and normal immortalized human mammary gland epithelial cell line (MTSV17) with SRB assay. The results showed that 1 mediates a strong cytotoxic response to the tested normal and cancer cell lines. It exhibits equal activity against MDA-MB-231 cells where estrogen receptors (ERs) are devoid with the one against MCF-7 where ERs are present. Molecular docking studies have shown that 1 is docked in the different pocket than that of the ERs modulators. The binding affinity of 1 towards the intracellular molecules DNA and lipoxygenase (LOX) was studied for the evaluation of the mechanism of its cytostasis. The binding constant (Kb) of 1 towards CT-DNA was calculated by UV-Vis and fluorescent spectra suggesting intercalation or electrostatic interactions of 1 into DNA. Docking studies on DNA-complex interactions confirm the binding of 1. Moreover, the influence of complex 1 on the catalytic peroxidation of linoleic acid to hydroperoxylinoleic acid by the enzyme lipoxygenase (LOX) was kinetically and theoretically studied. In addition

  16. 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.

  17. 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.

  18. electronic Ligand Builder and Optimization Workbench (eLBOW): a tool for ligand coordinate and restraint generation

    PubMed Central

    Moriarty, Nigel W.; Grosse-Kunstleve, Ralf W.; Adams, Paul D.

    2009-01-01

    The electronic Ligand Builder and Optimization Workbench (eLBOW) is a program module of the PHENIX suite of computational crystallographic software. It is designed to be a flexible procedure that uses 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 the attainment of a number of diverse goals including geometry optimization and generation of restraints. PMID:19770504

  19. 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

  20. 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

  1. Influence of variations in the chromophoric ligand on the properties of metal-to-ligand charge-transfer excited states

    SciTech Connect

    Johnson, S.R.; Westmoreland, T.D.; Caspar, J.V.; Barqawi, K.R.; Meyer, T.J.

    1988-09-07

    The effects of variations in the chromophoric ligand on the properties of the metal-to-ligand charge-transfer (MLCT) excited states in the series (Os(PP)/sub 3/)/sup 2+/, ((PP)/sub 2/Os(py)/sub 2/)/sup 2+/, and ((PP)/sub 2/Os(LL))/sup 2+/ (PP = 2,2'-bipyridine, 1,10-phenanthroline, or a substituted derivative; py = pyridine; LL = das, dppm, dppb, dppene) have been investigated. From a series of electrochemical and photophysical measurements it has been determined that (1) substituent variations in the chromophoric ligands have a relatively minor effect on the d/pi/(Os) levels as evidenced by variations in E/sub 1/2/ values for the ground-state Os(III/II) couples, (2) linear correlations exist between metal-to-ligand charge-transfer (MLCT) absorption or emission band energies and the difference in metal-based oxidation and ligand-based reduction potentials, E/sub 1/2/(Os/sup III/II/) - E/sub 1/2/(PP/sup 0//minus//), and (3) a linear relationship between 1n k/sub nr/ and the emission energy, E/sub em/, exists, consistent with the energy gap law. It appears that for nonradiative decay both the pattern of acceptor vibrations and the vibrationally induced electronic coupling term remain relatively constant as the chromophoric ligand is varied. 26 references, 4 figures, 2 tables.

  2. 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

  3. Non-peptide ligand binding to the formyl peptide receptor FPR2--A comparison to peptide ligand binding modes.

    PubMed

    Stepniewski, Tomasz M; Filipek, Slawomir

    2015-07-15

    Ligands of the FPR2 receptor initiate many signaling pathways including activation of phospholipase C, protein kinase C, the mitogen-activated protein kinase, and phosphatidylinositol 3-kinase/protein kinase B pathway. The possible actions include also calcium flux, superoxide generation, as well as migration and proliferation of monocytes. FPR2 activation may induce a pro- and anti-inflammatory effect depending on the ligand type. It is also found that this receptor is involved in tumor growth. Most of currently known FPR2 ligands are agonists since they were designed based on N-formyl peptides, which are natural agonists of formyl receptors. Since the non-peptide drugs are indispensable for effective treatment strategies, we performed a docking study of such ligands employing a generated dual template homology model of the FPR2 receptor. The study revealed different binding modes of particular classes of these drugs. Based on the obtained docking poses we proposed a detailed location of three hydrophobic pockets in orthosteric binding site of FPR2. Our model emphasizes the importance of aromatic stacking, especially with regard to residues His102(3.29) and Phe257(6.51), for binding of FPR2 ligands. We also identified other residues important for non-peptide ligand binding in the binding site of FPR2. PMID:25882522

  4. Ligand-to-Ligand Charge Transfer within Metal-Organic Frameworks Based on Manganese Coordination Polymers with Tetrathiafulvalene-Bicarboxylate and Bipyridine Ligands.

    PubMed

    Huo, Peng; Chen, Ting; Hou, Jin-Le; Yu, Lei; Zhu, Qin-Yu; Dai, Jie

    2016-07-01

    A systematic study on ligand-to-ligand charge-transfer (LLCT) properties of three closely related metal-organic frameworks (MOFs) is presented. These compounds are formulated as [MnL(4,4'-bpy)(H2O)]n·nCH3CN (1), [MnL(bpe)0.5(DMF)]n·2nH2O (2), and [MnL(bpa)(H2O)]n·2nH2O (3) (L = dimethylthio-tetrathiafulvalene-bicarboxylate, 4,4'-bpy = 4,4'-bipyridine, bpe = 1,2-bis(4-pyridyl)ethene, bpa = 1,2-bis(4-pyridyl)ethane). The X-ray single-crystal diffractions show that complexes 1-3 are all two-dimensional (2-D) coordination polymers with different frameworks in crystal lattices. Charge-transfer (CT) interactions within these MOFs are visually apparent in colors and vary according to the conjugated states of the bipyridine ligands (4,4'-bpy, bpe, and bpa). Theoretical calculations show that the charge transfer occurs from ligand L to bipyridine. The intensity of the LLCT is in the order of 2 > 1 > 3 investigated by theoretical calculations and ESR, which indicates that the intensity of CT is related to the bipyridyl conjugated state. Photocurrent responses of these compounds are consequently studied, and the results are in agreement with the intensity of charge transfer and linearly related to the LLCT energy. PMID:27285178

  5. 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.

  6. 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.

  7. 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. PMID:25043724

  8. Ligand Migration and Binding in Myoglobin Mutant L29W

    NASA Astrophysics Data System (ADS)

    Nienhaus, G. Ulrich; Waschipky, Robert; Nienhaus, Karin; Minkow, Oleksandr; Ostermann, Andreas; Parak, Fritz G.

    2001-09-01

    Myoglobin, a small globular heme protein that binds gaseous ligands such as O2, CO, and NO reversibly at the heme iron, has for many years been a paradigm for studying the effects of structure and dynamics on protein reactions. Time-resolved spectroscopic measurements after photodissociation of the ligand reveal a complex ligand binding reaction with multiple kinetic intermediates, resulting from protein relaxation and movements of the ligand within the protein. To observe structural changes induced by ligand dissociation, we have investigated carbonmonoxy myoglobin (MbCO) mutant L29W using time-resolved infrared spectroscopy in combination with x-ray crystallography. The presence of two distinct infrared stretch bands of the bound CO, AI at 1945 cm-1 and AII at 1955 cm-1, implies that L29W MbCO assumes two different conformations at neutral pH. Low-temperature flash photolysis experiments with monitoring of the absorption changes in the individual CO lines reveal markedly different rebinding properties. While recombination in AII is conceptually simple and well described by a two-state transition involving a distribution of enthalpy barriers, recombination in AI is more complicated: Besides a fast kinetic component, a second, slower kinetic component appears; its population grows with increasing temperature. X-ray crystallography of crystals illuminated below 180 K to photodissociate the CO reveals that the slow component arises from ligands that have migrated from their initial docking site to a remote site within the distal heme pocket. This process occurs in an essentially immobilized, frozen protein. Subsequently, ligands rebind by thermal activation over a barrier that is much higher than the barrier for recombination from the initial docking site. Upon photodissociation above 180 K, ligands escape from the distal pocket, aided by protein fluctuations that transiently open exit channels. The x-ray structure shows a large proportion of ligands in a cavity on

  9. 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

  10. 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

  11. NKG2D ligands mediate immunosurveillance of senescent cells

    PubMed Central

    Moshayev, Zhana; Vadai, Ezra; Wensveen, Felix; Ben-Dor, Shifra; Golani, Ofra; Polic, Bojan; Krizhanovsky, Valery

    2016-01-01

    Cellular senescence is a stress response mechanism that limits tumorigenesis and tissue damage. Induction of cellular senescence commonly coincides with an immunogenic phenotype that promotes self-elimination by components of the immune system, thereby facilitating tumor suppression and limiting excess fibrosis during wound repair. The mechanisms by which senescent cells regulate their immune surveillance are not completely understood. Here we show that ligands of an activating Natural Killer (NK) cell receptor (NKG2D), MICA and ULBP2 are consistently up-regulated following induction of replicative senescence, oncogene-induced senescence and DNA damage - induced senescence. MICA and ULBP2 proteins are necessary for efficient NK-mediated cytotoxicity towards senescent fibroblasts. The mechanisms regulating the initial expression of NKG2D ligands in senescent cells are dependent on a DNA damage response, whilst continuous expression of these ligands is regulated by the ERK signaling pathway. In liver fibrosis, the accumulation of senescent activated stellate cells is increased in mice lacking NKG2D receptor leading to increased fibrosis. Overall, our results provide new insights into the mechanisms regulating the expression of immune ligands in senescent cells and reveal the importance of NKG2D receptor-ligand interaction in protecting against liver fibrosis. PMID:26878797

  12. Ligand migration and binding in nonsymbiotic hemoglobins of Arabidopsis thaliana.

    PubMed

    Nienhaus, Karin; Dominici, Paola; Astegno, Alessandra; Abbruzzetti, Stefania; Viappiani, Cristiano; Nienhaus, G Ulrich

    2010-09-01

    We have studied carbon monoxide (CO) migration and binding in the nonsymbiotic hemoglobins AHb1 and AHb2 of Arabidopsis thaliana using Fourier transform infrared (FTIR) spectroscopy combined with temperature derivative spectroscopy (TDS) at cryogenic temperatures. Both proteins have similar amino acid sequences but display pronounced differences in ligand binding properties, at both physiological and cryogenic temperatures. Near neutral pH, the distal HisE7 side chain is close to the heme-bound ligand in the majority of AHb1-CO molecules, as indicated by a low CO stretching frequency at 1921 cm(-1). In this fraction, two CO docking sites can be populated, the primary site B and the secondary site C. When the pH is lowered, a high-frequency stretching band at approximately 1964 cm(-1) grows at the expense of the low-frequency band, indicating that HisE7 protonates and, concomitantly, moves away from the bound ligand. Geminate rebinding barriers are markedly different for the two conformations, and docking site C is not accessible in the low-pH conformation. Rebinding of NO ligands was observed only from site B of AHb1, regardless of conformation. In AHb2, the HisE7 side chain is removed from the bound ligand; rebinding barriers are low, and CO molecules can populate only primary docking site B. These results are interpreted in terms of differences in the active site structures and physiological functions. PMID:20666470

  13. 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

  14. Scoring functions for prediction of protein-ligand interactions.

    PubMed

    Wang, Jui-Chih; Lin, Jung-Hsin

    2013-01-01

    The scoring functions for protein-ligand interactions plays central roles in computational drug design, virtual screening of chemical libraries for new lead identification, and prediction of possible binding targets of small chemical molecules. An ideal scoring function for protein-ligand interactions is expected to be able to recognize the native binding pose of a ligand on the protein surface among decoy poses, and to accurately predict the binding affinity (or binding free energy) so that the active molecules can be discriminated from the non-active ones. Due to the empirical nature of most, if not all, scoring functions for protein-ligand interactions, the general applicability of empirical scoring functions, especially to domains far outside training sets, is a major concern. In this review article, we will explore the foundations of different classes of scoring functions, their possible limitations, and their suitable application domains. We also provide assessments of several scoring functions on weakly-interacting protein-ligand complexes, which will be useful information in computational fragment-based drug design or virtual screening. PMID:23016847

  15. KLIFS: a structural kinase-ligand interaction database.

    PubMed

    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

  16. 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.

  17. Cloud Computing for Protein-Ligand Binding Site Comparison

    PubMed Central

    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

  18. 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

  19. 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

  20. Probing heterotrimeric G protein activation: applications to biased ligands

    PubMed Central

    Denis, Colette; Saulière, Aude; Galandrin, Ségolène; Sénard, Jean-Michel; Galés, Céline

    2012-01-01

    Cell surface G protein-coupled receptors (GPCRs) drive numerous signaling pathways involved in the regulation of a broad range of physiologic processes. Today, they represent the largest target for modern drugs development with potential application in all clinical fields. Recently, the concept of “ligand-directed trafficking” has led to a conceptual revolution in pharmacological theory, thus opening new avenues for drug discovery. Accordingly, GPCRs do not function as simple on-off switch but rather as filters capable of selecting activation of specific signals and thus generating textured responses to ligands, a phenomenon often referred to as ligand-biased signaling. Also, one challenging task today remains optimization of pharmacological assays with increased sensitivity so to better appreciate the inherent texture of ligand responses. However, considering that a single receptor has pleiotropic signalling properties and that each signal can crosstalk at different levels, biased activity remains thus difficult to evaluate. One strategy to overcome these limitations would be examining the initial steps following receptor activation. Even if some G protein-independent functions have been recently described, heterotrimeric G protein activation remains a general hallmark for all GPCRs families and the first cellular event subsequent to agonist binding to the receptor. Herein, we review the different methodologies classically used or recently developed to monitor G protein activation and discuss them in the context of G protein biased -ligands. PMID:22229559

  1. A single ligand is sufficient to activate EGFR dimers

    PubMed Central

    Liu, Ping; Cleveland, Thomas E.; Bouyain, Samuel; Byrne, Patrick O.; Longo, Patti A.; Leahy, Daniel J.

