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

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Stéphanie Pérot

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

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

Science.gov (United States)

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

2013-01-01

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

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

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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.

Fas ligand exists on intervertebral disc cells: a potential molecular mechanism for immune privilege of the disc.

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Takada, Toru; Nishida, Kotaro; Doita, Minoru; Kurosaka, Masahiro

2002-07-15

Rat and human intervertebral disc specimens were examined immunohistochemically. Reverse transcription polymerase chain reaction (RT-PCR) analysis was also performed on rat disc tissue to demonstrate the existence of Fas ligand. To clarify the existence of Fas ligand on intact intervertebral disc cells. The nucleus pulposus has been reported to be an immune-privileged site. The immune-privileged characteristic in other tissues such as the retina and testis has been attributed to the local expression of Fas ligand, which acts by inducing apoptosis of invading Fas-positive T-cells. The existence of Fas ligand in normal disc cells has not yet been addressed. Skeletally mature SD male rats were killed, and the coccygeal discs were harvested. Human disc specimens were obtained from idiopathic scoliosis patients during surgical procedures. Immunohistochemical staining for Fas ligand was performed for cross-sections of the discs by standard procedures. Reverse transcription polymerase chain reaction analysis was also carried out to demonstrate Fas ligand mRNA expression on rat intervertebral discs. Testes of the rats were used for positive controls, and muscles were used for negative controls. The sections were observed by light microscopy. The nucleus pulposus cells exhibited intense positive immune staining for Fas ligand. The outer anulus fibrosus cells and notochordal cells exhibited little immunopositivity. The positive controls exhibited positive immune staining, and the negative control showed no immunopositivity. The result of RT-PCR confirmed the existence of Fas ligand in disc cells. The human nucleus pulposus cells showed a similar predilection to rat disc cells. We demonstrated the existence of Fas ligand on disc cells, which should play a key role in the potential molecular mechanism to maintain immune privilege of the disc. Immune privilege and Fas ligand expression of the intervertebral disc may provide a new insight for basic science research as well as

Ligand effect on the performance of organic light-emitting diodes based on europium complexes

International Nuclear Information System (INIS)

Fang Junfeng; You Han; Gao Jia; Lu Wu; Ma Dongge

2007-01-01

A series of europium complexes were synthesized and their electroluminescent (EL) characteristics were studied. It was found by comparison that the different substituted groups, such as methyl, chlorine, and nitryl, on ligand 1,10-phenanthroline affect significantly the EL performance of devices based on these complexes. The more methyl-substituted groups on ligand 1,10-phenanthroline led to higher device efficiency. A chlorine-substituted group showed the approximate EL performance as two methyl-substituted groups, whereas a nitryl substituent reduced significantly the EL luminous efficiency. However, β-diketonate ligand TTA and DBM exhibited similar EL performance. The improved EL luminous efficiency by proper substituted groups on the 1,10-phenanthroline was attributed to the reduction of the energy loss caused by light hydrogen atom vibration, as well as concentration quenching caused by intermolecular interaction, and the match of energy level between the ligand and Eu 3+

AutoSite: an automated approach for pseudo-ligands prediction—from ligand-binding sites identification to predicting key ligand atoms

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Ravindranath, Pradeep Anand; Sanner, Michel F.

2016-01-01

Motivation: The identification of ligand-binding sites from a protein structure facilitates computational drug design and optimization, and protein function assignment. We introduce AutoSite: an efficient software tool for identifying ligand-binding sites and predicting pseudo ligand corresponding to each binding site identified. Binding sites are reported as clusters of 3D points called fills in which every point is labelled as hydrophobic or as hydrogen bond donor or acceptor. From these fills AutoSite derives feature points: a set of putative positions of hydrophobic-, and hydrogen-bond forming ligand atoms. Results: We show that AutoSite identifies ligand-binding sites with higher accuracy than other leading methods, and produces fills that better matches the ligand shape and properties, than the fills obtained with a software program with similar capabilities, AutoLigand. In addition, we demonstrate that for the Astex Diverse Set, the feature points identify 79% of hydrophobic ligand atoms, and 81% and 62% of the hydrogen acceptor and donor hydrogen ligand atoms interacting with the receptor, and predict 81.2% of water molecules mediating interactions between ligand and receptor. Finally, we illustrate potential uses of the predicted feature points in the context of lead optimization in drug discovery projects. Availability and Implementation: http://adfr.scripps.edu/AutoDockFR/autosite.html Contact: sanner@scripps.edu Supplementary information: Supplementary data are available at Bioinformatics online. PMID:27354702

Interaction of calreticulin with CD40 ligand, TRAIL and Fas ligand

DEFF Research Database (Denmark)

Duus, K; Pagh, R T; Holmskov, U

2007-01-01

is utilized by many other functionally diverse molecules and in this work the interaction of calreticulin with C1q and structurally similar molecules was investigated. In addition to C1q and MBL, CD40 ligand (CD40L), tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and Fas ligand (FasL) were...... found to bind calreticulin strongly. A low level or no binding was observed for adiponectin, tumour necrosis factor-alpha (TNF-alpha), CD30L, surfactant protein-A and -D and collagen VIII. The interaction with calreticulin required a conformational change in CD40L, TRAIL and FasL and showed the same...

LigandRFs: random forest ensemble to identify ligand-binding residues from sequence information alone

KAUST Repository

Chen, Peng

2014-12-03

Background Protein-ligand binding is important for some proteins to perform their functions. Protein-ligand binding sites are the residues of proteins that physically bind to ligands. Despite of the recent advances in computational prediction for protein-ligand binding sites, the state-of-the-art methods search for similar, known structures of the query and predict the binding sites based on the solved structures. However, such structural information is not commonly available. Results In this paper, we propose a sequence-based approach to identify protein-ligand binding residues. We propose a combination technique to reduce the effects of different sliding residue windows in the process of encoding input feature vectors. Moreover, due to the highly imbalanced samples between the ligand-binding sites and non ligand-binding sites, we construct several balanced data sets, for each of which a random forest (RF)-based classifier is trained. The ensemble of these RF classifiers forms a sequence-based protein-ligand binding site predictor. Conclusions Experimental results on CASP9 and CASP8 data sets demonstrate that our method compares favorably with the state-of-the-art protein-ligand binding site prediction methods.

Length dependence of force generation exhibit similarities between rat cardiac myocytes and skeletal muscle fibres.

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Hanft, Laurin M; McDonald, Kerry S

2010-08-01

According to the Frank-Starling relationship, increased ventricular volume increases cardiac output, which helps match cardiac output to peripheral circulatory demand. The cellular basis for this relationship is in large part the myofilament length-tension relationship. Length-tension relationships in maximally calcium activated preparations are relatively shallow and similar between cardiac myocytes and skeletal muscle fibres. During twitch activations length-tension relationships become steeper in both cardiac and skeletal muscle; however, it remains unclear whether length dependence of tension differs between striated muscle cell types during submaximal activations. The purpose of this study was to compare sarcomere length-tension relationships and the sarcomere length dependence of force development between rat skinned left ventricular cardiac myocytes and fast-twitch and slow-twitch skeletal muscle fibres. Muscle cell preparations were calcium activated to yield 50% maximal force, after which isometric force and rate constants (k(tr)) of force development were measured over a range of sarcomere lengths. Myofilament length-tension relationships were considerably steeper in fast-twitch fibres compared to slow-twitch fibres. Interestingly, cardiac myocyte preparations exhibited two populations of length-tension relationships, one steeper than fast-twitch fibres and the other similar to slow-twitch fibres. Moreover, myocytes with shallow length-tension relationships were converted to steeper length-tension relationships by protein kinase A (PKA)-induced myofilament phosphorylation. Sarcomere length-k(tr) relationships were distinct between all three cell types and exhibited patterns markedly different from Ca(2+) activation-dependent k(tr) relationships. Overall, these findings indicate cardiac myocytes exhibit varied length-tension relationships and sarcomere length appears a dominant modulator of force development rates. Importantly, cardiac myocyte length

Ligand photo-isomerization triggers conformational changes in iGluR2 ligand binding domain.

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Tino Wolter

Full Text Available Neurological glutamate receptors bind a variety of artificial ligands, both agonistic and antagonistic, in addition to glutamate. Studying their small molecule binding properties increases our understanding of the central nervous system and a variety of associated pathologies. The large, oligomeric multidomain membrane protein contains a large and flexible ligand binding domains which undergoes large conformational changes upon binding different ligands. A recent application of glutamate receptors is their activation or inhibition via photo-switchable ligands, making them key systems in the emerging field of optochemical genetics. In this work, we present a theoretical study on the binding mode and complex stability of a novel photo-switchable ligand, ATA-3, which reversibly binds to glutamate receptors ligand binding domains (LBDs. We propose two possible binding modes for this ligand based on flexible ligand docking calculations and show one of them to be analogues to the binding mode of a similar ligand, 2-BnTetAMPA. In long MD simulations, it was observed that transitions between both binding poses involve breaking and reforming the T686-E402 protein hydrogen bond. Simulating the ligand photo-isomerization process shows that the two possible configurations of the ligand azo-group have markedly different complex stabilities and equilibrium binding modes. A strong but slow protein response is observed after ligand configuration changes. This provides a microscopic foundation for the observed difference in ligand activity upon light-switching.

EXAFS Studies of Some Copper(II) Mixed-Ligand Complexes

International Nuclear Information System (INIS)

Joshi, S. K.; Katare, R. K.; Shrivastava, B. D.

2007-01-01

X-ray K-absorption spectroscopic studies have been carried out on copper (II) mixed-ligand complexes with glutamic acid and aspartic acid as the primary ligands, where as water, pyridine, imidazole and benz-imidazole have been used as secondary ligands. Chemical shifts obtained from the X-ray absorption data have indicated that the glutamic acid complexes are more ionic as compared to their corresponding aspartic acid complexes having similar secondary ligands. Further, we have estimated the average metal-ligand bond distances from the from structure data. For the different complexes studied under the present investigation, the studies reveal that the bonding parameter α1 decreases with the increase in the percentage covalency of the metal-ligand bond. Thus, the bonding parameter α1 may be used for the estimation of percentage covalency of the metal-ligand bond in other similar complexes

Dancing attraction: followers of honey bee tremble and waggle dances exhibit similar behaviors

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Calvin Lam

2017-06-01

Full Text Available The function of the honey bee tremble dance and how it attracts signal receivers is poorly understood. We tested the hypothesis that tremble followers and waggle followers exhibit the same dance-following behavior. If correct, this could unify our understanding of dance following, provide insight into dance information transfer, and offer a way to identify the signal receivers of tremble dance information. Followers showed similar initial attraction to and tracking of dancers. However, waggle dancers were faster than tremble dancers, and follower-forward, -sideways, and -angular velocities were generally similar to the velocities of their respective dancers. Waggle dancers attracted followers from 1.3-fold greater distances away than tremble dancers. Both follower types were attracted to the lateral sides of dancers, but tremble followers were more attracted to the dancer's head, and waggle followers were more attracted to the dancer's abdomen. Tremble dancers engaged in 4-fold more brief food exchanges with their followers than waggle dancers. The behaviors of both follower types are therefore relatively conserved. Researchers can now take the next steps, observing tremble followers to determine their subsequent behaviors and testing the broader question of whether follower attraction and tracking is conserved in a wide range of social insects.

Autocrine signal transmission with extracellular ligand degradation

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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.

Distinct uptake mechanisms but similar intracellular processing of two different toll-like receptor ligand-peptide conjugates in dendritic cells.

Science.gov (United States)

Khan, Selina; Bijker, Martijn S; Weterings, Jimmy J; Tanke, Hans J; Adema, Gosse J; van Hall, Thorbald; Drijfhout, Jan W; Melief, Cornelis J M; Overkleeft, Hermen S; van der Marel, Gijsbert A; Filippov, Dmitri V; van der Burg, Sjoerd H; Ossendorp, Ferry

2007-07-20

Covalent conjugation of Toll-like receptor ligands (TLR-L) to synthetic antigenic peptides strongly improves antigen presentation in vitro and T lymphocyte priming in vivo. These molecularly well defined TLR-L-peptide conjugates, constitute an attractive vaccination modality, sharing the peptide antigen and a defined adjuvant in one single molecule. We have analyzed the intracellular trafficking and processing of two TLR-L conjugates in dendritic cells (DCs). Long synthetic peptides containing an ovalbumin cytotoxic T-cell epitope were chemically conjugated to two different TLR-Ls the TLR2 ligand, Pam(3)CysSK(4) (Pam) or the TLR9 ligand CpG. Rapid and enhanced uptake of both types of TLR-L-conjugated peptide occurred in DCs. Moreover, TLR-L conjugation greatly enhanced antigen presentation, a process that was dependent on endosomal acidification, proteasomal cleavage, and TAP translocation. The uptake of the CpG approximately conjugate was independent of endosomally-expressed TLR9 as reported previously. Unexpectedly, we found that Pam approximately conjugated peptides were likewise internalized independently of the expression of cell surface-expressed TLR2. Further characterization of the uptake mechanisms revealed that TLR2-L employed a different uptake route than TLR9-L. Inhibition of clathrin- or caveolin-dependent endocytosis greatly reduced uptake and antigen presentation of the Pam-conjugate. In contrast, internalization and antigen presentation of CpG approximately conjugates was independent of clathrin-coated pits but partly dependent on caveolae formation. Importantly, in contrast to the TLR-independent uptake of the conjugates, TLR expression and downstream TLR signaling was required for dendritic cell maturation and for priming of naïve CD8(+) T-cells. Together, our data show that targeting to two distinct TLRs requires distinct uptake mechanism but follows similar trafficking and intracellular processing pathways leading to optimal antigen

Autocrine signal transmission with extracellular ligand degradation

International Nuclear Information System (INIS)

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

2009-01-01

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

Selective extraction of trivalent actinides with hard-soft mixed donor ligands: role of intra-ligand synergism

International Nuclear Information System (INIS)

Ghanty, Tapan K.

2016-01-01

In recent years, considerable attention has been given to understand the coordination chemistry of trivalent lanthanide (Ln) and actinide (An) with various ligands because of its close link with the nuclear waste management processes. It is well known that lanthanide-actinide separation is a challenging and difficult task because of very similar chemical properties of these two series of ions, which are associated with similar ionic radii and coordination numbers. Recently, we have introduced a new concept, 'intra-ligand synergism', where hard donor atom, such as, oxygen preferentially binds to trivalent actinides (An(III)) as compared to the valence iso-electronic trivalent lanthanides (Ln(III)) in presence of another soft donor centre. In the present work, the conventional concept of selective complexation of actinides with soft donor ligands (either S or N donor) has been modified through exploiting this concept, and thereby the higher selectivity of 1,10-phenanthroline-2,9-dicarboxylamide (PDAM) based ligands, namely PDAM and its isobutyl and decyl derivatives towards Am(III) ion has been predicted theoretically through density functional calculations. Subsequently, several such amide derivatives have been synthesized to optimize the solubility of the ligands in organic phase. Finally, solvent extraction experiments have been carried out to validate the theoretical prediction on the selectivity of oxygen donor ligands towards Am(III) as compared to Eu(III), and a maximum separation factor of about 51 has been achieved experimentally using 2,9-bis(N-decylaminocarbonyl)-1,10-phenanthroline ligand. The separation factor is increased with the decrease in pH, which is very interesting since extraction of the Am 3+ ion is considered to be important under highly acidic conditions from the nuclear waste management point of view. (author)

Designer TGFβ superfamily ligands with diversified functionality.

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George P Allendorph

Full Text Available Transforming Growth Factor--beta (TGFβ superfamily ligands, including Activins, Growth and Differentiation Factors (GDFs, and Bone Morphogenetic Proteins (BMPs, are excellent targets for protein-based therapeutics because of their pervasiveness in numerous developmental and cellular processes. We developed a strategy termed RASCH (Random Assembly of Segmental Chimera and Heteromer, to engineer chemically-refoldable TGFβ superfamily ligands with unique signaling properties. One of these engineered ligands, AB208, created from Activin-βA and BMP-2 sequences, exhibits the refolding characteristics of BMP-2 while possessing Activin-like signaling attributes. Further, we find several additional ligands, AB204, AB211, and AB215, which initiate the intracellular Smad1-mediated signaling pathways more strongly than BMP-2 but show no sensitivity to the natural BMP antagonist Noggin unlike natural BMP-2. In another design, incorporation of a short N-terminal segment from BMP-2 was sufficient to enable chemical refolding of BMP-9, without which was never produced nor refolded. Our studies show that the RASCH strategy enables us to expand the functional repertoire of TGFβ superfamily ligands through development of novel chimeric TGFβ ligands with diverse biological and clinical values.

Role of ligands in permanganate oxidation of organics.