    2012-01-01

    Crystal structures of human epidermal growth factor receptor (EGFR) with bound ligand revealed symmetric, doubly ligated receptor dimers thought to represent physiologically active states. Such complexes fail to rationalize negative cooperativity of epidermal growth factor (EGF) binding to EGFR and the behavior of the ligandless EGFR homolog ErbB2/HER2, however. We report cell-based assays that provide evidence for active, singly ligated dimers of human EGFR and its homolog, ErbB4/HER4. We also report crystal structures of the ErbB4/HER4 extracellular region complexed with its ligand Neuregulin-1β that resolve two types of ErbB dimer when compared to EGFR:Ligand complexes. One type resembles the recently reported asymmetric dimer of Drosophila EGFR with a single high-affinity ligand bound and provides a model for singly ligated human ErbB dimers. These results unify models of vertebrate and invertebrate EGFR/ErbB signaling, imply that the tethered conformation of unliganded ErbBs evolved to prevent crosstalk among ErbBs, and establish a molecular basis for both negative cooperativity of ligand binding to vertebrate ErbBs and the absence of active ErbB2/HER2 homodimers in normal conditions. PMID:22699492

  2. 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

  3. 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

  4. Comparing ligand interactions with multiple receptors via serial docking.

    PubMed

    Fernandes, Miguel X; Kairys, Visvaldas; Gilson, Michael K

    2004-01-01

    Standard uses of ligand-receptor docking typically focus on the association of candidate ligands with a single targeted receptor, but actual applications increasingly require comparisons across multiple receptors. This study demonstrates that comparative docking to multiple receptors can help to select homology models for virtual compound screening and to discover ligands that bind to one set of receptors but not to another, potentially similar, set. A serial docking algorithm is furthermore described that reduces the computational costs of such calculations by testing compounds against a series of receptor structures and discarding a compound as soon as it fails to satisfy specified bind/no bind criteria for each receptor. The algorithm also realizes substantial efficiencies by taking advantage of the fact that a ligand typically binds in similar conformations to similar receptors. Thus, once detailed docking has been used to fit a ligand into the first of a series of similar receptors, much less extensive calculations can be used for the remaining structures. PMID:15554665

  5. Rapid flexible docking using a stochastic rotamer library of ligands

    PubMed Central

    Ding, Feng; Yin, Shuangye; Dokholyan, Nikolay V.

    2010-01-01

    Existing flexible docking approaches model the ligand and receptor flexibility either separately or in a loosely-coupled manner, which captures the conformational changes inefficiently. Here, we propose a flexible docking approach, MedusaDock, which models both ligand and receptor flexibility simultaneously with sets of discrete rotamers. We develop an algorithm to build the ligand rotamer library “on-the-fly” during docking simulations. MedusaDock benchmarks demonstrate a rapid sampling efficiency and high prediction accuracy in both self-docking (to the co-crystallized state) and cross-docking (to a state co-crystallized with a different ligand), the latter of which mimics the virtual-screening procedure in computational drug discovery. We also perform a virtual-screening test of four flexible kinase targets including cyclin-dependent kinase 2, vascular endothelial growth factor receptor 2, HIV reverse transcriptase, and HIV protease. We find significant improvements of virtual-screening enrichments when compared to rigid-receptor methods. The predictive power of MedusaDock in cross-docking and preliminary virtual-screening benchmarks highlights the importance to model both ligand and receptor flexibility simultaneously in computational docking. PMID:20712341

  6. PLIP: fully automated protein–ligand interaction profiler

    PubMed Central

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

    2015-01-01

    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

  7. Probing heterotrimeric G protein activation: applications to biased ligands.

    PubMed

    Denis, Colette; Saulière, Aude; Galandrin, Segolene; Sénard, Jean-Michel; Galés, Céline

    2012-01-01

    Cell surface G protein-coupled receptors (GPCRs) drive numerous signaling pathways involved in the regulation of a broad range of physiologic processes. Today, they represent the largest target for modern drugs development with potential application in all clinical fields. Recently, the concept of "ligand-directed trafficking" has led to a conceptual revolution in pharmacological theory, thus opening new avenues for drug discovery. Accordingly, GPCRs do not function as simple on-off switch but rather as filters capable of selecting the activation of specific signals and thus generating texture responses to ligands, a phenomenon often referred to as ligand-biased signaling. Also, one challenging task today remains optimization of pharmacological assays with increased sensitivity so to better appreciate the inherent texture of ligands. However, considering that a single receptor has pleiotropic signaling properties and that each signal can crosstalk at different levels, biased activity remains thus difficult to evaluate. One strategy to overcome these limitations would be examining the initial steps following receptor activation. Even, if some G protein independent functions have been recently described, heterotrimeric G protein activation remains a general hallmark for all GPCRs families and the first cellular event subsequent to agonist binding to the receptor. Herein, we review the different methodologies classically used or recently developed to monitor G protein activation and discussed them in the context of G protein biased-ligands. PMID:22229559

  8. 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

  9. 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

  10. 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.

  11. 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.

  12. Docking Screens for Novel Ligands Conferring New Biology.

    PubMed

    Irwin, John J; Shoichet, Brian K

    2016-05-12

    It is now plausible to dock libraries of 10 million molecules against targets over several days or weeks. When the molecules screened are commercially available, they may be rapidly tested to find new leads. Although docking retains important liabilities (it cannot calculate affinities accurately nor even reliably rank order high-scoring molecules), it can often can distinguish likely from unlikely ligands, often with hit rates above 10%. Here we summarize the improvements in libraries, target quality, and methods that have supported these advances, and the open access resources that make docking accessible. Recent docking screens for new ligands are sketched, as are the binding, crystallographic, and in vivo assays that support them. Like any technique, controls are crucial, and key experimental ones are reviewed. With such controls, docking campaigns can find ligands with new chemotypes, often revealing the new biology that may be docking's greatest impact over the next few years. PMID:26913380

  13. Aryl hydrocarbon receptor ligands in cancer: friend and foe.

    PubMed

    Murray, Iain A; Patterson, Andrew D; Perdew, Gary H

    2014-12-01

    The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that is best known for mediating the toxicity and tumour-promoting properties of the carcinogen 2,3,7,8-tetrachlorodibenzo-p-dioxin, commonly referred to as ‘dioxin’. AHR influences the major stages of tumorigenesis — initiation, promotion, progression and metastasis — and physiologically relevant AHR ligands are often formed during disease states or during heightened innate and adaptive immune responses. Interestingly, ligand specificity and affinity vary between rodents and humans. Studies of aggressive tumours and tumour cell lines show increased levels of AHR and constitutive localization of this receptor in the nucleus. This suggests that the AHR is chronically activated in tumours, thus facilitating tumour progression. This Review discusses the role of AHR in tumorigenesis and the potential for therapeutic modulation of its activity in tumours. PMID:25568920

  14. 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.

  15. Identification of nucleolin as a new L-selectin ligand.

    PubMed Central

    Harms, G; Kraft, R; Grelle, G; Volz, B; Dernedde, J; Tauber, R

    2001-01-01

    Apart from leucocyte-endothelial interactions, the adhesion molecule L-selectin mediates the homotypic adhesion of leucocytes during recruitment at sites of acute inflammation, as well as intercellular adhesion of haematopoietic progenitor cells during haematopoiesis. There is evidence that, in addition to P-selectin glycoprotein ligand-1, other as-yet-unidentified proteins function as L-selectin ligands on human leucocytes and haematopoietic progenitor cells. In the present study, we show: (i) by affinity chromatography on L-selectin-agarose; (ii) by protein identification using MS; and (iii) by covalent cell-surface labelling with sulphosuccinimidyl-2-(biotinamido)ethyl-1,3-dithiopropionate that the multifunctional nuclear protein nucleolin is partly exposed on the cell surface, and is a ligand of L-selectin in human leucocytes and haematopoietic progenitor cells. PMID:11736641

  16. Ligands for the Nuclear Peroxisome Proliferator-Activated Receptor Gamma.

    PubMed

    Sauer, Sascha

    2015-10-01

    Nuclear receptors are ligand-activated transcription factors, which represent a primary class of drug targets. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) is a key player in various biological processes. PPARγ is widely known as the target protein of the thiazolidinediones for treating type 2 diabetes. Moreover, PPARγ ligands can induce anti-inflammatory and potentially additional beneficial effects. Recent mechanistic insights of PPARγ modulation give hope the next generation of efficient PPARγ-based drugs with fewer side effects can be developed. Furthermore, chemical approaches that make use of synergistic action of combinatorial ligands are promising alternatives for providing tailored medicine. Lessons learned from fine-tuning the action of PPARγ can provide avenues for efficient molecular intervention via many other nuclear receptors to combat common diseases. PMID:26435213

  17. 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

  18. Chiroptical activity in colloidal quantum dots coated with achiral ligands.

    PubMed

    Melnikau, Dzmitry; Savateeva, Diana; Gaponik, Nikolai; Govorov, Alexander O; Rakovich, Yury P

    2016-01-25

    We studied the chiroptical properties of colloidal solution of CdSe and CdSe/ZnS quantum dots (QDs) with a cubic lattice structure which were initially prepared without use of any chiral molecules and coated with achiral ligands. We demonstrate circular dichroism (CD) activity around first and second excitonic transition of these CdSe based nanocrystals. We consider that this chiroptical activity is caused by imbalance in racemic mixtures of QDs between the left and right handed nanoparticles, which appears as a result of the formation of various defects or incorporation of impurities into crystallographic structure during their synthesis. We demonstrate that optical activity of colloidal solution of CdSe QDs with achiral ligands weakly depends on the QDs size and number of ZnS monolayers, but does not depend on the nature of achiral ligands or polarity of the solution. PMID:26832599

  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. Ligand-gated Diffusion Across the Bacterial Outer Membrane

    SciTech Connect

    B Lepore; M Indic; H Pham; E Hearn; D Patel; B van den Berg

    2011-12-31

    Ligand-gated channels, in which a substrate transport pathway is formed as a result of the binding of a small-molecule chemical messenger, constitute a diverse class of membrane proteins with important functions in prokaryotic and eukaryotic organisms. Despite their widespread nature, no ligand-gated channels have yet been found within the outer membrane (OM) of Gram-negative bacteria. Here we show, using in vivo transport assays, intrinsic tryptophan fluorescence and X-ray crystallography, that high-affinity (submicromolar) substrate binding to the OM long-chain fatty acid transporter FadL from Escherichia coli causes conformational changes in the N terminus that open up a channel for substrate diffusion. The OM long-chain fatty acid transporter FadL from E. coli is a unique paradigm for OM diffusion-driven transport, in which ligand gating within a {beta}-barrel membrane protein is a prerequisite for channel formation.

  1. 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

  2. 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

  3. RIBOSE MODIFIED NUCLEOSIDES AND NUCLEOTIDES AS LIGANDS FOR PURINE RECEPTORS

    PubMed Central

    Ravi, R. G.; Nandanan, E.; Kim, H. S.; Moro, S.; Kim, Y. C.; Lee, K.; Barak, D.; Marquez, V. E.; Ji, X. D.

    2016-01-01

    Molecular modeling of receptors for adenosine and nucleotide (P2) receptors with docked ligand, based on mutagenesis, was carried out. Adenosine 3′,5′-bisphosphate derivatives act as selective P2Y1 antagonists/partial agonists. The ribose moiety was replaced with carbocyclics, smaller and larger rings, conformationally constrained rings, and acyclics, producing compounds that retained receptor affinity. Conformational constraints were built into the ribose rings of nucleoside and nucleotide ligands using the methanocarba approach, i.e. fused cyclopropane and cyclopentane rings in place of ribose, suggesting a preference for the Northern (N) conformation among ligands for P2Y1 and A1 and A3ARs. PMID:11563046

  4. 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.

  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. 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. PMID:26238176

  7. Improved Estimation of Protein-Ligand Binding Free Energy by Using the Ligand-Entropy and Mobility of Water Molecules

    PubMed Central

    Fukunishi, Yoshifumi; Nakamura, Haruki

    2013-01-01

    We previously developed the direct interaction approximation (DIA) method to estimate the protein-ligand binding free energy (ΔG). The DIA method estimates the ΔG value based on the direct van der Waals and electrostatic interaction energies between the protein and the ligand. In the current study, the effect of the entropy of the ligand was introduced with protein dynamic properties by molecular dynamics simulations, and the interaction between each residue of the protein and the ligand was also weighted considering the hydration of each residue. The molecular dynamics simulation of the apo target protein gave the hydration effect of each residue, under the assumption that the residues, which strongly bind the water molecules, are important in the protein-ligand binding. These two effects improved the reliability of the DIA method. In fact, the parameters used in the DIA became independent of the target protein. The averaged error of ΔG estimation was 1.3 kcal/mol and the correlation coefficient between the experimental ΔG value and the calculated ΔG value was 0.75. PMID:24276169

  8. Secondary ligand-directed assembly of Co(II) coordination polymers based on a pyridine carboxylate ligand

    NASA Astrophysics Data System (ADS)

    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 [CoL2(H2O)2]n·2nH2O (1), which possesses a 1D chain structure. In the presence of ancillary ligands, namely, 1,3-adamantanedicarboxylic acid (H2adbc), terephthalic acid (H2tpa), thiophene-2,5-dicarboxylic acid (H2tdc) and 1,4-benzenedithioacetic acid (H2bdtc), four 3D structures [Co2L2(adbc)]n·nH2O (2), [Co2L2(tpa)]n (3), [Co2L2(tdc)]n (4), [Co2L2(bdtc)(H2O)]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.

  9. 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.

  10. 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

  11. Synthesis, characterization and antibacterial studies on some mixed ligand thorium complexes with N- and O-donor ligands.

    PubMed

    Patil, Sunil S; Thakur, Ganesh A; Shaikh, Manzoor M

    2011-01-01

    Mixed ligand Th(IV) complexes of the type [M(Q)(L)(NO3)2] x 2H2O have been synthesized using 8-hydroxyquinoline (HQ) as a primary ligand and N- and/or O- donor amino acids (HL) such as L-threonine, L-tryptophan and L-isoleucine as secondary ligands. The metal complexes have been characterized on the basis of elemental analysis, electrical conductance, room temperature magnetic susceptibility measurements, spectral and thermal studies. The electrical conductance studies of the complexes in DMF in 10(-3). M concentration indicate their non-electrolytic nature. Room temperature magnetic susceptibility measurements revealed diamagnetic nature of the complexes. Electronic absorption spectra of the complexes show intra-ligand and charge transfer transitions, respectively. Bonding of the metal ion through N- and O-donor atoms of the ligands revealed by IR studies and the chemical environment of the protons is also confirmed by NMR studies. The thermal analysis data of the complexes indicate the presence of crystalline water molecules. The tube dilution method has been used to study the antibacterial activity of the complexes against the pathogenic bacteria S. aureus, C. diphtheriae, S. typhi and E. coli. PMID:22125953

  12. Cellular trafficking of quantum dot-ligand bioconjugates and their induction of changes in normal routing of unconjugated ligands.

    PubMed

    Tekle, Christina; Deurs, Bo van; Sandvig, Kirsten; Iversen, Tore-Geir

    2008-07-01

    Can quantum dots (Qdots) act as relevant intracellular probes to investigate routing of ligands in live cells? The intracellular trafficking of Qdots that were coupled to the plant toxin ricin, Shiga toxin, or the ligand transferrin (Tf) was studied by confocal fluorescence microscopy. The Tf:Qdots were internalized by clathrin-dependent endocytosis as fast as Tf, but their recycling was blocked. Unlike Shiga toxin, the Shiga:Qdot bioconjugate was not routed to the Golgi apparatus. The internalized ricin:Qdot bioconjugates localized to the same endosomes as ricin itself but could not be visualized in the Golgi apparatus. Importantly, we find that the endosomal accumulation of ricin:Qdots affects endosome-to-Golgi transport of both ricin and Shiga toxin: Transport of ricin was reduced whereas transport of Shiga toxin was increased. In conclusion, the data reveal that, although coupling of Qdots to a ligand does not necessarily change the endocytic pathway normally used by the ligands studied, it appears that the ligand-coupled Qdot nanoparticles can be arrested within endosomes and somehow perturb the normal endosomal sorting in cells. Thus, the results demonstrate that Qdots may have severe consequences on cell physiology. PMID:18570482

  13. 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

  14. Dithiocarbamates as capping ligands for water-soluble quantum dots.

    PubMed

    Zhang, Yanjie; Schnoes, Allison M; Clapp, Aaron R

    2010-11-01

    We investigated the suitability of dithiocarbamate (DTC) species as capping ligands for colloidal CdSe-ZnS quantum dots (QDs). DTC ligands are generated by reacting carbon disulfide (CS(2)) with primary or secondary amines on appropriate precursor molecules. A biphasic exchange procedure efficiently replaces the existing hydrophobic capping ligands on the QD surface with the newly formed DTCs. The reaction conversion is conveniently monitored by UV-vis absorption spectroscopy. Due to their inherent water solubility and variety of side chain functional groups, we used several amino acids as precursors in this reaction/exchange procedure. The performance of DTC-ligands, as evaluated by the preservation of luminescence and colloidal stability, varied widely among amino precursors. For the best DTC-ligand and QD combinations, the quantum yield of the water-soluble QDs rivaled that of the original hydrophobic-capped QDs dispersed in organic solvents. The mean density of DTC-ligands per nanocrystal was estimated through a mass balance calculation which suggested nearly complete coverage of the available nanocrystal surface. The accessibility of the QD surface was evaluated by self-assembly of His-tagged dye-labeled proteins and peptides using fluorescence resonance energy transfer. DTC-capped QDs were also exposed to cell cultures to evaluate their stability and potential use for biological applications. In general, DTC-capped CdSe-ZnS QDs have many advantages over other water-soluble QD formulations and provide a flexible chemistry for controlling the QD surface functionalization. Despite previous literature reports of DTC-stabilized nanocrystals, this study is the first formal investigation of a biphasic exchange method for generating biocompatible core-shell QDs. PMID:21053924

  15. Protein-ligand docking with multiple flexible side chains.

    PubMed

    Zhao, Yong; Sanner, Michel F

    2008-09-01

    In this work, we validate and analyze the results of previously published cross docking experiments and classify failed dockings based on the conformational changes observed in the receptors. We show that a majority of failed experiments (i.e. 25 out of 33, involving four different receptors: cAPK, CDK2, Ricin and HIVp) are due to conformational changes in side chains near the active site. For these cases, we identify the side chains to be made flexible during docking calculation by superimposing receptors and analyzing steric overlap between various ligands and receptor side chains. We demonstrate that allowing these side chains to assume rotameric conformations enables the successful cross docking of 19 complexes (ligand all atom RMSD < 2.0 A) using our docking software FLIPDock. The number of side receptor side chains interacting with a ligand can vary according to the ligand's size and shape. Hence, when starting from a complex with a particular ligand one might have to extend the region of potential interacting side chains beyond the ones interacting with the known ligand. We discuss distance-based methods for selecting additional side chains in the neighborhood of the known active site. We show that while using the molecular surface to grow the neighborhood is more efficient than Euclidian-distance selection, the number of side chains selected by these methods often remains too large and additional methods for reducing their count are needed. Despite these difficulties, using geometric constraints obtained from the network of bonded and non-bonded interactions to rank residues and allowing the top ranked side chains to be flexible during docking makes 22 out of 25 complexes successful. PMID:18034309

  16. Bifunctional Ligands Allow Deliberate Extrinsic Reprogramming of the Glucocorticoid Receptor

    PubMed Central

    Højfeldt, Jonas W.; Cruz-Rodríguez, Osvaldo; Imaeda, Yasuhiro; Van Dyke, Aaron R.; Carolan, James P.; Mapp, Anna K.

    2014-01-01

    Therapies based on conventional nuclear receptor ligands are extremely powerful, yet their broad and long-term use is often hindered by undesired side effects that are often part of the receptor's biological function. Selective control of nuclear receptors such as the glucocorticoid receptor (GR) using conventional ligands has proven particularly challenging. Because they act solely in an allosteric manner, conventional ligands are constrained to act via cofactors that can intrinsically partner with the receptor. Furthermore, effective means to rationally encode a bias for specific coregulators are generally lacking. Using the (GR) as a framework, we demonstrate here a versatile approach, based on bifunctional ligands, that extends the regulatory repertoire of GR in a deliberate and controlled manner. By linking the macrolide FK506 to a conventional agonist (dexamethasone) or antagonist (RU-486), we demonstrate that it is possible to bridge the intact receptor to either positively or negatively acting coregulatory proteins bearing an FK506 binding protein domain. Using this strategy, we show that extrinsic recruitment of a strong activation function can enhance the efficacy of the full agonist dexamethasone and reverse the antagonist character of RU-486 at an endogenous locus. Notably, the extrinsic recruitment of histone deacetylase-1 reduces the ability of GR to activate transcription from a canonical GR response element while preserving ligand-mediated repression of nuclear factor-κB. By providing novel ways for the receptor to engage specific coregulators, this unique ligand design approach has the potential to yield both novel tools for GR study and more selective therapeutics. PMID:24422633

  17. Nanocrystal Inks without Ligands: Stable Colloids of Bare Germanium Nanocrystals

    SciTech Connect

    Holman, Zachary C.; Kortshagen, Uwe R.

    2011-05-11

    Colloidal semiconductor nanocrystals typically have ligands attached to their surfaces that afford solubility in common solvents but hinder charge transport in nanocrystal films. Here, an alternative route is explored in which bare germanium nanocrystals are solubilized by select solvents to form stable colloids without the use of ligands. A survey of candidate solvents shows that germanium nanocrystals are completely solubilized by benzonitrile, likely because of electrostatic stabilization. Films cast from these dispersions are uniform, dense, and smooth, making them suitable for device applications without postdeposition treatment.

  18. 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.

  19. Two ligands for a GPCR, proton vs lysolipid.

    PubMed

    Im, Dong-Soon

    2005-12-01

    Recently, two different chemicals have been matched as ligands with the same G-protein-coupled receptor (GPCR). Double-pairing of OGR1 family GPCRs with proton and lysolipid raises several questions. First, whether both are the real ligands for the GPCRs. Second, whether modulation of a GPCR by two chemicals could be possible. Third, one of the chemicals is proton. Proton-sensing not only is a new action mode of GPCR activation, but also it could be generalized in other GPCRs. In this review, I would like to summarize the issue and discuss questions with pharmacological criteria. PMID:16297340

  20. 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.

  1. 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.

  2. 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.

  3. Ultrafast electron trapping in ligand-exchanged quantum dot assemblies.

    PubMed

    Turk, Michael E; Vora, Patrick M; Fafarman, Aaron T; Diroll, Benjamin T; Murray, Christopher B; Kagan, Cherie R; Kikkawa, James M

    2015-02-24

    We use time-integrated and time-resolved photoluminescence and absorption to characterize the low-temperature optical properties of CdSe quantum dot solids after exchanging native aliphatic ligands for thiocyanate and subsequent thermal annealing. In contrast to trends established at room temperature, our data show that at low temperature the band-edge absorptive bleach is dominated by 1S3/2h hole occupation in the quantum dot interior. We find that our ligand treatments, which bring enhanced interparticle coupling, lead to faster surface state electron trapping, a greater proportion of surface-related photoluminescence, and decreased band-edge photoluminescence lifetimes. PMID:25635923

  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. Coordination chemistry of poly(thioether)borate ligands.

    PubMed

    Riordan, Charles G

    2010-08-01

    This review traces the development and application of the tris(thioether)borate ligands, tripodal ligands with highly polarizable thioether donors. Areas of emphasis include the basic coordination chemistry of the mid-to-late first row transition metals (Fe, Ni, Co, Cu), and the role of the thioether substituent in directing complex formation, the modeling of zinc thiolate protein active sites, high-spin organo-iron and organo-cobalt chemistry, the preparation of monovalent complexes of Fe, Co and Ni, and dioxygen and sulfur activation by monovalent nickel complexes. PMID:20607091

  6. Glucagon-Like Peptide-1 Receptor Ligand Interactions: Structural Cross Talk between Ligands and the Extracellular Domain

    PubMed Central

    West, Graham M.; Willard, Francis S.; Sloop, Kyle W.; Showalter, Aaron D.; Pascal, Bruce D.; Griffin, Patrick R.

    2014-01-01

    Activation of the glucagon-like peptide-1 receptor (GLP-1R) in pancreatic β-cells potentiates insulin production and is a current therapeutic target for the treatment of type 2 diabetes mellitus (T2DM). Like other class B G protein-coupled receptors (GPCRs), the GLP-1R contains an N-terminal extracellular ligand binding domain. N-terminal truncations on the peptide agonist generate antagonists capable of binding to the extracellular domain, but not capable of activating full length receptor. The main objective of this study was to use Hydrogen/deuterium exchange (HDX) to identify how the amide hydrogen bonding network of peptide ligands and the extracellular domain of GLP-1R (nGLP-1R) were altered by binding interactions and to then use this platform to validate direct binding events for putative GLP-1R small molecule ligands. The HDX studies presented here for two glucagon-like peptide-1 receptor (GLP-1R) peptide ligands indicates that the antagonist exendin-4[9-39] is significantly destabilized in the presence of nonionic detergents as compared to the agonist exendin-4. Furthermore, HDX can detect stabilization of exendin-4 and exendin-4[9-39] hydrogen bonding networks at the N-terminal helix [Val19 to Lys27] upon binding to the N-terminal extracellular domain of GLP-1R (nGLP-1R). In addition we show hydrogen bonding network stabilization on nGLP-1R in response to ligand binding, and validate direct binding events with the extracellular domain of the receptor for putative GLP-1R small molecule ligands. PMID:25180755

  7. Predicting Electrophoretic Mobility of Protein-Ligand Complexes for Ligands from DNA-Encoded Libraries of Small Molecules.

    PubMed

    Bao, Jiayin; Krylova, Svetlana M; Cherney, Leonid T; Hale, Robert L; Belyanskaya, Svetlana L; Chiu, Cynthia H; Shaginian, Alex; Arico-Muendel, Christopher C; Krylov, Sergey N

    2016-05-17

    Selection of target-binding ligands from DNA-encoded libraries of small molecules (DELSMs) is a rapidly developing approach in drug-lead discovery. Methods of kinetic capillary electrophoresis (KCE) may facilitate highly efficient homogeneous selection of ligands from DELSMs. However, KCE methods require accurate prediction of electrophoretic mobilities of protein-ligand complexes. Such prediction, in turn, requires a theory that would be applicable to DNA tags of different structures used in different DELSMs. Here we present such a theory. It utilizes a model of a globular protein connected, through a single point (small molecule), to a linear DNA tag containing a combination of alternating double-stranded and single-stranded DNA (dsDNA and ssDNA) regions of varying lengths. The theory links the unknown electrophoretic mobility of protein-DNA complex with experimentally determined electrophoretic mobilities of the protein and DNA. Mobility prediction was initially tested by using a protein interacting with 18 ligands of various combinations of dsDNA and ssDNA regions, which mimicked different DELSMs. For all studied ligands, deviation of the predicted mobility from the experimentally determined value was within 11%. Finally, the prediction was tested for two proteins and two ligands with a DNA tag identical to those of DELSM manufactured by GlaxoSmithKline. Deviation between the predicted and experimentally determined mobilities did not exceed 5%. These results confirm the accuracy and robustness of our model, which makes KCE methods one step closer to their practical use in selection of drug leads, and diagnostic probes from DELSMs. PMID:27119259

  8. 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.

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

    PubMed

    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(+) [BAr(4)](-) (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

  10. 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.

  11. 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

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

    PubMed

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

    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(2)O 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*, DeltaH*, DeltaS* and DeltaG* 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. PMID:15741103

  13. Local Innate Responses to TLR Ligands in the Chicken Trachea

    PubMed Central

    Barjesteh, Neda; Alkie, Tamiru Negash; Hodgins, Douglas C.; Nagy, Éva; Sharif, Shayan

    2016-01-01

    The chicken upper respiratory tract is the portal of entry for respiratory pathogens, such as avian influenza virus (AIV). The presence of microorganisms is sensed by pathogen recognition receptors (such as Toll-like receptors (TLRs)) of the innate immune defenses. Innate responses are essential for subsequent induction of potent adaptive immune responses, but little information is available about innate antiviral responses of the chicken trachea. We hypothesized that TLR ligands induce innate antiviral responses in the chicken trachea. Tracheal organ cultures (TOC) were used to investigate localized innate responses to TLR ligands. Expression of candidate genes, which play a role in antiviral responses, was quantified. To confirm the antiviral responses of stimulated TOC, chicken macrophages were treated with supernatants from stimulated TOC, prior to infection with AIV. The results demonstrated that TLR ligands induced the expression of pro-inflammatory cytokines, type I interferons and interferon stimulated genes in the chicken trachea. In conclusion, TLR ligands induce functional antiviral responses in the chicken trachea, which may act against some pathogens, such as AIV. PMID:27455308

  14. 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.