Science.gov (United States)

Jiang, Jin; Pang, Su-Yan; Ma, Jun

2010-06-01

We previously demonstrated that several ligands such as phosphate, pyrophosphate, EDTA, and humic acid could significantly enhance permanganate oxidation of triclosan (one phenolic biocide), which was explained by the contribution of ligand-stabilized reactive manganese intermediates in situ formed upon permanganate reduction. To further understand the underlying mechanism, we comparatively investigated the influence of ligands on permanganate oxidation of bisphenol A (BPA, one phenolic endocrine-disrupting chemical), carbamazepine (CBZ, a pharmaceutical containing the olefinic group), and methyl p-tolyl sulfoxide (TMSO, a typical oxygen-atom acceptor). Selected ligands exerted oxidation enhancement for BPA but had negligible influence for CBZ and TMSO. This was mainly attributed to the effects of identified Mn(III) complexes, which would otherwise disproportionate spontaneously in the absence of ligands. The one-electron oxidant Mn(III) species exhibited no reactivity toward CBZ and TMSO for which the two-electron oxygen donation may be the primary oxidation mechanism but readily oxidized BPA. The latter case was a function of pH, the complexing ligand, and the molar [Mn(III)]:[ligand] ratio, generally consistent with the patterns of ligand-affected permanganate oxidation. Moreover, the combination of the one-electron reduction of Mn(III) (Mn(III) + e(-) -->Mn(II)) and the Mn(VII)/Mn(II) reaction in excess ligands (Mn(VII) + 4Mn(II) ----> (ligands) 5Mn(III)) suggested a catalytic role of the Mn(III)/Mn(II) pair in permanganate oxidation of some phenolics in the presence of ligands.

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

International Nuclear Information System (INIS)

Cao, Ke-Li; Zhang, Yi-Ping; Cai, Yi-Ni; Xu, Xiao-Wei; Feng, Yun-Long

2014-01-01

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 2 (H 2 O) 2 ] n ·2nH 2 O (1), which possesses a 1D chain structure. In the presence of ancillary ligands, namely, 1,3-adamantanedicarboxylic acid (H 2 adbc), terephthalic acid (H 2 tpa), thiophene-2,5-dicarboxylic acid (H 2 tdc) and 1,4-benzenedithioacetic acid (H 2 bdtc), four 3D structures [Co 2 L 2 (adbc)] n ·nH 2 O (2), [Co 2 L 2 (tpa)] n (3), [Co 2 L 2 (tdc)] n (4), [Co 2 L 2 (bdtc)(H 2 O)] 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

Entangled zinc-ditetrazolate frameworks involving in situ ligand synthesis and topological modulation by various secondary N-donor ligands

International Nuclear Information System (INIS)

Li Yunwu; Chen Weilin; Wang Yonghui; Li Yangguang; Wang Enbo

2009-01-01

The introduction of various secondary N-donor ligands into an in situ ditetrazolate-ligand synthesis system of terephthalonitrile, NaN 3 and ZnCl 2 led to the formation of three new entangled frameworks Zn(pdtz)(4,4'-bipy).3H 2 O (1), [Zn(pdtz)(bpp)] 2 .3H 2 O (2) and Zn(pdtz) 0.5 (N 3 )(2,2'-bipy) (3) (4,4'-bipy=4,4'-bipyridine; bpp=1,3-bis(4-pyridyl)propane; 2,2'-bipy=2,2'-bipyridine; H 2 pdtz=5,5'-1,4-phenylene-ditetrazole). The formation of pdtz 2- ligand involves the Sharpless [2+3] cycloaddition reaction between terephthalonitrile and NaN 3 in the presence of Zn 2+ ion as a Lewis-acid catalyst under hydrothermal conditions. Compound 1 exhibits a fivefold interpenetrating 3D framework based on the diamondoid topology. Compound 2 displays a twofold parallel interpenetrating framework based on the wavelike individual network. Compound 3 possesses a 2D puckered network. These new Zn-ditetrazolate frameworks are highly dependent on the modulation of different secondary N-donor ligands. Their luminescent properties were investigated. - Graphical abstract: Three new entangled frameworks were prepared by an in situ ditetrazolate-ligand synthesis system assisted with various auxiliary N-donor ligands. The entangled structures can be modulated by different secondary ligands.

Prediction of GPCR-Ligand Binding Using Machine Learning Algorithms

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Sangmin Seo

2018-01-01

Full Text Available We propose a novel method that predicts binding of G-protein coupled receptors (GPCRs and ligands. The proposed method uses hub and cycle structures of ligands and amino acid motif sequences of GPCRs, rather than the 3D structure of a receptor or similarity of receptors or ligands. The experimental results show that these new features can be effective in predicting GPCR-ligand binding (average area under the curve [AUC] of 0.944, because they are thought to include hidden properties of good ligand-receptor binding. Using the proposed method, we were able to identify novel ligand-GPCR bindings, some of which are supported by several studies.

Evaluation of TSPO PET Ligands [18F]VUIIS1009A and [18F]VUIIS1009B: Tracers for Cancer Imaging.

Science.gov (United States)

Tang, Dewei; Li, Jun; Buck, Jason R; Tantawy, Mohamed Noor; Xia, Yan; Harp, Joel M; Nickels, Michael L; Meiler, Jens; Manning, H Charles

2017-08-01

Positron emission tomography (PET) ligands targeting translocator protein (TSPO) are potential imaging diagnostics of cancer. In this study, we report two novel, high-affinity TSPO PET ligands that are 5,7 regioisomers, [ 18 F]VUIIS1009A ([ 18 F]3A) and [ 18 F]VUIIS1009B ([ 18 F]3B), and their initial in vitro and in vivo evaluation in healthy mice and glioma-bearing rats. VUIIS1009A/B was synthesized and confirmed by X-ray crystallography. Interactions between TSPO binding pocket and novel ligands were evaluated and compared with contemporary TSPO ligands using 2D 1 H- 15 N heteronuclear single quantum coherence (HSQC) spectroscopy. In vivo biodistribution of [ 18 F]VUIIS1009A and [ 18 F]VUIIS1009B was carried out in healthy mice with and without radioligand displacement. Dynamic PET imaging data were acquired simultaneously with [ 18 F]VUIIS1009A/B injections in glioma-bearing rats, with binding reversibility and specificity evaluated by radioligand displacement. In vivo radiometabolite analysis was performed using radio-TLC, and quantitative analysis of PET data was performed using metabolite-corrected arterial input functions. Imaging was validated with histology and immunohistochemistry. Both VUIIS1009A (3A) and VUIIS1009B (3B) were found to exhibit exceptional binding affinity to TSPO, with observed IC 50 values against PK11195 approximately 500-fold lower than DPA-714. However, HSQC NMR suggested that VUIIS1009A and VUIIS1009B share a common binding pocket within mammalian TSPO (mTSPO) as DPA-714 and to a lesser extent, PK11195. [ 18 F]VUIIS1009A ([ 18 F]3A) and [ 18 F]VUIIS1009B ([ 18 F]3B) exhibited similar biodistribution in healthy mice. In rats bearing C6 gliomas, both [ 18 F]VUIIS1009A and [ 18 F]VUIIS1009B exhibited greater binding potential (k 3 /k 4 )in tumor tissue compared to [ 18 F]DPA-714. Interestingly, [ 18 F]VUIIS1009B exhibited significantly greater tumor uptake (V T ) than [ 18 F]VUIIS1009A, which was attributed primarily to greater plasma

Ligand mobility modulates immunological synapse formation and T cell activation.

Directory of Open Access Journals (Sweden)

Chih-Jung Hsu

Full Text Available T cell receptor (TCR engagement induces clustering and recruitment to the plasma membrane of many signaling molecules, including the protein tyrosine kinase zeta-chain associated protein of 70 kDa (ZAP70 and the adaptor SH2 domain-containing leukocyte protein of 76 kDa (SLP76. This molecular rearrangement results in formation of the immunological synapse (IS, a dynamic protein array that modulates T cell activation. The current study investigates the effects of apparent long-range ligand mobility on T cell signaling activity and IS formation. We formed stimulatory lipid bilayers on glass surfaces from binary lipid mixtures with varied composition, and characterized these surfaces with respect to diffusion coefficient and fluid connectivity. Stimulatory ligands coupled to these surfaces with similar density and orientation showed differences in their ability to activate T cells. On less mobile membranes, central supramolecular activation cluster (cSMAC formation was delayed and the overall accumulation of CD3ζ at the IS was reduced. Analysis of signaling microcluster (MC dynamics showed that ZAP70 MCs exhibited faster track velocity and longer trajectories as a function of increased ligand mobility, whereas movement of SLP76 MCs was relatively insensitive to this parameter. Actin retrograde flow was observed on all surfaces, but cell spreading and subsequent cytoskeletal contraction were more pronounced on mobile membranes. Finally, increased tyrosine phosphorylation and persistent elevation of intracellular Ca(2+ were observed in cells stimulated on fluid membranes. These results point to ligand mobility as an important parameter in modulating T cell responses.

Cell-specific targeting by heterobivalent ligands.