  15. (Hydro)peroxide ligands on colloidal cerium oxide nanoparticles.

    PubMed

    Damatov, Delina; Mayer, James M

    2016-08-11

    Anhydrous H2O2 reacts with organic colloidal solutions of ceria nanoparticles to form a stable surface peroxo/hydroperoxo species with the release of oleate capping ligands into solution. A new optical spectroscopic signature was identified for cerium-peroxo/hydroperoxo species in solution and correlated with solid-state IR spectroscopy and chemical reactivity. PMID:27468991

  16. NAIP inflammasomes give the NOD to bacterial ligands.

    PubMed

    Maltez, Vivien I; Miao, Edward A

    2014-11-01

    NLRs are innate immune sensors that monitor the sanctity of the cytosolic compartment. In a recent paper in Molecular Cell, Tenthorey et al. reveal a novel ligand-sensing interface within regions of the oligomerization domain of the NAIPs, rather than within the leucine-rich repeats, as was anticipated. PMID:25443492

  17. Selective Electrocatalytic Activity of Ligand Stabilized Copper Oxide Nanoparticles

    SciTech Connect

    Kauffman, Douglas R; Ohodnicki, Paul R; Kail, Brian W; Matranga, Christopher

    2011-01-01

    Ligand stabilization can influence the surface chemistry of Cu oxide nanoparticles (NPs) and provide unique product distributions for electrocatalytic methanol (MeOH) oxidation and CO{sub 2} reduction reactions. Oleic acid (OA) stabilized Cu{sub 2}O and CuO NPs promote the MeOH oxidation reaction with 88% and 99.97% selective HCOH formation, respectively. Alternatively, CO{sub 2} is the only reaction product detected for bulk Cu oxides and Cu oxide NPs with no ligands or weakly interacting ligands. We also demonstrate that OA stabilized Cu oxide NPs can reduce CO{sub 2} into CO with a {approx}1.7-fold increase in CO/H{sub 2} production ratios compared to bulk Cu oxides. The OA stabilized Cu oxide NPs also show 7.6 and 9.1-fold increases in CO/H{sub 2} production ratios compared to weakly stabilized and non-stabilized Cu oxide NPs, respectively. Our data illustrates that the presence and type of surface ligand can substantially influence the catalytic product selectivity of Cu oxide NPs.

  18. 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. PMID:25535798

  19. REACTIVITY PROFILE OF CONFORMATIONALLY-FLEXIBLE RETINOID RECEPTOR LIGANDS

    EPA Science Inventory

    Retinoids and associated derivatives represent a class of endogenousr hormones that bind to and activate different families of retinoic acid receptors (RARs, RXRs), and control many aspects of normal vertebrate development. Identification of potential RAR and RXRs ligands is of i...

  20. The imidazoline receptors and ligands in pain modulation

    PubMed Central

    Bektas, Nurcan; Nemutlu, Dilara; Arslan, Rana

    2015-01-01

    Pain is an unpleasant experience and effects daily routine negatively. Although there are various drugs, many of them are not entirely successful in relieving pain, since pain modulation is a complex process involving numerous mediators and receptors. Therefore, it is a rational approach to identify the factors involved in the complex process and develop new agents that act on these pain producing mechanisms. In this respect, the involvement of the imidazoline receptors in pain modulation has drawn attention in recent years. In this review, it is aimed to focus on the imidazoline receptors and their ligands which contribute to the pain modulation. It is demonstrated that imidazoline-2 (I2) receptors are steady new drug targets for analgesics. Even if the mechanism of I2 receptor is not well known in the modulation of pain, it is known that it plays a role in tonic and chronic pain but not in acute phasic pain. Moreover, the I2 receptor ligands increase the analgesic effects of opioids in both acute and chronic pain and prevent the development of opioid tolerance. So, they are valuable for the chronic pain treatment and also therapeutic coadjuvants in the management of chronic pain with opiate drugs due to the attenuation of opioid tolerance and addiction. Thus, the use of the ligands which bind to the imidazoline receptors is an effective strategy for relieving pain. This educational forum exhibits the role of imidazoline receptors and ligands in pain process by utilizing experimental studies. PMID:26600633

  1. 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…

  2. Synthesis of supported metal nanoparticle catalysts using ligand assisted methods.

    PubMed

    Costa, Natalia J S; Rossi, Liane M

    2012-09-28

    The synthesis and characterization methods of metal nanoparticles (NPs) have advanced greatly in the last few decades, allowing an increasing understanding of structure-property-performance relationships. However, the role played by the ligands used as stabilizers for metal NPs synthesis or for NPs immobilization on solid supports has been underestimated. Here, we highlight some recent progress in the preparation of supported metal NPs with the assistance of ligands in solution or grafted on solid supports, a modified deposition-reduction method, with special attention to the effects on NPs size, metal-support interactions and, more importantly, catalytic activities. After presenting the general strategies in metal NP synthesis assisted by ligands grafted on solid supports, we highlight some recent progress in the deposition of pre-formed colloidal NPs on functionalized solids. Another important aspect that will be reviewed is related to the separation and recovery of NPs. Finally, we will outline our personal understanding and perspectives on the use of supported metal NPs prepared through ligand-assisted methods. PMID:22915064

  3. Solvent-induced desorption of alkanethiol ligands from Au nanoparticles.

    PubMed

    Huang, Yuanyuan; Liu, Wei; Cheng, Hao; Yao, Tao; Yang, Lina; Bao, Jie; Huang, Ting; Sun, Zhihu; Jiang, Yong; Wei, Shiqiang

    2016-06-21

    Removing surfactants from a colloidal metal nanoparticle surface is necessary for their realistic applications, and how they could be stripped is a subject of active investigation. Here, we report a solvent-induced desorption of dodecanethiol ligands from the gold nanoparticle surface, and traced this desorption process using a combination of in situ X-ray absorption fine structure (XAFS) and Raman spectroscopic techniques. In situ analysis results reveal that the solvent exchange of ethanol with tetrahydrofuran (THF) can effectively remove dodecanethiol ligands while keeping the particle morphology unchanged. Upon increasing the THF/ethanol ratio from 0 : 1 to 5 : 1, the surface coverage of thiol on the Au surface is reduced from 0.47 to 0.07, suggesting the depletion of ligands first from the nanoparticle facet sites, then from the edge sites, while the ligands at the corner sites are intact. This work enriches our knowledge on surfactant removal and may pave the way towards preparing surface-clean nanoparticles for practical applications. PMID:27241025

  4. Theoretical investigations of silver clusters and silver-ligand systems.

    SciTech Connect

    Jellinek, J.; Salian, U.; Srinivas, S.

    1999-05-19

    Studies directed at understanding structural and electronic properties of silver clusters have been and remain the subject of an active theoretical [1-22] and experimental [23- 38] effort. One of the reasons is the (still) important role these systems play in the photographic process. Investigations of interactions of silver clusters with different atoms and molecules are motivated primarily by a possible utility of these clusters in catalytic processes. The important role of silver in the selective oxidation of ethylene into ethylene oxide, the feedstock for polyester production, is well-known [39]. Possible variations in chemical reactivity with the cluster size and understanding of the mechanisms of interactions with different ligands may lead to new and more efficient applications. Investigations of cluster-ligand systems also contribute a great deal to a better understanding of gas-surface interactions. Accordingly, theoretical studies of silver clusters and cluster-ligand systems [40-44] fall into two categories--those that use clusters as models for silver surfaces [40], and those that target clusters and cluster-ligand interactions as subjects in their own right [41-44]. The common goal of all these studies is to elucidate the nature of the interatomic interactions and bonding at the microscopic level and thereby arrive at a fundamental understanding and description of the various structural and electronic properties.

  5. The biologically active conformations of ligand CCK B receptor

    NASA Astrophysics Data System (ADS)

    Kuznetsov, Pavel E.; Kuznetsova, Nina B.; Schulgin, Sergey V.; Rogacheva, Svetlana M.; Sinyakov, Valeriy V.; Kovtun, Viktor A.

    2006-07-01

    We analyzed literature data about structures of ligands of CCK B receptor. The structure of the binding site (fragments of the third extracellular loop and the seventh transmembrane helix of CCK B receptor) was determined recently by experiments. We were finding presumable biologically active conformations (BAC) of the ligands by two methods. One of them is based on the fact that the most stable conformations of the biologically active peptide on the phase interface "water-lipophilic medium" are often similar to the BAC. Another method is based on the formation of the stable ligand-receptor complex during the modeling procedure. We used Monte-Carlo method with the fixed geometry of the receptor and the optimized geometry of tetrapeptide cholecystokinin (CCK-4). It has been shown, that the first method should be used to find BAC of antagonists of CCK B receptor. The strategy of the formation of the stable ligand-receptor complex during the modeling procedure can be used for the designing of peptide agonists of CCK B receptor.

  6. Local Innate Responses to TLR Ligands in the Chicken Trachea.

    PubMed

    Barjesteh, Neda; Alkie, Tamiru Negash; Hodgins, Douglas C; Nagy, Éva; Sharif, Shayan

    2016-01-01

    The chicken upper respiratory tract is the portal of entry for respiratory pathogens, such as avian influenza virus (AIV). The presence of microorganisms is sensed by pathogen recognition receptors (such as Toll-like receptors (TLRs)) of the innate immune defenses. Innate responses are essential for subsequent induction of potent adaptive immune responses, but little information is available about innate antiviral responses of the chicken trachea. We hypothesized that TLR ligands induce innate antiviral responses in the chicken trachea. Tracheal organ cultures (TOC) were used to investigate localized innate responses to TLR ligands. Expression of candidate genes, which play a role in antiviral responses, was quantified. To confirm the antiviral responses of stimulated TOC, chicken macrophages were treated with supernatants from stimulated TOC, prior to infection with AIV. The results demonstrated that TLR ligands induced the expression of pro-inflammatory cytokines, type I interferons and interferon stimulated genes in the chicken trachea. In conclusion, TLR ligands induce functional antiviral responses in the chicken trachea, which may act against some pathogens, such as AIV. PMID:27455308

  7. Tunable P-Chiral Bisdihydrobenzooxaphosphole Ligands for Enantioselective Hydroformylation.

    PubMed

    Tan, Renchang; Zheng, Xin; Qu, Bo; Sader, C Avery; Fandrick, Keith R; Senanayake, Chris H; Zhang, Xumu

    2016-07-15

    Air-stable and tunable chiral bisdihydrobenzooxaphosphole ligands (BIBOPs) were employed in rhodium-catalyzed asymmetric hydroformylation of various terminal olefins with excellent conversions (>99%), moderate-to-excellent enantioselectivities (up to 95:5 er), and branched to linear ratios (b:l) of up to 400. PMID:27333435

  8. 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

  9. Molecules with polymerizable ligands as precursors to porous doped materials

    SciTech Connect

    Hubert-Pfalzgraf, L.G.; Pajot, N.; Papiernik, R.; Parraud, S.

    1996-12-31

    Titanium and aluminum alkoxide derivatives with polymerizable ligands such as 2-(methacryloyloxy)ethylacetoacetate (HAAEMA), oleic acid and geraniol (HOGE) have been obtained. The various compounds have been characterized by FT-IR and NMR {sup 1}H. Copolymerization with styrene and divinylbenzene affords porous doped organic materials which have been characterized by scanning electron microscopy (SEM), elemental analysis, density measurements.

  10. 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

  11. Ligand-Controlled Regiodivergent Copper-Catalyzed Alkylboration of Alkenes.

    PubMed

    Su, Wei; Gong, Tian-Jun; Lu, Xi; Xu, Meng-Yu; Yu, Chu-Guo; Xu, Zheng-Yang; Yu, Hai-Zhu; Xiao, Bin; Fu, Yao

    2015-10-26

    A novel copper-catalyzed regiodivergent alkylboration of alkenes with bis(pinacolato)diboron and alkyl halides has been developed. The regioselectivity of the alkylboration was controlled by subtle differences in the ligand structure. The reaction thus enables the practical, regiodivergent synthesis of two different alkyl boronic esters with complex structures from a single alkene. PMID:26338141

  12. RXR function requires binding to an endogenous terpenoid ligand

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The issue of whether the nuclear receptor RXR must bind to an endogenous, nanomolar affinity ligand in order to perform its natural function is still unsettled (1). On the basis of our previous studies establishing that the Drosophilamelanogaster ortholog of the retinoid X receptor ("ultraspiracle,"...

  13. Ligand Induced Spin Crossover in Penta-Coordinated Ferric Dithiocarbamates

    NASA Astrophysics Data System (ADS)

    Ganguli, P.; Iyer, R. M.

    1981-09-01

    On addition of lewis bases to Fe(dtc)2X, ligand exchange takes place through a SN2 mechanism, with a parallel spin crossover in the ferric ion. The two species (S = 3/2 and S = 5/2) formed are in dynamic chemical equilibrium, and a slow decomposition is then initiated.

  14. Adsorption kinetic process of thiol ligands on gold nanocrystals.

    PubMed

    Cheng, Hao; Yang, Lina; Jiang, Yong; Huang, Yuanyuan; Sun, Zhihu; Zhang, Jing; Hu, Tiandou; Pan, Zhiyun; Pan, Guoqiang; Yao, Tao; Bian, Qing; Wei, Shiqiang

    2013-12-01

    Understanding the kinetic mechanism during ligand adsorption on gold nanocrystals is important for designing and fine-tuning their properties and implications. Here, we report a kinetic study on the adsorption process of dodecanethiol ligands on Au nanocrystals of 3.3 nm by an in situ time-resolved X-ray absorption fine structure technique. A two-step process of dodecanethiol adsorption on Au NC surfaces is proposed based on the obtained ligand coverage, which shows a quick increase from 0 to 0.40 within the first 20 min, followed by a much slower increase to the limiting value of 0.94. In-depth analysis suggests that the first stage involves the quick adsorption of dodecanethiol to the corner and edge sites of Au NCs surfaces, leading to remarkable surface Au-Au bond length relaxation (from 2.79 to 2.81 Å) and pronounced gold-to-ligand charge transfer. The second step that corresponds to the much slower adsorption process to the surface facets could be described by the Langmuir kinetics equation with an adsorption rate constant of 0.0132 min(-1) and an initial coverage of 0.41, in good agreement with the initially preferable adsorption of thiols to the most favorable sites. PMID:24122096

  15. Small Molecule Ligands for Bulged RNA Secondary Structures

    PubMed Central

    Meyer, S. Todd; Hergenrother, Paul J.

    2016-01-01

    A class of wedge-shaped small molecules has been designed, synthesized, and shown to bind bulged RNA secondary structures. These minimally cationic ligands exhibit good affinity and selectivity for certain RNA bulges as demonstrated in a fluorescent intercalator displacement assay. PMID:19678613

  16. Supramolecular coordination and antimicrobial activities of constructed mixed ligand complexes

    NASA Astrophysics Data System (ADS)

    El-Sonbati, A. Z.; Diab, M. A.; El-Bindary, A. A.; Abou-Dobara, M. I.; Seyam, H. A.

    2013-03-01

    A novel series of copper(II) and palladium(II) with 4-derivatives benzaldehyde pyrazolone (Ln) were synthesized. The mixed ligand complexes were prepared by using 1,10-phenanthroline (Phen) as second ligand. The structure of these complexes was identified and confirm by elemental analysis, molar conductivity, UV-Vis, IR and 1H NMR spectroscopy and magnetic moment measurements as well as thermal analysis. The ligand behaves as a neutral bidentate ligand through ON donor sites. ESR spectra show the simultaneous presence of a planar trans and a nearly planar cis isomers in the 1:2 ratio for all N,O complexes [Cu(Ln)2]Cl2ṡ2H2O. Schiff bases (Ln) were tested against bacterial species; namely two Gram positive bacteria (Staphylococcus aureus and Bacillus cereus) and two Gram negative bacteria (Escherichia coli and Klebsiella pneumoniae) and fungal species (Aspergillus niger, Fusarium oxysporium, Penicillium italicum and Alternaria alternata). The tested compounds have antibacterial activity against S. aureus, B. cereus and K. pneumoniae.

  17. Proton-dependent zinc release from intracellular ligands

    PubMed Central

    Kiedrowski, Lech

    2014-01-01

    In cultured cortical and hippocampal neurons when intracellular pH drops from 6.6 to 6.1, yet unclear intracellular stores release micromolar amounts of Zn2+ into the cytosol. Mitochondria, acidic organelles, and/or intracellular ligands could release this Zn2+. Although exposure to the protonophore FCCP precludes re-loading of the mitochondria and acidic organelles with Zn2+, FCCP failed to compromise the ability of the intracellular stores to repeatedly release Zn2+. Therefore, Zn2+-releasing stores were not mitochondria or acidic organelles but rather intracellular Zn2+ ligands. To test which ligands might be involved, the rate of acid-induced Zn2+ release from complexes with cysteine, glutathione, histidine, aspartate, glutamate, glycine, and carnosine was investigated; [Zn2+] was monitored in vitro using the ratiometric Zn2+-sensitive fluorescent probe FuraZin-1. Carnosine failed to chelate Zn2+ but did chelate Cu2+; the remaining ligands chelated Zn2+ and upon acidification were releasing it into the medium. However, when pH was decreasing from 6.6 to 6.1, only zinc-cysteine complexes rapidly accelerated the rate of Zn2+ release. The zinc-cysteine complexes also released Zn2+ when a histidine-modifying agent, diethylpyrocarbonate, was applied at pH 7.2. Since the cytosolic zinc-cysteine complexes can contain micromolar amounts of Zn2+, these complexes may represent the stores responsible for an acid-induced intracellular Zn2+ release. PMID:24606401

  18. Trapping of palindromic ligands within native transthyretin prevents amyloid formation

    PubMed Central

    Kolstoe, Simon E.; Mangione, Palma P.; Bellotti, Vittorio; Taylor, Graham W.; Tennent, Glenys A.; Deroo, Stéphanie; Morrison, Angus J.; Cobb, Alexander J. A.; Coyne, Anthony; McCammon, Margaret G.; Warner, Timothy D.; Mitchell, Jane; Gill, Raj; Smith, Martin D.; Ley, Steven V.; Robinson, Carol V.; Wood, Stephen P.; Pepys, Mark B.

    2010-01-01

    Transthyretin (TTR) amyloidosis is a fatal disease for which new therapeutic approaches are urgently needed. We have designed two palindromic ligands, 2,2'-(4,4'-(heptane-1,7-diylbis(oxy))bis(3,5-dichloro-4,1-phenylene)) bis(azanediyl)dibenzoic acid (mds84) and 2,2'-(4,4'-(undecane-1,11-diylbis(oxy))bis(3,5-dichloro-4,1-phenylene)) bis(azanediyl)dibenzoic acid (4ajm15), that are rapidly bound by native wild-type TTR in whole serum and even more avidly by amyloidogenic TTR variants. One to one stoichiometry, demonstrable in solution and by MS, was confirmed by X-ray crystallographic analysis showing simultaneous occupation of both T4 binding sites in each tetrameric TTR molecule by the pair of ligand head groups. Ligand binding by native TTR was irreversible under physiological conditions, and it stabilized the tetrameric assembly and inhibited amyloidogenic aggregation more potently than other known ligands. These superstabilizers are orally bioavailable and exhibit low inhibitory activity against cyclooxygenase (COX). They offer a promising platform for development of drugs to treat and prevent TTR amyloidosis. PMID:21059958

  19. Diversity of Potassium Channel Ligands: Focus on Scorpion Toxins.

    PubMed

    Kuzmenkov, A I; Grishin, E V; Vassilevski, A A

    2015-12-01

    Potassium (K+) channels are a widespread superfamily of integral membrane proteins that mediate selective transport of K+ ions through the cell membrane. They have been found in all living organisms from bacteria to higher multicellular animals, including humans. Not surprisingly, K+ channels bind ligands of different nature, such as metal ions, low molecular mass compounds, venom-derived peptides, and antibodies. Functionally these substances can be K+ channel pore blockers or modulators. Representatives of the first group occlude the channel pore, like a cork in a bottle, while the second group of ligands alters the operation of channels without physically blocking the ion current. A rich source of K+ channel ligands is venom of different animals: snakes, sea anemones, cone snails, bees, spiders, and scorpions. More than a half of the known K+ channel ligands of polypeptide nature are scorpion toxins (KTx), all of which are pore blockers. These compounds have become an indispensable molecular tool for the study of K+ channel structure and function. A recent special interest is the possibility of toxin application as drugs to treat diseases involving K+ channels or related to their dysfunction (channelopathies). PMID:26878580

  20. Dynamics of methionine ligand rebinding in cytochrome c.

    PubMed

    Zhang, Ping; Małolepsza, Edyta; Straub, John E

    2012-06-14

    Geminate recombination of the methionine ligand to the heme iron in ferrous cytochrome c protein following photodissociation displays rich kinetics. It is of particular interest to develop an understanding of fast and slow rebinding time scales, observed in experimental studies, in terms of features of the underlying complex energy landscape. The classical empirical force field in the heme pocket has been extended by incorporating ab initio potential energy surface calculations representing the ground singlet state and quintet state associated with methionine bond breaking and rebinding. An algorithm based on the Landau-Zener nonadiabatic transition theory has been employed to model the electronic surface hopping between two spin states during the process of ligand dissociation and recombination. Multiple conformational substates of the dissociated methionine ligand are found to participate in the reaction dynamics. Varying time scales for interconversion between substates lead to a mechanism elucidating the fast and slow rebinding time scales. The reaction system may be understood in terms of a two-dimensional reaction coordinate distinctly separated from the coupled bath of surrounding protein and solvent degrees of freedom. Insights into the reaction dynamics provided by this study lead to suggestions for future experiments to further probe the role of dynamic heterogeneity in the kinetics of ligand-protein binding. PMID:22432601

  1. 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…

  2. 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

  3. Spin-dependent mechanism for diatomic ligand binding to heme

    PubMed Central

    Franzen, Stefan

    2002-01-01

    The nature of diatomic ligand recombination in heme proteins is elucidated by using a Landau–Zener model for the electronic coupling in the recombination rate constant. The model is developed by means of explicit potential energy surfaces calculated by using density functional theory (DFT). The interaction of all possible spin states of the three common diatomic ligands, CO, NO, and O2, and high-spin heme iron is compared. The electronic coupling, rebinding barrier, and Landau–Zener force terms can be obtained and used to demonstrate significant differences among the ligands. In particular the intermediate spin states of NO (S = 3/2) and O2 (S = 1) are shown to be bound states. Rapid recombination occurs from these bound states in agreement with experimental data. The slower phases of O2 recombination can be explained by the presence of two higher spin states, S = 2 and S = 3, which have a small and relatively large barrier to ligand recombination, respectively. By contrast, the intermediate spin state for CO is not a bound state, and the only recombination pathway for CO involves direct recombination from the S = 2 state. This process is significantly slower according to the Landau–Zener model. Quantitative estimates of the parameters used in the rate constants provide a complete description that explains rebinding rates that range from femtoseconds to milliseconds at ambient temperature. PMID:12477933

  4. Analyzing Ligand Depletion in a Saturation Equilibrium Binding Experiment

    ERIC Educational Resources Information Center

    Claro, Enrique

    2006-01-01

    I present a proposal for a laboratory practice to generate and analyze data from a saturation equilibrium binding experiment addressed to advanced undergraduate students. [[superscript 3]H]Quinuclidinyl benzilate is a nonselective muscarinic ligand with very high affinity and very low nonspecific binding to brain membranes, which contain a high…

  5. Ultrafast Electron Trapping in Ligand-Exchanged Quantum Dot Assemblies

    NASA Astrophysics Data System (ADS)

    Kikkawa, J. M.; Turk, M. E.; Vora, P. M.; Fafarman, A. T.; Diroll, B. T.; Murray, C. B.; Kagan, C. R.

    2015-03-01

    We use time-integrated and time-resolved photoluminescence and absorption to characterize the low-temperature (10 K) optical properties of CdSe quantum dot (QD) solids with different ligand and annealing preparation. Close-packed CdSe quantum dot solids are prepared with native aliphatic ligands and with thiocyanate with and without thermal annealing. Using sub-picosecond, broadband time-resolved photoluminescence and absorption, we find that ligand exchange increases the rate of carrier surface trapping. We further determine that holes within the QD core, rather than electrons, can bleach the band-edge transition in these samples at low temperature, a finding that comes as a surprise given what is known about the surface treatment in these QDs. We find that our ligand treatments lead to faster electron trapping to the quantum dot surface, a greater proportion of surface photoluminescence, and an increased rate of nonradiative decay due to enhanced interparticle coupling upon exchange and annealing. All aspects of this work supported by the U.S. Department of Energy Office of Basic Energy Sciences, Division of Materials Science and Engineering, under Award No. DE-SC0002158.

  6. Modeling of metal interaction geometries for protein-ligand docking.

    PubMed

    Seebeck, Birte; Reulecke, Ingo; Kämper, Andreas; Rarey, Matthias

    2008-05-15

    The accurate modeling of metal coordination geometries plays an important role for structure-based drug design applied to metalloenzymes. For the development of a new metal interaction model, we perform a statistical analysis of metal interaction geometries that are relevant to protein-ligand complexes. A total of 43,061 metal sites of the Protein Data Bank (PDB), containing amongst others magnesium, calcium, zinc, iron, manganese, copper, cadmium, cobalt, and nickel, were evaluated according to their metal coordination geometry. Based on statistical analysis, we derived a model for the automatic calculation and definition of metal interaction geometries for the purpose of molecular docking analyses. It includes the identification of the metal-coordinating ligands, the calculation of the coordination geometry and the superposition of ideal polyhedra to identify the optimal positions for free coordination sites. The new interaction model was integrated in the docking software FlexX and evaluated on a data set of 103 metalloprotein-ligand complexes, which were extracted from the PDB. In a first step, the quality of the automatic calculation of the metal coordination geometry was analyzed. In 74% of the cases, the correct prediction of the coordination geometry could be determined on the basis of the protein structure alone. Secondly, the new metal interaction model was tested in terms of predicting protein-ligand complexes. In the majority of test cases, the new interaction model resulted in an improved docking accuracy of the top ranking placements. PMID:18041759

  7. Sequestering ability of polycarboxylic ligands towards dioxouranium(VI).

    PubMed

    Crea, Francesco; Foti, Claudia; Sammartano, Silvio

    2008-05-15

    In this paper we report a comparison on the sequestering ability of some polycarboxylic ligands towards dioxouranium(VI) (UO(2)(2+), uranyl). Ligands taken into account are mono- (acetate), di- (oxalate, malonate, succinate and azelate), tri- (1,2,3-propanetricarboxylate) and hexa-carboxylate (1,2,3,4,5,6-benzenehexacarboxylate). The sequestering ability of polycarboxylic ligands towards UO(2)(2+) was quantified by a new approach expressed by means of a sigmoid Boltzman type equation and of a empirical parameters (pL(50)) which defines the amount of ligand necessary to sequester 50% of the total UO(2)(2+) concentration. A fairly linear correlation was obtained between pL(50) or log K(110) (log K(110) refers to the equilibrium: UO(2)(2+)+L(z-)=UO(2)L((2-z)); L=generic ligand) and the polyanion charges. In order to complete the picture, a tetra-carboxylate ligand (1,2,3,4-butanetetracarboxylate) was studied in NaCl aqueous solutions at 0ligand protonation constants and of the complex formation constants of UO(2)(2+)-polycarboxylate systems was modelled by the SIT (specific ion interaction theory) approach and by the Pitzer equations. PMID:18585146

  8. Magnesium incorporation in calcite in the presence of organic ligands

    NASA Astrophysics Data System (ADS)