Science.gov (United States)

Josan, Jatinder S; Handl, Heather L; Sankaranarayanan, Rajesh; Xu, Liping; Lynch, Ronald M; Vagner, Josef; Mash, Eugene A; Hruby, Victor J; Gillies, Robert J

2011-07-20

Current cancer therapies exploit either differential metabolism or targeting to specific individual gene products that are overexpressed in aberrant cells. The work described herein proposes an alternative approach--to specifically target combinations of cell-surface receptors using heteromultivalent ligands ("receptor combination approach"). As a proof-of-concept that functionally unrelated receptors can be noncovalently cross-linked with high avidity and specificity, a series of heterobivalent ligands (htBVLs) were constructed from analogues of the melanocortin peptide ligand ([Nle(4), dPhe(7)]-α-MSH) and the cholecystokinin peptide ligand (CCK-8). Binding of these ligands to cells expressing the human Melanocortin-4 receptor and the Cholecystokinin-2 receptor was analyzed. The MSH(7) and CCK(6) were tethered with linkers of varying rigidity and length, constructed from natural and/or synthetic building blocks. Modeling data suggest that a linker length of 20-50 Å is needed to simultaneously bind these two different G-protein coupled receptors (GPCRs). These ligands exhibited up to 24-fold enhancement in binding affinity to cells that expressed both (bivalent binding), compared to cells with only one (monovalent binding) of the cognate receptors. The htBVLs had up to 50-fold higher affinity than that of a monomeric CCK ligand, i.e., Ac-CCK(6)-NH(2). Cell-surface targeting of these two cell types with labeled heteromultivalent ligand demonstrated high avidity and specificity, thereby validating the receptor combination approach. This ability to noncovalently cross-link heterologous receptors and target individual cells using a receptor combination approach opens up new possibilities for specific cell targeting in vivo for therapy or imaging.

Neurons in red nucleus and primary motor cortex exhibit similar responses to mechanical perturbations applied to the upper-limb during posture

Directory of Open Access Journals (Sweden)

Troy Michael Herter

2015-04-01

Full Text Available Primary motor cortex (M1 and red nucleus (RN are brain regions involved in limb motor control. Both structures are highly interconnected with the cerebellum and project directly to the spinal cord, although the contribution of RN is smaller than M1. It remains uncertain whether RN and M1 serve similar or distinct roles during posture and movement. Many neurons in M1 respond rapidly to mechanical disturbances of the limb, but it remains unclear whether RN neurons also respond to such limb perturbations. We have compared discharges of single neurons in RN (n = 49 and M1 (n = 109 of one monkey during a postural perturbation task. Neural responses to whole-limb perturbations were examined by transiently applying (300 ms flexor or extensor torques to the shoulder and/or elbow while the monkeys attempted to maintain a static hand posture. Relative to baseline discharges before perturbation onset, perturbations evoked rapid (<100 ms changes of neural discharges in many RN (28 of 49, 57% and M1 (43 of 109, 39% neurons. In addition to exhibiting a greater proportion of perturbation-related neurons, RN neurons also tended to exhibit higher peak discharge frequencies in response to perturbations than M1 neurons. Importantly, neurons in both structures exhibited similar response latencies and tuning properties (preferred torque directions and tuning widths in joint-torque space. Proximal arm muscles also displayed similar tuning properties in joint-torque space. These results suggest that RN is more sensitive than M1 to mechanical perturbations applied during postural control but both structures may play a similar role in feedback control of posture.

Virtual screening applications: a study of ligand-based methods and different structure representations in four different scenarios.

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Hristozov, Dimitar P; Oprea, Tudor I; Gasteiger, Johann

2007-01-01

Four different ligand-based virtual screening scenarios are studied: (1) prioritizing compounds for subsequent high-throughput screening (HTS); (2) selecting a predefined (small) number of potentially active compounds from a large chemical database; (3) assessing the probability that a given structure will exhibit a given activity; (4) selecting the most active structure(s) for a biological assay. Each of the four scenarios is exemplified by performing retrospective ligand-based virtual screening for eight different biological targets using two large databases--MDDR and WOMBAT. A comparison between the chemical spaces covered by these two databases is presented. The performance of two techniques for ligand--based virtual screening--similarity search with subsequent data fusion (SSDF) and novelty detection with Self-Organizing Maps (ndSOM) is investigated. Three different structure representations--2,048-dimensional Daylight fingerprints, topological autocorrelation weighted by atomic physicochemical properties (sigma electronegativity, polarizability, partial charge, and identity) and radial distribution functions weighted by the same atomic physicochemical properties--are compared. Both methods were found applicable in scenario one. The similarity search was found to perform slightly better in scenario two while the SOM novelty detection is preferred in scenario three. No method/descriptor combination achieved significant success in scenario four.

Testicular cells exhibit similar molecular responses to cigarette smoke condensate ex vivo and in vivo.

Science.gov (United States)

Esakky, Prabagaran; Hansen, Deborah A; Drury, Andrea M; Felder, Paul; Cusumano, Andrew; Moley, Kelle H

2018-01-01

Male exposure to cigarette smoke is associated with seminal defects and with congenital anomalies and childhood cancers in offspring. In mice, paternal exposure to cigarette smoke condensate (CSC) causes molecular defects in germ cells and phenotypic effects in their offspring. Here we used an ex vivo testicular explant model and in vivo exposure to determine the concentration at which CSC impairs spermatogenesis and offspring development. We explanted testis tissue at postnatal day (P)5.5 and cultured it until P11.5. Assessment of growth parameters by analyzing expression of cell-specific markers revealed that the explant system maintained structural and functional integrity. We exposed the P5.5 to -11.5 explants to various concentrations (40-160 µg/ml) of CSC and confirmed that nicotine in the CSC was metabolized to cotinine. We assessed various growth and differentiation parameters, as well as testosterone production, and observed that many spermatogenesis features were impaired at 160 µg/ml CSC. The same parameters were impaired by a similar CSC concentration in vivo Finally, females mated to males that were exposed to 160 µg/ml CSC neonatally had increased rates of pup resorption. We conclude that male exposure to CSC impairs offspring development and that the concentration at which CSC impairs spermatogenesis is similar in vivo and ex vivo. Given that the concentrations of CSC we used contained similar doses of nicotine as human smokers are exposed to, we argue that our model mimics human male reproductive effects of smoking.-Esakky, P., Hansen, D. A., Drury, A. M., Felder, P., Cusumano, A., Moley, K. H. Testicular cells exhibit similar molecular responses to cigarette smoke condensate ex vivo and in vivo . © FASEB.

Classification of Beta-lactamases and penicillin binding proteins using ligand-centric network models.

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Hakime Öztürk

Full Text Available β-lactamase mediated antibiotic resistance is an important health issue and the discovery of new β-lactam type antibiotics or β-lactamase inhibitors is an area of intense research. Today, there are about a thousand β-lactamases due to the evolutionary pressure exerted by these ligands. While β-lactamases hydrolyse the β-lactam ring of antibiotics, rendering them ineffective, Penicillin-Binding Proteins (PBPs, which share high structural similarity with β-lactamases, also confer antibiotic resistance to their host organism by acquiring mutations that allow them to continue their participation in cell wall biosynthesis. In this paper, we propose a novel approach to include ligand sharing information for classifying and clustering β-lactamases and PBPs in an effort to elucidate the ligand induced evolution of these β-lactam binding proteins. We first present a detailed summary of the β-lactamase and PBP families in the Protein Data Bank, as well as the compounds they bind to. Then, we build two different types of networks in which the proteins are represented as nodes, and two proteins are connected by an edge with a weight that depends on the number of shared identical or similar ligands. These models are analyzed under three different edge weight settings, namely unweighted, weighted, and normalized weighted. A detailed comparison of these six networks showed that the use of ligand sharing information to cluster proteins resulted in modules comprising proteins with not only sequence similarity but also functional similarity. Consideration of ligand similarity highlighted some interactions that were not detected in the identical ligand network. Analysing the β-lactamases and PBPs using ligand-centric network models enabled the identification of novel relationships, suggesting that these models can be used to examine other protein families to obtain information on their ligand induced evolutionary paths.

A chemometric analysis of ligand-induced changes in intrinsic fluorescence of folate binding protein indicates a link between altered conformational structure and physico-chemical characteristics

DEFF Research Database (Denmark)

Bruun, Susanne W; Holm, Jan; Hansen, Steen Ingemann

2009-01-01

Ligand binding alters the conformational structure and physico-chemical characteristics of bovine folate binding protein (FBP). For the purpose of achieving further information we analyzed ligand (folate and methotrexate)-induced changes in the fluorescence landscape of FBP. Fluorescence excitation...... of folate accords fairly well with the disappearance of strongly hydrophobic tryptophan residues from the solvent-exposed surface of FBP. The PARAFAC has thus proven useful to establish a hitherto unexplained link between parallel changes in conformational structure and physico-chemical characteristics...... of FBP induced by folate binding. Parameters for ligand binding derived from PARAFAC analysis of the fluorescence data were qualitatively and quantitatively similar to those obtained from binding of radiofolate to FBP. Herein, methotrexate exhibited a higher affinity for FBP than in competition...