    Mavromatis, Vasileios; Baldermann, Andre; Purgstaller, Bettina; Dietzel, Martin

    2015-04-01

    The formation of authigenic Mg-calcites in marine early diagenetic environments is commonly driven by a bio-induced process, the anaerobic oxidation of methane (AOM), which provides inorganic carbon required for the precipitation of such authigenic carbonates. In such settings the availability of major and/or trace divalent metal cations (Me2+) incorporated in calcite and their aqueous speciation are controlled by the presence of aqueous organic molecules that are produced either as (by-)products of biological activity (i.e. exopolymeric substances) or during degradation of allochthonous organic matter in the sediments. Despite the fact that the presence of aqueous organic ligands strongly affects the growth rates and the mineralogy of precipitating CaCO3 polymorphs, till now no study addresses the role of Me2+-ligand aqueous complexes on the extent of Mg and/or other trace element content of Mg-calcites. In order to shed light on this process, relevant to authigenic calcite formation in organic-rich marine sediments and continental soils, we precipitated calcite in the presence of aqueous Mg and a variety of low molecular weight carboxylic- and aminoacids. Our experimental data indicate that the presence of organic ligands augments significantly the saturation state of calcite in the parent fluid during its precipitation. Moreover, they suggest that the higher the ligand concentration, the higher the obtained distribution coefficient of Mg in calcite. The latter is directly proportional to the ratio of Mg2+/Ca2+ aqueous ions for all ligands used. Hydrogeochemical modelling of the aqueous fluids indicate that the observed correlation can be explained by the stronger complexation of Ca2+ with organic ligands compared to Mg2+, which results in higher availability of Mg2+ vs. Ca2+ aqueous ions. Overall the obtained results suggest that the higher the organic ligand aqueous concentration the higher the Mg content of calcite forming from this fluid. These findings are

  9. Electron Transfer Reactions in Colloidal Quantum Dot-Ligand Complexes

    NASA Astrophysics Data System (ADS)

    Morris-Cohen, Adam Joshua

    This thesis describes a quantitative analysis of the chemical composition of colloidal II-VI quantum dot (QD)-ligand complexes and transient absorption experiments analyzing the rates of electron transfer reactions in these complexes functionalized with redox active ligands. Chemical analysis reveals that phosphonate impurities in the surfactants used to synthesize CdSe QDs are the dominant ligands on the surface of the QDs, and these phosphonate impurities cause size-dependent Cd-enrichment of the QD surface. A study of the adsorption equilibrium of solution-phase CdS quantum dots and acid-derivatized viologen ligands (V2+) reveals that the structure of the surfaces of the QDs depends on the concentration of the QDs. A new model based on the Langmuir isotherm that treats both the number of adsorbed ligands per QD and the number of available binding sites per QD as binomially-distributed quantities is described. Transient absorption spectroscopy of solution-phase mixtures of colloidal CdS QDs and V2+ indicates electron transfer occurs from the conduction band of the QD to the LUMO of V2+. The rate constant for photoinduced electron transfer (PET) is independent of the number of methylene groups in the alkyl chain on the acid-derivatized viologen. The insensitivity of the electron transfer rate constant to the length of the functional groups on the viologen suggests a van der Waals (vdW) pathway for PET, where the electron bypasses the alkylcarboxylate and tunnels through the orbitals of the QD and of the bipyridinium core. The rate of PET from colloidal CdSe quantum dots (QDs) to oxo-centered triruthenium clusters (Ru 3O) depends on the structure of the chemical headgroup by which the Ru3O clusters adsorb to the QDs. Complexes comprising QDs and Ru 3O clusters adsorbed through a pyridine-4-carboxylic acid ligand have a PET rate constant of (4.9 ± 0.9)×109 s -1 whereas complexes comprising QDs and Ru3O clusters adsorbed through a 4-mercaptopyridine ligand have an

  10. Nanomaterials can Dynamically Steer Cell Responses to Biological Ligands

    PubMed Central

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

    2011-01-01

    Traditional tissue regeneration approaches to activate cell behaviours on biomaterials rely on the use of extracellular matrix based or soluble growth factor cues. In this article, we highlight a novel approach to dynamically steer cellular phenomena such as cell motility based on nanoscale substratum features of biological ligands. Albumin derived nanocarriers (ANCs) of variable nanoscale size features were functionalized with fibronectin III9–10 matrix ligand and effects on primary human keratinocyte activation were investigated. The display of fibronectin fragment from ANCs significantly enhanced cell migration compared to free ligands at equivalent concentrations. Notably, cell migration was influenced by the size of underlying ANCs even for variably sized ANCs presenting comparable levels of fibronectin fragment. For equivalent ligand concentrations, cell migration on the smaller-sized ANCs (30 nm and 50 nm) was significantly more enhanced compared to that on larger-sized ANCs (75 nm and 100 nm). In contrast, the enhancement of cell migration on nanocarriers was 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 indicated that larger-sized ANCs showed delayed endocytic kinetics and hence could present barriers for internalization during the cell adhesion and motility processes. Motile cells exhibited 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 was found between the degree of nanocarrier cytointernalization rate and cell migration rate, suggesting the possibility of designing biointerfacial features for dynamic control of cell migration. Thus, the major

  11. The interplay of catechol ligands with nanoparticulate iron oxides.

    PubMed

    Yuen, Alexander K L; Hutton, Georgina A; Masters, Anthony F; Maschmeyer, Thomas

    2012-03-01

    The unique properties exhibited by nanoscale materials, coupled with the multitude of chemical surface derivatisation possibilities, enable the rational design of multifunctional nanoscopic devices. Such functional devices offer exciting new opportunities in medical research and much effort is currently invested in the area of "nanomedicine", including: multimodal imaging diagnostic tools, platforms for drug delivery and vectorisation, polyvalent, multicomponent vaccines, and composite devices for "theranostics". Here we will review the surface derivatisation of nanoparticulate oxides of iron and iron@iron-oxide core-shells. They are attractive candidates for MRI-active therapeutic platforms, being potentially less toxic than lanthanide-based materials, and amenable to functionalisation with ligands. However successful grafting of groups onto the surface of iron-based nanoparticles, thus adding functionality whilst preserving their inherent properties, is one of the most difficult challenges for creating truly useful nanodevices from them. Functionalised catechol-derived ligands have enjoyed success as agents for the masking of superparamagnetic iron-oxide particles, often so as to render them biocompatible with medium to long-term colloidal stability in the complex chemical environments of biological milieux. In this perspective, the opportunities and limitations of functionalising the surfaces of iron-oxide nanoparticles, using coatings containing a catechol-derived anchor, are analysed and discussed, including recent advances using dopamine-terminated stabilising ligands. If light-driven ligand to metal charge transfer (LMCT) processes, and pH-dependent ligand desorption, leading to nanoparticle degradation under physiologically relevant conditions can be suppressed, colloidal stability of samples can be maintained and toxicity ascribed to degradation products avoided. Modulation of the redox behaviour of iron catecholate systems through the introduction of an

  12. Benchmarking the Predictive Power of Ligand Efficiency Indices in QSAR.

    PubMed

    Cortes-Ciriano, Isidro

    2016-08-22

    Compound physicochemical properties favoring in vitro potency are not always correlated to desirable pharmacokinetic profiles. Therefore, using potency (i.e., IC50) as the main criterion to prioritize candidate drugs at early stage drug discovery campaigns has been questioned. Yet, the vast majority of the virtual screening models reported in the medicinal chemistry literature predict the biological activity of compounds by regressing in vitro potency on topological or physicochemical descriptors. Two studies published in this journal showed that higher predictive power on external molecules can be achieved by using ligand efficiency indices as the dependent variable instead of a metric of potency (IC50) or binding affinity (Ki). The present study aims at filling the shortage of a thorough assessment of the predictive power of ligand efficiency indices in QSAR. To this aim, the predictive power of 11 ligand efficiency indices has been benchmarked across four algorithms (Gradient Boosting Machines, Partial Least Squares, Random Forest, and Support Vector Machines), two descriptor types (Morgan fingerprints, and physicochemical descriptors), and 29 data sets collected from the literature and ChEMBL database. Ligand efficiency metrics led to the highest predictive power on external molecules irrespective of the descriptor type or algorithm used, with an R(2)test difference of ∼0.3 units and a this difference ∼0.4 units when modeling small data sets and a normalized RMSE decrease of >0.1 units in some cases. Polarity indices, such as SEI and NSEI, led to higher predictive power than metrics based on molecular size, i.e., BEI, NBEI, and LE. LELP, which comprises a polarity factor (cLogP) and a size parameter (LE) constantly led to the most predictive models, suggesting that these two properties convey a complementary predictive signal. Overall, this study suggests that using ligand efficiency indices as the dependent variable might be an efficient strategy to model

  13. Structural evidence for asymmetric ligand binding to transthyretin.

    PubMed

    Cianci, Michele; Folli, Claudia; Zonta, Francesco; Florio, Paola; Berni, Rodolfo; Zanotti, Giuseppe

    2015-08-01

    Human transthyretin (TTR) represents a notable example of an amyloidogenic protein, and several compounds that are able to stabilize its native state have been proposed as effective drugs in the therapy of TTR amyloidosis. The two thyroxine (T4) binding sites present in the TTR tetramer display negative binding cooperativity. Here, structures of TTR in complex with three natural polyphenols (pterostilbene, quercetin and apigenin) have been determined, in which this asymmetry manifests itself as the presence of a main binding site with clear ligand occupancy and related electron density and a second minor site with a much lower ligand occupancy. The results of an analysis of the structural differences between the two binding sites are consistent with such a binding asymmetry. The different ability of TTR ligands to saturate the two T4 binding sites of the tetrameric protein can be ascribed to the different affinity of ligands for the weaker binding site. In comparison, the high-affinity ligand tafamidis, co-crystallized under the same experimental conditions, was able to fully saturate the two T4 binding sites. This asymmetry is characterized by the presence of small but significant differences in the conformation of the cavity of the two binding sites. Molecular-dynamics simulations suggest the presence of even larger differences in solution. Competition binding assays carried out in solution revealed the presence of a preferential binding site in TTR for the polyphenols pterostilbene and quercetin that was different from the preferential binding site for T4. The TTR binding asymmetry could possibly be exploited for the therapy of TTR amyloidosis by using a cocktail of two drugs, each of which exhibits preferential binding for a distinct binding site, thus favouring saturation of the tetrameric protein and consequently its stabilization. PMID:26249340

  14. A new method of synthesizing biopolymeric affinity ligands.

    PubMed

    Chaga, G S; Guzman, R; Porath, J O

    1997-08-01

    (1) A new concept for producing soluble polymeric affinity ligands is proposed and exemplified. By solid-phase synthesis, an insoluble hydrophilic polymer is converted into an affinity gel. The gel is hydrolytically degraded to water-soluble affinity polymeric ligands which are recovered and purified. (2) A water-soluble biopolymeric metal-affinity carrier based on an iminodiacetic acid (IDA) derivative of dextran has been synthesized through the modification of Sephadex G-200 by IDA, followed by hydrolysis with dextranase and size-exclusion-chromatographic purification of the high-molecular-mass fragments. (3) The molecular size of the soluble products as a function of hydrolysis time with dextranase from Penicillium sp. was determined. The range of molecular size of the biopolymeric chelating ligand varies from around 200 Da to greater than 580 kDa. (4) The influence of three metal ions chelated with the Sephadex derivative on the hydrolysis rate and the molecular-size distribution of end products was studied. Eu3+ was found to improve the rate of solubilization. Ni2+ and Cu2+ decreased the hydrolysis rate, as compared with that of the metal-free IDA-Sephadex. (5) The method introduced here has the potential of being developed and applied as a general technology for synthesis of soluble multifunctional affinity ligands. Such ligands should be useful for liquid-phase extraction as well as for the synthesis of adsorbents with localized multiple binding sites. Other possible fields of applications are to be found in medicine, where they could be used for slow drug delivery or detoxification, and in analytical chemistry, where they could be used in various assays. PMID:9261997

  15. Targeted delivery to bone and mineral deposits using bisphosphonate ligands.

    PubMed

    Cole, Lisa E; Vargo-Gogola, Tracy; Roeder, Ryan K

    2016-04-01

    The high concentration of mineral present in bone and pathological calcifications is unique compared with all other tissues and thus provides opportunity for targeted delivery of pharmaceutical drugs, including radiosensitizers and imaging probes. Targeted delivery enables accumulation of a high local dose of a therapeutic or imaging contrast agent to diseased bone or pathological calcifications. Bisphosphonates (BPs) are the most widely utilized bone-targeting ligand due to exhibiting high binding affinity to hydroxyapatite mineral. BPs can be conjugated to an agent that would otherwise have little or no affinity for the sites of interest. This article summarizes the current state of knowledge and practice for the use of BPs as ligands for targeted delivery to bone and mineral deposits. The clinical history of BPs is briefly summarized to emphasize the success of these molecules as therapeutics for metabolic bone diseases. Mechanisms of binding and the relative binding affinity of various BPs to bone mineral are introduced, including common methods for measuring binding affinity in vitro and in vivo. Current research is highlighted for the use of BP ligands for targeted delivery of BP conjugates in various applications, including (1) therapeutic drug delivery for metabolic bone diseases, bone cancer, other bone diseases, and engineered drug delivery platforms; (2) imaging probes for scintigraphy, fluorescence, positron emission tomography, magnetic resonance imaging, and computed tomography; and (3) radiotherapy. Last, and perhaps most importantly, key structure-function relationships are considered for the design of drugs with BP ligands, including the tether length between the BP and drug, the size of the drug, the number of BP ligands per drug, cleavable tethers between the BP and drug, and conjugation schemes. PMID:26482186