Phenanthroline-2,9-bistriazoles as selective G-quadruplex ligands

DEFF Research Database (Denmark)

Nielsen, Mads Corvinius; Larsen, Anders Foller; Abdikadir, Faisal Hussein

2014-01-01

G-quadruplex (G4) ligands are currently receiving considerable attention as potential anticancer therapeutics. A series of phenanthroline-2,9-bistriazoles carrying tethered positive end groups has been synthesized and evaluated as G4 stabilizers. The compounds were efficiently assembled by copper......(I)-catalyzed azide-alkyne cycloaddition (CuAAC) in CH2Cl2 and water in the presence of a complexing agent. Characterization of the target compounds on telomeric and c-KIT G4 sequences led to the identification of guanidinium-substituted compounds as potent G4 DNA ligands with high selectivity over duplex DNA....... The diisopropylguanidium ligands exhibited high selectivity for the proto-oncogenic sequence c-KIT over the human telomeric sequence in the surface plasmon resonance (SPR) assay, whereas the compounds appeared potent on both G4 structures in the FRET melting temperature assay. The phenanthroline-2,9-bistriazole ligands...

Supramolecular architectures constructed using angular bipyridyl ligands

International Nuclear Information System (INIS)

Barnett, Sarah Ann

2003-01-01

This work details the synthesis and characterization of a series of coordination frameworks that are formed using bidentate angular N-donor ligands. Pyrimidine was reacted with metal(ll) nitrate salts. Reactions using Cd(NO 3 ) 2 receive particular focus and the analogous reactions using the linear ligand, pyrazine, were studied for comparison. In all cases, two-dimensional coordination networks were prepared. Structural diversity is observed for the Cd(ll) centres including metal-nitrate bridging. In contrast, first row transition metal nitrates form isostructural one-dimensional chains with only the bridging N-donor ligands generating polymeric propagation. The angular ligand, 2,4-bis(4-pyridyl)-1,3,5-triazine (dpt), was reacted with Cd(NO 3 ) 2 and Zn(NO 3 ) 2 . Whereas Zn(NO 3 ) 2 compounds exhibit solvent mediated polymorphism, a range of structures were obtained for the reactions with Cd(NO 3 ) 2 , including the first example of a doubly parallel interpenetrated 4.8 2 net. 4,7-phenanthroline, was reacted with various metal(ll) nitrates as well as cobalt(ll) and copper(ll) halides. The ability of 4,7-phenanthroline to act as both a N-donor ligand and a hydrogen bond acceptor has been discussed. Reactions of CuSCN with pyrimidine yield an unusual three-dimensional structure in which polymeric propagation is not a result of ligand bridging. The reaction of CuSCN with dpt yielded structural supramolecular isomers. (author)

Evaluation of innovative stationary phase ligand chemistries and analytical conditions for the analysis of basic drugs by supercritical fluid chromatography.

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Desfontaine, Vincent; Veuthey, Jean-Luc; Guillarme, Davy

2016-03-18

Similar to reversed phase liquid chromatography, basic compounds can be highly challenging to analyze by supercritical fluid chromatography (SFC), as they tend to exhibit poor peak shape, especially those with high pKa values. In this study, three new stationary phase ligand chemistries available in sub -2 μm particle sizes, namely 2-picolylamine (2-PIC), 1-aminoanthracene (1-AA) and diethylamine (DEA), were tested in SFC conditions for the analysis of basic drugs. Due to the basic properties of these ligands, it is expected that the repulsive forces may improve peak shape of basic substances, similarly to the widely used 2-ethypyridine (2-EP) phase. However, among the 38 tested basic drugs, less of 10% displayed Gaussian peaks (asymmetry between 0.8 and 1.4) using pure CO2/methanol on these phases. The addition of 10mM ammonium formate as mobile phase additive, drastically improved peak shapes and increased this proportion to 67% on 2-PIC. Introducing the additive in the injection solvent rather than in the organic modifier, gave acceptable results for 2-PIC only, with 31% of Gaussian peaks with an average asymmetry of 1.89 for the 38 selected basic drugs. These columns were also compared to hybrid silica (BEH), DIOL and 2-EP stationary phases, commonly employed in SFC. These phases commonly exhibit alternative retention and selectivity. In the end, the two most interesting ligands used as complementary columns were 2-PIC and BEH, as they provided suitable peak shapes for the basic drugs and almost orthogonal selectivities. Copyright © 2016 Elsevier B.V. All rights reserved.

A robust ligand exchange approach for preparing hydrophilic, biocompatible photoluminescent quantum dots

Energy Technology Data Exchange (ETDEWEB)

Wang, Sujuan; Zhou, Changhua [Key Laboratory for Special Functional Materials of the Ministry of Education, Henan University, Kaifeng 475004 (China); Yuan, Hang [Life Science Division, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055 (China); Shen, Huaibin [Key Laboratory for Special Functional Materials of the Ministry of Education, Henan University, Kaifeng 475004 (China); Zhao, Wenxiu [Life Science Division, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055 (China); Ma, Lan, E-mail: malan@sz.tsinghua.edu.cn [Life Science Division, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055 (China); Li, Lin Song, E-mail: lsli@henu.edu.cn [Key Laboratory for Special Functional Materials of the Ministry of Education, Henan University, Kaifeng 475004 (China)

2013-08-01

Graphical abstract: - Highlights: • Aqueous CdSe/ZnS QDs were prepared using polymaleic anhydrides as capping ligand. • Effect of reaction temperature and time were systematically studied in the synthesis process. • Water-soluble QDs exhibited a good stability in physiological relevant environment. • The aqueous QDs were applied as biological probe to detect human embryonic stem cell. - Abstract: This paper describes a robust ligand exchange approach for preparing biocompatible CdSe/ZnS quantum dots (QDs) to make bioprobe for effective cell imaging. In this method, polymaleic anhydride (PMA) ligand are first used to replace original hydrophobic ligand (oleic acid) and form a protection shell with multiple hydrophilic groups to coat and protect CdSe/ZnS QDs. The as-prepared aqueous QDs exhibit small particle size, good colloidal stability in aqueous solutions with a wide range of pH, salt concentrations and under thermal treatment, which are necessary for biological applications. The use of this new class of aqueous QDs for effective cell imaging shows strong fluorescence signal to human embryonic stem cell, which demonstrate that PMA coated QDs are fully satisfied with the requirements of preparing high quality biological probe.

Database of ligand-induced domain movements in enzymes

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Hayward Steven

2009-03-01

Full Text Available Abstract Background Conformational change induced by the binding of a substrate or coenzyme is a poorly understood stage in the process of enzyme catalysed reactions. For enzymes that exhibit a domain movement, the conformational change can be clearly characterized and therefore the opportunity exists to gain an understanding of the mechanisms involved. The development of the non-redundant database of protein domain movements contains examples of ligand-induced domain movements in enzymes, but this valuable data has remained unexploited. Description The domain movements in the non-redundant database of protein domain movements are those found by applying the DynDom program to pairs of crystallographic structures contained in Protein Data Bank files. For each pair of structures cross-checking ligands in their Protein Data Bank files with the KEGG-LIGAND database and using methods that search for ligands that contact the enzyme in one conformation but not the other, the non-redundant database of protein domain movements was refined down to a set of 203 enzymes where a domain movement is apparently triggered by the binding of a functional ligand. For these cases, ligand binding information, including hydrogen bonds and salt-bridges between the ligand and specific residues on the enzyme is presented in the context of dynamical information such as the regions that form the dynamic domains, the hinge bending residues, and the hinge axes. Conclusion The presentation at a single website of data on interactions between a ligand and specific residues on the enzyme alongside data on the movement that these interactions induce, should lead to new insights into the mechanisms of these enzymes in particular, and help in trying to understand the general process of ligand-induced domain closure in enzymes. The website can be found at: http://www.cmp.uea.ac.uk/dyndom/enzymeList.do

Cloud computing for protein-ligand binding site comparison.

Science.gov (United States)

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.

New functionalized β-diketiminate ligands and f elements

International Nuclear Information System (INIS)

Dulong, Florian

2013-01-01

β-diketiminate ligands have received increased interest in coordination chemistry, especially for homogeneous catalysis. Their successful applications arise from an easy and fine tuning of the ligand electronic and geometric properties. However, these modifications are limited to the introduction of neutral donors (ethers or amines), on the nitrogen substituents of the β-diketiminate skeleton. The main focus of this research project is to overcome this limitation by synthesizing new β-diketiminate ligands functionalized by one or two anionic aryl-oxide groups, and to study their coordination chemistry with lanthanide and actinide ions. Access to these species relies on a fine understanding of the mechanism underlying their formation, and the sensitivity of the β-di-iminium skeleton towards nucleophiles (phenols) has been identified as the limiting side reaction in the synthetic route. Addition of reactants in well defined order allowed the formation of two new N-aryl-oxy-β-diketiminate dianions on a multi-gram scale. The two ligands differ by their steric bulk and exhibit different coordination behaviors towards lanthanides and actinide ions, which were rationalized on geometric considerations. The reactivity of three of these new complexes has been investigated. A Ce(III) N-aryl-oxy-β-diketiminate complex exhibits interesting reduction properties, due to the shift of its oxidation potential to negative values by its coordination environment. A Th(IV) complex presents a vacant coordination site, which has been probed with different Lewis bases, emphasizing two spatial arrangements ruled by inter-ligand repulsion. It has been compared to its U(IV) analogue, which can be oxidized to a rare terminal mono-oxo uranium(VI) species. The latter was reversibly reduced to its U(V) and U(IV) derivatives, creating the first series of terminal mono-oxo uranium complexes with three successive oxidation states. These compounds represent an opportunity to better understand

Application of Shape Similarity in Pose Selection and Virtual Screening in CSARdock2014 Exercise.

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Kumar, Ashutosh; Zhang, Kam Y J

2016-06-27

To evaluate the applicability of shape similarity in docking-based pose selection and virtual screening, we participated in the CSARdock2014 benchmark exercise for identifying the correct docking pose of inhibitors targeting factor XA, spleen tyrosine kinase, and tRNA methyltransferase. This exercise provides a valuable opportunity for researchers to test their docking programs, methods, and protocols in a blind testing environment. In the CSARdock2014 benchmark exercise, we have implemented an approach that uses ligand 3D shape similarity to facilitate docking-based pose selection and virtual screening. We showed here that ligand 3D shape similarity between bound poses could be used to identify the native-like pose from an ensemble of docking-generated poses. Our method correctly identified the native pose as the top-ranking pose for 73% of test cases in a blind testing environment. Moreover, the pose selection results also revealed an excellent correlation between ligand 3D shape similarity scores and RMSD to X-ray crystal structure ligand. In the virtual screening exercise, the average RMSD for our pose prediction was found to be 1.02 Å, and it was one of the top performances achieved in CSARdock2014 benchmark exercise. Furthermore, the inclusion of shape similarity improved virtual screening performance of docking-based scoring and ranking. The coefficient of determination (r(2)) between experimental activities and docking scores for 276 spleen tyrosine kinase inhibitors was found to be 0.365 but reached 0.614 when the ligand 3D shape similarity was included.

Preparation, Spectroscopic Investigation and Biological Activity of New Mixed Ligand Chelates

International Nuclear Information System (INIS)

Alassbaly, F.S.; Ajaily, M.M.E.

2014-01-01

Preparation and investigation of new Co(II), Ni(II), Zn(II) and Cr(III) chelates with mixed ligands including Schiff base (L1) formed from the condensation of 4-dimethylaminobenzaldehyde with 2-aminophenol and anthranilic acid (L2) were studied. The obtained Schiff base and mixed ligand chelates were subjected to several physiochemical techniques, in terms of CHN elemental analyses, molar conductivity, magnetic moment measurements, infrared, proton nuclear magnetic resonance, electronic and mass spectra. The analytical data showed the formation of the Schiff base compound and the ratio of metal to ligands of the chelates are 1:1:1(M:L1:L2). The infrared spectral data exhibited that the used ligands behaving as bidentate ligands towards the metal ions. The proton nuclear magnetic resonance spectral data showed the signals of the active groups in the ligands which entered in chelation with Zn(II) metal ion. The electronic spectral results showed the existence of pie (phenyl ring) and n = pie (C=N) of the ligands and suggested the geometrical structures of the chelates. Meanwhile, the mass spectral data revealed the fragmentations of the Schiff base, anthranilic acid and their Ni(II) mixed ligand chelate has been preformed the only chelate conducted for justification. All the prepared mixed chelates were non-electrolyte in nature. The antibacterial activity of the Schiff base, anthranilic acid, metal salts and mixed ligand chelates were studied and found to be that mixed ligand chelates have the most biological activity in comparison to the free ligands and salts. (author)

Ligand cluster-based protein network and ePlatton, a multi-target ligand finder.

Science.gov (United States)

Du, Yu; Shi, Tieliu

2016-01-01

Small molecules are information carriers that make cells aware of external changes and couple internal metabolic and signalling pathway systems with each other. In some specific physiological status, natural or artificial molecules are used to interact with selective biological targets to activate or inhibit their functions to achieve expected biological and physiological output. Millions of years of evolution have optimized biological processes and pathways and now the endocrine and immune system cannot work properly without some key small molecules. In the past thousands of years, the human race has managed to find many medicines against diseases by trail-and-error experience. In the recent decades, with the deepening understanding of life and the progress of molecular biology, researchers spare no effort to design molecules targeting one or two key enzymes and receptors related to corresponding diseases. But recent studies in pharmacogenomics have shown that polypharmacology may be necessary for the effects of drugs, which challenge the paradigm, 'one drug, one target, one disease'. Nowadays, cheminformatics and structural biology can help us reasonably take advantage of the polypharmacology to design next-generation promiscuous drugs and drug combination therapies. 234,591 protein-ligand interactions were extracted from ChEMBL. By the 2D structure similarity, 13,769 ligand emerged from 156,151 distinct ligands which were recognized by 1477 proteins. Ligand cluster- and sequence-based protein networks (LCBN, SBN) were constructed, compared and analysed. For assisting compound designing, exploring polypharmacology and finding possible drug combination, we integrated the pathway, disease, drug adverse reaction and the relationship of targets and ligand clusters into the web platform, ePlatton, which is available at http://www.megabionet.org/eplatton. Although there were some disagreements between the LCBN and SBN, communities in both networks were largely the same

Controlling Nanocrystal Superlattice Symmetry and Shape-Anisotropic Interactions through Variable Ligand Surface Coverage

KAUST Repository

Choi, Joshua J.; Bealing, Clive R.; Bian, Kaifu; Hughes, Kevin J.; Zhang, Wenyu; Smilgies, Detlef-M.; Hennig, Richard G.; Engstrom, James R.; Hanrath, Tobias

2011-01-01

The assembly of colloidal nanocrystals (NCs) into superstructures with long-range translational and orientational order is sensitive to the molecular interactions between ligands bound to the NC surface. We illustrate how ligand coverage on colloidal PbS NCs can be exploited as a tunable parameter to direct the self-assembly of superlattices with predefined symmetry. We show that PbS NCs with dense ligand coverage assemble into face-centered cubic (fcc) superlattices whereas NCs with sparse ligand coverage assemble into body-centered cubic (bcc) superlattices which also exhibit orientational ordering of NCs in their lattice sites. Surface chemistry characterization combined with density functional theory calculations suggest that the loss of ligands occurs preferentially on {100} than on reconstructed {111} NC facets. The resulting anisotropic ligand distribution amplifies the role of NC shape in the assembly and leads to the formation of superlattices with translational and orientational order. © 2011 American Chemical Society.

Controlling Nanocrystal Superlattice Symmetry and Shape-Anisotropic Interactions through Variable Ligand Surface Coverage

KAUST Repository

Choi, Joshua J.

2011-03-09

The assembly of colloidal nanocrystals (NCs) into superstructures with long-range translational and orientational order is sensitive to the molecular interactions between ligands bound to the NC surface. We illustrate how ligand coverage on colloidal PbS NCs can be exploited as a tunable parameter to direct the self-assembly of superlattices with predefined symmetry. We show that PbS NCs with dense ligand coverage assemble into face-centered cubic (fcc) superlattices whereas NCs with sparse ligand coverage assemble into body-centered cubic (bcc) superlattices which also exhibit orientational ordering of NCs in their lattice sites. Surface chemistry characterization combined with density functional theory calculations suggest that the loss of ligands occurs preferentially on {100} than on reconstructed {111} NC facets. The resulting anisotropic ligand distribution amplifies the role of NC shape in the assembly and leads to the formation of superlattices with translational and orientational order. © 2011 American Chemical Society.

Protein-ligand interfaces are polarized: discovery of a strong trend for intermolecular hydrogen bonds to favor donors on the protein side with implications for predicting and designing ligand complexes.