  16. Solution structure of ligands involved in purine salvage pathway.

    PubMed

    Karnawat, Vishakha; Puranik, Mrinalini

    2015-12-01

    Analogues of intermediates involved in the purine salvage pathway can be exploited as potential drug molecules against enzymes of protozoan parasites. To develop such analogues we need knowledge of the solution structures, predominant tautomer at physiological pH and protonation-state of the corresponding natural ligand. In this regard, we have employed ultraviolet resonance Raman spectroscopy (UVRR) in combination with density functional theory (DFT) to study the solution structures of two relatively unexplored intermediates, 6-phosphoryl IMP (6-pIMP) and succinyl adenosine-5'-monophosphate (sAMP), of purine salvage pathway. These molecules are intermediates in a two step enzymatic process that converts inosine-5'-monpophosphate (IMP) to adenosine-5'-monophosphate (AMP). Experimental data on the molecular structure of these ligands is lacking. We report UVRR spectra of these two ligands, obtained at an excitation wavelength of 260 nm. Using isotope induced shifts and DFT calculations we assigned observed spectra to computed normal modes. We find that sAMP exists as neutral species at physiological pH and the predominant tautomer in solution bears proton at N10 position of purine ring. Though transient in solution, 6-pIMP is captured in the enzyme-bound form. This work provides the structural information of these ligands in solution state at physiological pH. We further compare these structures with the structures of AMP and IMP. Despite the presence of similar purine rings in AMP and sAMP, their UVRR spectra are found to be very different. Similarly, though the purine ring in 6-pIMP resembles that of IMP, UVRR spectra of the two molecules are distinct. These differences in the vibrational spectra provide direct information on the effects of exocyclic groups on the skeletal structures of these molecules. Our results identify key bands in the vibrational spectra of these ligands which may serve as markers of hydrogen bonding interactions upon binding to the active

  17. Ligand pathways in myoglobin: a review of Trp cavity mutations.

    PubMed

    Olson, J S; Soman, J; Phillips, G N

    2007-01-01

    The pathways for ligand entry and exit in myoglobin have now been well established by a wide variety of experimental results, including pico- to nano- to microsecond transient absorbance measurements and time-resolved X-ray crystallographic measurements. Trp insertions have been used to block, one at a time, the three major cavities occupied by photodissociated ligands. In this work, we review the effects of the L29(B10)W mutation, which places a large indole ring in the initial 'docking site' for photodissociated ligands. Then, the effects of blocking the Xe4 site with I28W, V68W, and I107W mutations and the Xe1 cavity with L89W, L104W, and F138W mutations are described. The structures of four of these mutants are shown for the first time (Trp28, Trp68, Trp107, and Trp 138 sperm whale metMb). All available results support a 'side path' mechanism in which ligands move into and out of myoglobin by outward rotation of the HisE7 side chain, but after entry can migrate into internal cavities, including the distal Xe4 and proximal Xe1 binding sites. The distal cavities act like the pocket of a baseball glove, catching the ligand and holding it long enough for the histidine gate to close and facilitate internal coordination with the heme iron atom. The physiological role of the proximal Xe1 site is less clear because changes in the size of this cavity have minimal effects on overall O(2) binding parameters. PMID:17701550

  18. Impact of As-Synthesized Ligands and Low-Oxygen Conditions on Silver Nanoparticle Surface Functionalization.

    PubMed

    Johnston, Kathryn A; Smith, Ashley M; Marbella, Lauren E; Millstone, Jill E

    2016-04-26

    Here, we compare the ligand exchange behaviors of silver nanoparticles synthesized in the presence of two different surface capping agents: poly(vinylpyrrolidone) (MW = 10 or 40 kDa) or trisodium citrate, and under either ambient or low-oxygen conditions. In all cases, we find that the polymer capping agent exhibits features of a weakly bound ligand, producing better ligand exchange efficiencies with an incoming thiolated ligand compared to citrate. The polymer capping agent also generates nanoparticles that are more susceptible to reactions with oxygen during both synthesis and ligand exchange. The influence of the original ligand on the outcome of ligand exchange reactions with an incoming thiolated ligand highlights important aspects of silver nanoparticle surface chemistry, crucial for applications ranging from photocatalysis to antimicrobials. PMID:27077550

  19. Thermodynamic study of the complexation between Nd(3+) and functionalized diacetamide ligands in solution.

    PubMed

    Dau, Phuong V; Zhang, Zhicheng; Dau, Phuong D; Gibson, John K; Rao, Linfeng

    2016-07-26

    A series of amine functionalized ligands, including 2,2'-(benzylazanediyl)bis(N,N'-dimethylacetamide) (BnABDMA), 2,2'-azanediylbis(N,N'-dimethylacetamide) (ABDMA), and 2,2'-(methylazanediyl)bis(N,N'-dimethylacetamide) (MABDMA), are synthesized for the thermodynamic study of their complexation with Nd(3+) ions. Their complexation in solution is investigated using potentiometry, spectrophotometry, calorimetry, and electrospray ionization mass spectrometry. The results suggest that these ligands act as tridentate ligands. Furthermore, direct comparison between ABDMA and an analogous ether-functionalized ligand, 2,2'-oxybis(N,N'-dimethylacetamide) (TMDGA), showed that the amine functionalized ligand forms thermodynamically stronger complexes with Nd(3+) ions than the ether-functionalized ligand. In addition, the amine functionalized ligand can allow the fine-tuning of the binding strength with metal ions via substitution on the central amine N atom with different functional groups, which is not possible for ether functionalized ligands such as TMDGA. PMID:27222301

  20. Reactivity of halide and pseudohalide ligands in transition-metal complexes

    SciTech Connect

    Kukushkin, Yu.N.; Kukushkin, V.Yu.

    1985-10-01

    The experimental material on the reactions of coordinated halide ligands, as well as cyanide, azido, thiocyanato, and cyanato ligands, in transition-metal complexes has been generalized in this review.

  1. LISE: a server using ligand-interacting and site-enriched protein triangles for prediction of ligand-binding sites.

    PubMed

    Xie, Zhong-Ru; Liu, Chuan-Kun; Hsiao, Fang-Chih; Yao, Adam; Hwang, Ming-Jing

    2013-07-01

    LISE is a web server for a novel method for predicting small molecule binding sites on proteins. It differs from a number of servers currently available for such predictions in two aspects. First, rather than relying on knowledge of similar protein structures, identification of surface cavities or estimation of binding energy, LISE computes a score by counting geometric motifs extracted from sub-structures of interaction networks connecting protein and ligand atoms. These network motifs take into account spatial and physicochemical properties of ligand-interacting protein surface atoms. Second, LISE has now been more thoroughly tested, as, in addition to the evaluation we previously reported using two commonly used small benchmark test sets and targets of two community-based experiments on ligand-binding site predictions, we now report an evaluation using a large non-redundant data set containing >2000 protein-ligand complexes. This unprecedented test, the largest ever reported to our knowledge, demonstrates LISE's overall accuracy and robustness. Furthermore, we have identified some hard to predict protein classes and provided an estimate of the performance that can be expected from a state-of-the-art binding site prediction server, such as LISE, on a proteome scale. The server is freely available at http://lise.ibms.sinica.edu.tw. PMID:23609546

  2. Effect of complexing ligands on the adsorption of Cu(II) onto the silica gel surface. 1: Adsorption of ligands

    SciTech Connect

    Park, Y.J.; Jung, K.H.; Park, K.K.; Park, K.K.

    1995-04-01

    The adsorption of several ligands on silica gel was investigated in aqueous solutions. The ligands used were 2,2{prime},6{prime},2{double_prime}-terpyridine, pyridine, 3,4-lutidine, 2-aminomethyl pyridine, 2-pyridine methanol, picolinic acid, salicylic acid, and 5-sulfosalicylic acid. The adsorption behaviors of these ligands were interpreted by means of three adsorption modes: ion exchange, hydrogen bonding, and hydrophobic interaction. For 2,2{prime},6{prime},2{double_prime}-terpyridine, pyridine, and 3,4-lutidine, the adsorption maxima appeared near their respective pK{sub a} values and were found to be due mainly to ion exchange, whereas the adsorption of these ligands at low pH was strongly attributed to hydrophobic interaction. The adsorption of 2-aminomethyl pyridine increased with increasing pH over the entire pH range investigated and was due mainly to ion exchange. Picolinic acid was adsorbed mainly by hydrogen bonding either via pyridine N atoms at low pH or via carboxylic O atoms at high pH. 2-Pyridine methanol was adsorbed by hydrophobic interaction at low pH and by hydrogen bonding at high pH. The adsorptions of salicylic and 5-sulfosalicylic acid were very small over the entire pH ranges investigated. For the adsorption mechanism, the Stern model was used to fit adsorption data.

  3. A 3-fold-symmetric ligand based on 2-hydroxypyridine: regulation of ligand binding by hydrogen bonding.

    PubMed

    Moore, Cameron M; Quist, David A; Kampf, Jeff W; Szymczak, Nathaniel K

    2014-04-01

    A tripodal ligand based on 2-hydroxypyridine is presented. Cu-Cl adducts of H3thpa with Cu(I) and Cu(II) provide complexes featuring highly directed, intramolecular hydrogen-bonding interactions. An upper limit for the hydrogen-bonding free energy to Cu(I)-Cl was estimated at ∼18 kcal/mol. PMID:24654846

  4. Electron-transfer catalysis of ligand substitution in triiron clusters. The role of the bridging ligand in anion radical intermediates

    SciTech Connect

    Ohst, H.H.; Kochi, J.K.

    1986-05-28

    The polynuclear cluster Fe/sub 3/(CO)/sub 9/(..mu../sub 3/-PPh)/sub 2/ (I) undergoes rapid ligand substitution by electron-transfer catalysis (ETC) under conditions in which the thermal process is nonexistent. X-ray crystallography and /sup 31/P NMR spectroscopy establish the stepwise substitution of the CO ligands by trimethyl phosphite to take place selectively at three separate iron centers. The high selectivity to the mono-substitution product II is achieved by tuning the reduction potential specifically to generate catalytic amounts of the anion radical Fe/sub 3/(CO)/sub 9/(PPh)/sub 2//sup -/ (I/sup -/) in either acetonitrile or tetrahydrofuran. Transient ESR spectroscopy of I/sup -/ and three related paramagnetic intermediates establish the sequential transformation of anion radicals as they evolve in the ETC mechanism. The rate-limiting rearrangement of I/sup -/ by the slippage of a phosphinidene cap from ..mu../sub 3/ ..-->.. ..mu../sub 2/ coordination underscores the key role of the bridging ligand in the substitution process. The importance of this critical transformation related to the formation of a 17-electron, coordinatively unsaturated iron center in the otherwise intact cluster. As such, it emphasizes the key role that the bridging ligand can play in cluster activation.

  5. Distinguishing of tumor cell-targeting peptide ligands through a color-encoding microarray.

    PubMed

    Wang, Zihua; Wang, Weizhi; Geng, Lingling; Hu, Zhiyuan

    2015-12-21

    A silicon-based microarray system was constructed to discover the affinity peptides and to distinguish the specific peptides from a high throughput library. Using a color-encoding strategy, in situ peptide distinguishing between HER1 ligands and HER2 ligands was achieved. Novel affinity peptide sequences H1P (HER1 ligand) and H2P (HER2 ligand) were determined with nmol affinity. PMID:26530232

  6. O-fucosylation of the notch ligand mDLL1 by POFUT1 is dispensable for ligand function.

    PubMed

    Müller, Julia; Rana, Nadia A; Serth, Katrin; Kakuda, Shinako; Haltiwanger, Robert S; Gossler, Achim

    2014-01-01

    Fucosylation of Epidermal Growth Factor-like (EGF) repeats by protein O-fucosyltransferase 1 (POFUT1 in vertebrates, OFUT1 in Drosophila) is pivotal for NOTCH function. In Drosophila OFUT1 also acts as chaperone for Notch independent from its enzymatic activity. NOTCH ligands are also substrates for POFUT1, but in Drosophila OFUT1 is not essential for ligand function. In vertebrates the significance of POFUT1 for ligand function and subcellular localization is unclear. Here, we analyze the importance of O-fucosylation and POFUT1 for the mouse NOTCH ligand Delta-like 1 (DLL1). We show by mass spectral glycoproteomic analyses that DLL1 is O-fucosylated at the consensus motif C²XXXX(S/T)C³ (where C² and C³ are the second and third conserved cysteines within the EGF repeats) found in EGF repeats 3, 4, 7 and 8. A putative site with only three amino acids between the second cysteine and the hydroxy amino acid within EGF repeat 2 is not modified. DLL1 proteins with mutated O-fucosylation sites reach the cell surface and accumulate intracellularly. Likewise, in presomitic mesoderm cells of POFUT1 deficient embryos DLL1 is present on the cell surface, and in mouse embryonic fibroblasts lacking POFUT1 the same relative amount of overexpressed wild type DLL1 reaches the cell surface as in wild type embryonic fibroblasts. DLL1 expressed in POFUT1 mutant cells can activate NOTCH, indicating that POFUT1 is not required for DLL1 function as a Notch ligand. PMID:24533113

  7. Label-free integrative pharmacology on-target of opioid ligands at the opioid receptor family

    PubMed Central

    2013-01-01

    Background In vitro pharmacology of ligands is typically assessed using a variety of molecular assays based on predetermined molecular events in living cells. Many ligands including opioid ligands pose the ability to bind more than one receptor, and can also provide distinct operational bias to activate a specific receptor. Generating an integrative overview of the binding and functional selectivity of ligands for a receptor family is a critical but difficult step in drug discovery and development. Here we applied a newly developed label-free integrative pharmacology on-target (iPOT) approach to systematically survey the selectivity of a library of fifty-five opioid ligands against the opioid receptor family. All ligands were interrogated using dynamic mass redistribution (DMR) assays in both recombinant and native cell lines that express specific opioid receptor(s). The cells were modified with a set of probe molecules to manifest the binding and functional selectivity of ligands. DMR profiles were collected and translated to numerical coordinates that was subject to similarity analysis. A specific set of opioid ligands were then selected for quantitative pharmacology determination. Results Results showed that among fifty-five opioid ligands examined most ligands displayed agonist activity in at least one opioid receptor expressing cell line under different conditions. Further, many ligands exhibited pathway biased agonism. Conclusion We demonstrate that the iPOT effectively sorts the ligands into distinct clusters based on their binding and functional selectivity at the opioid receptor family. PMID:23497702

  8. New biphenol-based, fine-tunable monodentate phosphoramidite ligands for catalytic asymmetric transformations

    PubMed Central

    Hua, Zihao; Vassar, Victor C.; Choi, Hojae; Ojima, Iwao

    2004-01-01

    Monodentate phosphoramidite ligands have been developed based on enantiopure 6,6′-dimethylbiphenols with axial chirality. These chiral ligands are easy to prepare and flexible for modifications. The fine-tuning capability of these ligands plays a significant role in achieving high enantioselectivity in the asymmetric hydroformylation of allyl cyanide and the conjugate addition of diethylzinc to cycloalkenones. PMID:15020764

  9. Conformational Transitions upon Ligand Binding: Holo-Structure Prediction from Apo Conformations

    PubMed Central

    Seeliger, Daniel; de Groot, Bert L.