Science.gov (United States)

Raschka, Sebastian; Wolf, Alex J; Bemister-Buffington, Joseph; Kuhn, Leslie A

2018-04-01

Understanding how proteins encode ligand specificity is fascinating and similar in importance to deciphering the genetic code. For protein-ligand recognition, the combination of an almost infinite variety of interfacial shapes and patterns of chemical groups makes the problem especially challenging. Here we analyze data across non-homologous proteins in complex with small biological ligands to address observations made in our inhibitor discovery projects: that proteins favor donating H-bonds to ligands and avoid using groups with both H-bond donor and acceptor capacity. The resulting clear and significant chemical group matching preferences elucidate the code for protein-native ligand binding, similar to the dominant patterns found in nucleic acid base-pairing. On average, 90% of the keto and carboxylate oxygens occurring in the biological ligands formed direct H-bonds to the protein. A two-fold preference was found for protein atoms to act as H-bond donors and ligand atoms to act as acceptors, and 76% of all intermolecular H-bonds involved an amine donor. Together, the tight chemical and geometric constraints associated with satisfying donor groups generate a hydrogen-bonding lock that can be matched only by ligands bearing the right acceptor-rich key. Measuring an index of H-bond preference based on the observed chemical trends proved sufficient to predict other protein-ligand complexes and can be used to guide molecular design. The resulting Hbind and Protein Recognition Index software packages are being made available for rigorously defining intermolecular H-bonds and measuring the extent to which H-bonding patterns in a given complex match the preference key.

Protein-ligand interfaces are polarized: discovery of a strong trend for intermolecular hydrogen bonds to favor donors on the protein side with implications for predicting and designing ligand complexes

Science.gov (United States)

Raschka, Sebastian; Wolf, Alex J.; Bemister-Buffington, Joseph; Kuhn, Leslie A.

2018-02-01

Understanding how proteins encode ligand specificity is fascinating and similar in importance to deciphering the genetic code. For protein-ligand recognition, the combination of an almost infinite variety of interfacial shapes and patterns of chemical groups makes the problem especially challenging. Here we analyze data across non-homologous proteins in complex with small biological ligands to address observations made in our inhibitor discovery projects: that proteins favor donating H-bonds to ligands and avoid using groups with both H-bond donor and acceptor capacity. The resulting clear and significant chemical group matching preferences elucidate the code for protein-native ligand binding, similar to the dominant patterns found in nucleic acid base-pairing. On average, 90% of the keto and carboxylate oxygens occurring in the biological ligands formed direct H-bonds to the protein. A two-fold preference was found for protein atoms to act as H-bond donors and ligand atoms to act as acceptors, and 76% of all intermolecular H-bonds involved an amine donor. Together, the tight chemical and geometric constraints associated with satisfying donor groups generate a hydrogen-bonding lock that can be matched only by ligands bearing the right acceptor-rich key. Measuring an index of H-bond preference based on the observed chemical trends proved sufficient to predict other protein-ligand complexes and can be used to guide molecular design. The resulting Hbind and Protein Recognition Index software packages are being made available for rigorously defining intermolecular H-bonds and measuring the extent to which H-bonding patterns in a given complex match the preference key.

An Efficient ABC_DE_Based Hybrid Algorithm for Protein–Ligand Docking

Directory of Open Access Journals (Sweden)

Boxin Guan

2018-04-01

Full Text Available Protein–ligand docking is a process of searching for the optimal binding conformation between the receptor and the ligand. Automated docking plays an important role in drug design, and an efficient search algorithm is needed to tackle the docking problem. To tackle the protein–ligand docking problem more efficiently, An ABC_DE_based hybrid algorithm (ADHDOCK, integrating artificial bee colony (ABC algorithm and differential evolution (DE algorithm, is proposed in the article. ADHDOCK applies an adaptive population partition (APP mechanism to reasonably allocate the computational resources of the population in each iteration process, which helps the novel method make better use of the advantages of ABC and DE. The experiment tested fifty protein–ligand docking problems to compare the performance of ADHDOCK, ABC, DE, Lamarckian genetic algorithm (LGA, running history information guided genetic algorithm (HIGA, and swarm optimization for highly flexible protein–ligand docking (SODOCK. The results clearly exhibit the capability of ADHDOCK toward finding the lowest energy and the smallest root-mean-square deviation (RMSD on most of the protein–ligand docking problems with respect to the other five algorithms.

Ligand-independent canonical Wnt activity in canine mammary tumor cell lines associated with aberrant LEF1 expression.

Directory of Open Access Journals (Sweden)

Ana Gracanin

Full Text Available Pet dogs very frequently develop spontaneous mammary tumors and have been suggested as a good model organism for breast cancer research. In order to obtain an insight into underlying signaling mechanisms during canine mammary tumorigenesis, in this study we assessed the incidence and the mechanism of canonical Wnt activation in a panel of 12 canine mammary tumor cell lines. We show that a subset of canine mammary cell lines exhibit a moderate canonical Wnt activity that is dependent on Wnt ligands, similar to what has been described in human breast cancer cell lines. In addition, three of the tested canine mammary cell lines have a high canonical Wnt activity that is not responsive to inhibitors of Wnt ligand secretion. Tumor cell lines with highly active canonical Wnt signaling often carry mutations in key members of the Wnt signaling cascade. These cell lines, however, carry no mutations in the coding regions of intracellular Wnt pathway components (APC, β-catenin, GSK3β, CK1α and Axin1 and have a functional β-catenin destruction complex. Interestingly, however, the cell lines with high canonical Wnt activity specifically overexpress LEF1 mRNA and the knock-down of LEF1 significantly inhibits TCF-reporter activity. In addition, LEF1 is overexpressed in a subset of canine mammary carcinomas, implicating LEF1 in ligand-independent activation of canonical Wnt signaling in canine mammary tumors. We conclude that canonical Wnt activation may be a frequent event in canine mammary tumors both through Wnt ligand-dependent and novel ligand-independent mechanisms.

Effects of electrostatic interactions on ligand dissociation kinetics

Science.gov (United States)

Erbaş, Aykut; de la Cruz, Monica Olvera; Marko, John F.

2018-02-01

We study unbinding of multivalent cationic ligands from oppositely charged polymeric binding sites sparsely grafted on a flat neutral substrate. Our molecular dynamics simulations are suggested by single-molecule studies of protein-DNA interactions. We consider univalent salt concentrations spanning roughly a 1000-fold range, together with various concentrations of excess ligands in solution. To reveal the ionic effects on unbinding kinetics of spontaneous and facilitated dissociation mechanisms, we treat electrostatic interactions both at a Debye-Hückel (DH) (or implicit ions, i.e., use of an electrostatic potential with a prescribed decay length) level and by the more precise approach of considering all ionic species explicitly in the simulations. We find that the DH approach systematically overestimates unbinding rates, relative to the calculations where all ion pairs are present explicitly in solution, although many aspects of the two types of calculation are qualitatively similar. For facilitated dissociation (FD) (acceleration of unbinding by free ligands in solution) explicit-ion simulations lead to unbinding at lower free-ligand concentrations. Our simulations predict a variety of FD regimes as a function of free-ligand and ion concentrations; a particularly interesting regime is at intermediate concentrations of ligands where nonelectrostatic binding strength controls FD. We conclude that explicit-ion electrostatic modeling is an essential component to quantitatively tackle problems in molecular ligand dissociation, including nucleic-acid-binding proteins.

Designer Ligands. Part 13. Synthesis and Catalytic Activity of ...

African Journals Online (AJOL)

Copper(I), copper(II), cobalt(II) and zinc(II) complexes of a macrocyclic, multidentate Schiff-base ligand have been prepared and, with the exception of the zinc(II) complex, have been shown to exhibit biomimetic catecholase activity. Keywords: Copper(II);Cobalt(II); Zinc(II); Biomimetic complexes; Catecholase activity

Reversible Redox-Induced Modulation of Sterics in an α-Diimine Ligand Coordinated to Gallium

Energy Technology Data Exchange (ETDEWEB)

Zarkesh, Ryan A. [Sandia National Lab. (SNL-CA), Livermore, CA (United States); Foster, Michael E. [Sandia National Lab. (SNL-CA), Livermore, CA (United States); Ichimura, Andrew S. [San Francisco State Univ., CA (United States); Anstey, Mitchell R. [Davidson College, Davidson, NC (United States)

2017-07-01

The ability to tune the steric envelope through redox events post-synthetically or in tandem with other chemical processes is a powerful tool that could assist in enabling new catalytic methodologies and understanding potential pitfalls in ligand design. The α-diimine ligand, dmp-BIAN, exhibits the peculiar and previously unreported feature of varying steric profiles depending on oxidation state when paired with a main group element. A study of the factors that give rise to this behaviour as well as its impact on the incorporation of other ligands is performed.

Zn and Fe complexes containing a redox active macrocyclic biquinazoline ligand.