    2010-01-01

    Biological function of proteins is frequently associated with the formation of complexes with small-molecule ligands. Experimental structure determination of such complexes at atomic resolution, however, can be time-consuming and costly. Computational methods for structure prediction of protein/ligand complexes, particularly docking, are as yet restricted by their limited consideration of receptor flexibility, rendering them not applicable for predicting protein/ligand complexes if large conformational changes of the receptor upon ligand binding are involved. Accurate receptor models in the ligand-bound state (holo structures), however, are a prerequisite for successful structure-based drug design. Hence, if only an unbound (apo) structure is available distinct from the ligand-bound conformation, structure-based drug design is severely limited. We present a method to predict the structure of protein/ligand complexes based solely on the apo structure, the ligand and the radius of gyration of the holo structure. The method is applied to ten cases in which proteins undergo structural rearrangements of up to 7.1 Å backbone RMSD upon ligand binding. In all cases, receptor models within 1.6 Å backbone RMSD to the target were predicted and close-to-native ligand binding poses were obtained for 8 of 10 cases in the top-ranked complex models. A protocol is presented that is expected to enable structure modeling of protein/ligand complexes and structure-based drug design for cases where crystal structures of ligand-bound conformations are not available. PMID:20066034

  10. Understanding ligand effects in gold clusters using mass spectrometry.

    PubMed

    Johnson, Grant E; Laskin, Julia

    2016-06-21

    This review summarizes recent research on the influence of phosphine ligands on the size, stability, and reactivity of gold clusters synthesized in solution. Sub-nanometer clusters exhibit size- and composition-dependent properties that are unique from those of larger nanoparticles. The highly tunable properties of clusters and their high surface-to-volume ratio make them promising candidates for a variety of technological applications. However, because "each-atom-counts" toward defining cluster properties it is critically important to develop robust synthesis methods to efficiently prepare clusters of predetermined size. For decades phosphines have been known to direct the size-selected synthesis of gold clusters. Despite the preparation of numerous species it is still not understood how different functional groups at phosphine centers affect the size and properties of gold clusters. Using electrospray ionization mass spectrometry (ESI-MS) it is possible to characterize the effect of ligand substitution on the distribution of clusters formed in solution at defined reaction conditions. In addition, ligand exchange reactions on preformed clusters may be monitored using ESI-MS. Collision induced dissociation (CID) may also be employed to obtain qualitative insight into the fragmentation of mixed ligand clusters and the relative binding energies of differently substituted phosphines. Quantitative ligand binding energies and cluster stability may be determined employing surface induced dissociation (SID) in a custom-built Fourier transform ion cyclotron resonance mass spectrometer (FT-ICR-MS). Rice-Ramsperger-Kassel-Marcus (RRKM) based modeling of the SID data allows dissociation energies and entropy values to be extracted. The charge reduction and reactivity of atomically precise gold clusters, including partially ligated species generated in the gas-phase by in source CID, on well-defined surfaces may be explored using ion soft landing (SL) in a custom

  11. Affinity of An(VI) for N4-Tetradentate Donor Ligands: Complexation of the Actinyl(VI) Ions with N4-Tetradentate Ligands

    SciTech Connect

    Ogden, Mark; Sinkov, Sergey I.; Lumetta, Gregg J.; Nash, Kenneth L.

    2012-05-01

    In this report the affinity of four N4-tetradentate ligands that incorporate the 2- methylpyridyl functionality with hexavalent actinides (AnO2+2 ) has been investigated in methanol solution. The ligands studied include N,N*-bis(2-methylpyridyl)diaminoethane (BPMDAE), N,N-bis(2-methylpyridyl)-1,3-diaminopropane (BPMDAP), N,N*-bis(2-pyridylmethyl) piperazine (BPMPIP), and trans-N,N-bis(2-pyridylmethyl)-1,2-diaminocyclohexane (BPMDAC). Conditional stability constants describing the strength of the interaction were determined by UV-visible spectrophotometry. The log10K101 values for both U(VI) and Pu(VI) are comparable and show the same trend of stability with ligand structure. Dinuclear complexes are also indicated as being important. The log10K201 values for Pu(VI) complexation with the N4-ligands are identical for the four ligands (within experimental error), indicating that the structure of the ligand backbone has little effect on the stability of the (PuO2)2L2+ complex. The exception to this trend is the behavior of N,N*- bis(2-pyridylmethyl)piperazine (BPMPIP) with Pu(VI). This ligand displays a tendency to reduce Pu(VI) within the experimental time frame of 45 minutes. BPMPIP is the only ligand tested that contains tertiary amines in the ligand backbone. The decomposition of BPMPIP by Pu(VI) suggests a susceptibility of tertiary amines to oxidative degradation.

  12. A Structural Switch between Agonist and Antagonist Bound Conformations for a Ligand-Optimized Model of the Human Aryl Hydrocarbon Receptor Ligand Binding Domain

    PubMed Central

    Perkins, Arden; Phillips, Jessica L.; Kerkvliet, Nancy I.; Tanguay, Robert L.; Perdew, Gary H.; Kolluri, Siva K.; Bisson, William H.

    2014-01-01

    The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that regulates the expression of a diverse group of genes. Exogenous AHR ligands include the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which is a potent agonist, and the synthetic AHR antagonist N-2-(1H-indol-3yl)ethyl)-9-isopropyl-2-(5-methylpyridin-3-yl)-9H-purin-6-amine (GNF351). As no experimentally determined structure of the ligand binding domain exists, homology models have been utilized for virtual ligand screening (VLS) to search for novel ligands. Here, we have developed an “agonist-optimized” homology model of the human AHR ligand binding domain, and this model aided in the discovery of two human AHR agonists by VLS. In addition, we performed molecular dynamics simulations of an agonist TCDD-bound and antagonist GNF351-bound version of this model in order to gain insights into the mechanics of the AHR ligand-binding pocket. These simulations identified residues 307–329 as a flexible segment of the AHR ligand pocket that adopts discrete conformations upon agonist or antagonist binding. This flexible segment of the AHR may act as a structural switch that determines the agonist or antagonist activity of a given AHR ligand. PMID:25329374

  13. Anisotropic energy flow and allosteric ligand binding in albumin

    PubMed Central

    Li, Guifeng; Magana, Donny; Dyer, R. Brian

    2014-01-01

    Allosteric interactions in proteins generally involve propagation of local structural changes through the protein to a remote site. Anisotropic energy transport is thought to couple the remote sites, but the nature of this process is poorly understood. Here, we report the relationship between energy flow through the structure of bovine serum albumin and allosteric interactions between remote ligand binding sites of the protein. Ultrafast infrared spectroscopy is used to probe the flow of energy through the protein backbone following excitation of a heater dye, a metalloporphyrin or malachite green, bound to different binding sites in the protein. We observe ballistic and anisotropic energy flow through the protein structure following input of thermal energy into the flexible ligand binding sites, without local heating of the rigid helix bundles that connect these sites. This efficient energy transport mechanism enables the allosteric propagation of binding energy through the connecting helix structures. PMID:24445265

  14. Ligand regulation of a constitutively dimeric EGF receptor.

    PubMed

    Freed, Daniel M; Alvarado, Diego; Lemmon, Mark A

    2015-01-01

    Ligand-induced receptor dimerization has traditionally been viewed as the key event in transmembrane signalling by epidermal growth factor receptors (EGFRs). Here we show that the Caenorhabditis elegans EGFR orthologue LET-23 is constitutively dimeric, yet responds to its ligand LIN-3 without changing oligomerization state. SAXS and mutational analyses further reveal that the preformed dimer of the LET-23 extracellular region is mediated by its domain II dimerization arm and resembles other EGFR extracellular dimers seen in structural studies. Binding of LIN-3 induces only minor structural rearrangements in the LET-23 dimer to promote signalling. Our results therefore argue that EGFR can be regulated by allosteric changes within an existing receptor dimer--resembling signalling by insulin receptor family members, which share similar extracellular domain compositions but form covalent dimers. PMID:26060020

  15. Biophysics of selectin-ligand interactions in inflammation and cancer

    NASA Astrophysics Data System (ADS)

    Siu-Lun Cheung, Luthur; Raman, Phrabha S.; Balzer, Eric M.; Wirtz, Denis; Konstantopoulos, Konstantinos

    2011-02-01

    Selectins (l-, e- and p-selectin) are calcium-dependent transmembrane glycoproteins that are expressed on the surface of circulating leukocytes, activated platelets, and inflamed endothelial cells. Selectins bind predominantly to sialofucosylated glycoproteins and glycolipids (e-selectin only) present on the surface of apposing cells, and mediate transient adhesive interactions pertinent to inflammation and cancer metastasis. The rapid turnover of selectin-ligand bonds, due to their fast on- and off-rates along with their remarkably high tensile strengths, enables them to mediate cell tethering and rolling in shear flow. This paper presents the current body of knowledge regarding the role of selectins in inflammation and cancer metastasis, and discusses experimental methodologies and mathematical models used to resolve the biophysics of selectin-mediated cell adhesion. Understanding the biochemistry and biomechanics of selectin-ligand interactions pertinent to inflammatory disorders and cancer metastasis may provide insights for developing promising therapies and/or diagnostic tools to combat these disorders.

  16. Scintillation Proximity Radioimmunoassay Utilizing 125I-Labeled Ligands

    NASA Astrophysics Data System (ADS)

    Udenfriend, Sidney; Diekmann Gerber, Louise; Brink, Larry; Spector, Sydney

    1985-12-01

    A unique type of radioimmunoassay is described that does not require centrifugation or separation. Microbeads containing a fluorophor are covalently linked to antibody. When an 125I-labeled antigen is added it binds to the beads and, by its proximity, the emitted short-range electrons of the 125I excite the fluorophor in the beads. The light emitted can be measured in a standard scintillation counter. Addition of unlabeled antigen from tissue extracts displaces the labeled ligand and diminishes the fluorescent signal. Application of scintillation proximity immunoassay to tissue enkephalins, serum thyroxin, and urinary morphine is described. Applications of the principle to study the kinetics of interaction between receptors and ligands are discussed.

  17. Ligand regulation of a constitutively dimeric EGF receptor

    NASA Astrophysics Data System (ADS)

    Freed, Daniel M.; Alvarado, Diego; Lemmon, Mark A.

    2015-06-01

    Ligand-induced receptor dimerization has traditionally been viewed as the key event in transmembrane signalling by epidermal growth factor receptors (EGFRs). Here we show that the Caenorhabditis elegans EGFR orthologue LET-23 is constitutively dimeric, yet responds to its ligand LIN-3 without changing oligomerization state. SAXS and mutational analyses further reveal that the preformed dimer of the LET-23 extracellular region is mediated by its domain II dimerization arm and resembles other EGFR extracellular dimers seen in structural studies. Binding of LIN-3 induces only minor structural rearrangements in the LET-23 dimer to promote signalling. Our results therefore argue that EGFR can be regulated by allosteric changes within an existing receptor dimer--resembling signalling by insulin receptor family members, which share similar extracellular domain compositions but form covalent dimers.

  18. Finding gas migration pathways in proteins using implicit ligand sampling.

    PubMed

    Cohen, Jordi; Olsen, Kenneth W; Schulten, Klaus

    2008-01-01

    Implicit ligand sampling is a practical, efficient, and accurate method for finding the gas migration pathways for small hydrophobic gas molecules, such as oxygen, inside proteins. The method infers the gas migration pathways by calculating the potential of mean force for the gas molecule everywhere inside the protein by means of a molecular dynamics simulation of the protein in the absence of the gas molecule. Pathways can be constructed by connecting the areas of the protein that are favorable to the presence of gas. This method has the advantage of providing a comprehensive overview of all possible gas migration pathways and barriers in a given protein from a single simulation run. Implicit ligand sampling has been applied to a large number of hemoproteins. The example of the truncated hemoglobin from Paramecium caudatum is given to illustrate the method. PMID:18433641

  19. Poly(vinylpyrrolidone) for bioconjugation and surface ligand immobilization.

    PubMed

    Zelikin, Alexander N; Such, Georgina K; Postma, Almar; Caruso, Frank

    2007-09-01

    Poly(vinylpyrrolidone) (PVP), a nonionic and nontoxic polymer with antifouling properties, has been synthesized via RAFT polymerization to obtain thiol-terminated PVP. We demonstrate that when the polymer is adsorbed onto the surface of colloidal silica particles, the terminal thiol groups of PVP remain accessible for chemical modification and lend themselves to the immobilization of ligands. We show that ligand attachment onto the surface via conjugation to PVP is reversible, as the polymer can be desorbed from the surface for conjugate and surface recovery. We present the conjugation of a model peptide and an oligonucleotide to PVP via the polymer terminal thiol and demonstrate that conjugates remain functional in molecular recognition assay. The developed technique offers a novel method to functionalize low-fouling surfaces for a variety of biomedical applications and presents opportunities to use PVP as a macromolecular drug carrier. PMID:17715962

  20. gp130 receptor ligands as potential therapeutic targets for obesity

    PubMed Central

    Febbraio, Mark A.

    2007-01-01

    Obesity and its related cluster of pathophysiologic conditions including insulin resistance, glucose intolerance, dyslipidemia, and hypertension are recognized as growing threats to world health. It is now estimated that 10% of the world’s population is overweight or obese. As a result, new therapeutic options for the treatment of obesity are clearly warranted. Recent research has focused on the role that gp130 receptor ligands may play as potential therapeutic targets in obesity. One cytokine in particular, ciliary neurotrophic factor (CNTF), acts both centrally and peripherally and mimics the biologic actions of the appetite control hormone leptin, but unlike leptin, CNTF appears to be effective in obesity and as such may have therapeutic potential. In addition, CNTF suppresses inflammatory signaling cascades associated with lipid accumulation in liver and skeletal muscle. This review examines the potential role of gp130 receptor ligands as part of a therapeutic strategy to treat obesity. PMID:17404609