Science.gov (United States)

Banerjee, Priyabrata; Company, Anna; Weyhermüller, Thomas; Bill, Eckhard; Hess, Corinna R

2009-04-06

A series of iron and zinc complexes has been synthesized, coordinated by the macrocyclic biquinazoline ligand, 2-4:6-8-bis(3,3,4,4-tetramethyldihydropyrrolo)-10-15-(2,2'-biquinazolino)-[15]-1,3,5,8,10,14-hexaene-1,3,7,9,11,14-N(6) (Mabiq). The Mabiq ligand consists of a bipyrimidine moiety and two dihydropyrrole units. The electronic structures of the metal-Mabiq complexes have been characterized using spectroscopic and density-functional theory (DFT) computational methods. The parent zinc complex exhibits a ligand-centered reduction to generate the metal-coordinated Mabiq radical dianion, establishing the redox non-innocence of this ligand. Iron-Mabiq complexes have been isolated in three oxidation states. This redox series includes low-spin ferric and low-spin ferrous species, as well as an intermediate-spin Fe(II) compound. In the latter complex, the iron ion is antiferromagnetically coupled to a Mabiq-centered pi-radical. The results demonstrate the rich redox chemistry and electronic properties of metal complexes coordinated by the Mabiq ligand.

Superior serum half life of albumin tagged TNF ligands

International Nuclear Information System (INIS)

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

2010-01-01

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.

LIBRA: LIgand Binding site Recognition Application.

Science.gov (United States)

Hung, Le Viet; Caprari, Silvia; Bizai, Massimiliano; Toti, Daniele; Polticelli, Fabio

2015-12-15

In recent years, structural genomics and ab initio molecular modeling activities are leading to the availability of a large number of structural models of proteins whose biochemical function is not known. The aim of this study was the development of a novel software tool that, given a protein's structural model, predicts the presence and identity of active sites and/or ligand binding sites. The algorithm implemented by ligand binding site recognition application (LIBRA) is based on a graph theory approach to find the largest subset of similar residues between an input protein and a collection of known functional sites. The algorithm makes use of two predefined databases for active sites and ligand binding sites, respectively, derived from the Catalytic Site Atlas and the Protein Data Bank. Tests indicate that LIBRA is able to identify the correct binding/active site in 90% of the cases analyzed, 90% of which feature the identified site as ranking first. As far as ligand binding site recognition is concerned, LIBRA outperforms other structure-based ligand binding sites detection tools with which it has been compared. The application, developed in Java SE 7 with a Swing GUI embedding a JMol applet, can be run on any OS equipped with a suitable Java Virtual Machine (JVM), and is available at the following URL: http://www.computationalbiology.it/software/LIBRAv1.zip. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Rational construction of an ssa-type of MOF through pre-organizing the ligand's conformation and its exceptional gas adsorption properties.

Science.gov (United States)

Wang, Yao; He, Minghui; Tian, Zhi; Zhong, Haoyan; Zhu, Lisha; Zhang, Yingying; Zhang, Xiaoping; Chen, De-Li; He, Yabing

2018-02-13

Ssa-type MOFs constructed from dicopper paddlewheels and bent diisophthalate ligands exhibit a promising potential for gas adsorption which benefits from their rich open copper sites and polyhedron-based cages with suitable sizes. However, the rational construction of such types of MOFs is exceedingly challenging because the bent diisophthalate ligands employed are inclined to exhibit various conformations and thus are prone to form MOFs with varied topologies. In this work, by pre-organizing the ligand's conformation, we successfully targeted an ssa-type MOF ZJNU-57 from a bent diisophthalate ligand. More significantly, ZJNU-57 exhibits excellent hydrolytic stability and high C 2 H 2 and CO 2 uptake capacities as well as impressive C 2 H 2 /CH 4 and CO 2 /CH 4 adsorption selectivities, indicating its promising potential for C 2 H 2 /CH 4 and CO 2 /CH 4 separation, which are relevant to acetylene production and natural gas purification. This work not only provides a rare water-stable MOF based on the Cu 2 (COO) 4 cluster for highly selective adsorption of C 2 H 2 and CO 2 from CH 4 , but also demonstrates that the ligand conformation-controlled assembly strategy may be an efficient approach toward the construction of MOF materials with definite topologies for specific applications.

Trapping of palindromic ligands within native transthyretin prevents amyloid formation

Science.gov (United States)

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

Synthesis and characterization ligand tris-(2-thiosalicylamidoethyl)amine and its iron complexes and indium

International Nuclear Information System (INIS)

Guerra-Garcia, Pedro Pablo; Valle Bourrouet, Grettel

2006-01-01

The synthesis of coordination chemistry ligand tris-(2-tiosalicilamidoetil)amine is presented within the framework of study of tripod ligands, the corresponding complexes of iron and indium. Also, its spectroscopic characterization by proton magnetic resonance is showed; so the influence of ligand on a redox active metal and an inactive is compared. Electrochemical methods have been used. The presence of sulfur atoms modifies the redox and magnetic behavior of iron ion (III), as has been found in other similar ligands [es

Ligand Electron Density Shape Recognition Using 3D Zernike Descriptors

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Gunasekaran, Prasad; Grandison, Scott; Cowtan, Kevin; Mak, Lora; Lawson, David M.; Morris, Richard J.

We present a novel approach to crystallographic ligand density interpretation based on Zernike shape descriptors. Electron density for a bound ligand is expanded in an orthogonal polynomial series (3D Zernike polynomials) and the coefficients from this expansion are employed to construct rotation-invariant descriptors. These descriptors can be compared highly efficiently against large databases of descriptors computed from other molecules. In this manuscript we describe this process and show initial results from an electron density interpretation study on a dataset containing over a hundred OMIT maps. We could identify the correct ligand as the first hit in about 30 % of the cases, within the top five in a further 30 % of the cases, and giving rise to an 80 % probability of getting the correct ligand within the top ten matches. In all but a few examples, the top hit was highly similar to the correct ligand in both shape and chemistry. Further extensions and intrinsic limitations of the method are discussed.

Oxygen infrared spectra of oxyhemoglobins and oxymyoglobins. Evidence of two major liganded O2 structures

International Nuclear Information System (INIS)

Potter, W.T.; Tucker, M.P.; Houtchens, R.A.; Caughey, W.S.

1987-01-01

The dioxygen stretch bands in infrared spectra for solutions of oxy species of human hemoglobin A and its separated subunits, human mutant hemoglobin Zurich (β63His to Arg), rabbit hemoglobin, lamprey, hemoglobin, sperm whale myoglobin, bovine myoglobin, and a sea worm chlorocruorin are examined. Each protein exhibits multiple isotope-sensitive bands between 1160 and 1060 cm -1 for the liganded 16 O 2 , 17 O 2 , and 18 O 2 . The O-O stretch bands for each of the mammalian myoglobins and hemoglobins are similar, with frequencies that differ between proteins by only 3-5 cm -1 . The spectra for the lamprey and sea worm hemoglobins exhibit greater diversity. For all proteins an O-O stretch band expected to occur near 1125 cm -1 for 16 O 2 and 17 O 2 , but not 18 O 2 , appears split by ∼25 cm -1 due to an unidentified perturbation. The spectrum for each dioxygen isotope, if unperturbed, would contain two strong bands for the mammalian myoglobins (1150 and 1120 cm -1 ) and hemoglobins (1155 and 1125 cm -1 ). Two strong bands separated by ∼30 cm -1 for each oxy heme protein subunit indicate that two major protein conformations (structure) that differ substantially in O 2 bonding are present. The two dioxygen structures can result from a combination of dynamic distal and proximal effects upon the O 2 ligand bound in a bent-end-on stereochemistry

Two novel mixed-ligand complexes containing organosulfonate ligands.

Science.gov (United States)

Li, Mingtian; Huang, Jun; Zhou, Xuan; Fang, Hua; Ding, Liyun

2008-07-01

The structures reported herein, viz. bis(4-aminonaphthalene-1-sulfonato-kappaO)bis(4,5-diazafluoren-9-one-kappa(2)N,N')copper(II), [Cu(C(10)H(8)NO(3)S)(2)(C(11)H(6)N(2)O)(2)], (I), and poly[[[diaquacadmium(II)]-bis(mu-4-aminonaphthalene-1-sulfonato)-kappa(2)O:N;kappa(2)N:O] dihydrate], {[Cd(C(10)H(8)NO(3)S)(2)(H(2)O)(2)].2H(2)O}(n), (II), are rare examples of sulfonate-containing complexes where the anion does not fulfill a passive charge-balancing role, but takes an active part in coordination as a monodentate and/or bridging ligand. Monomeric complex (I) possesses a crystallographic inversion center at the Cu(II) atom, and the asymmetric unit contains one-half of a Cu atom, one complete 4-aminonaphthalene-1-sulfonate (ans) ligand and one 4,5-diazafluoren-9-one (DAFO) ligand. The Cu(II) atom has an elongated distorted octahedral coordination geometry formed by two O atoms from two monodentate ans ligands and by four N atoms from two DAFO molecules. Complex (II) is polymeric and its crystal structure is built up by one-dimensional chains and solvent water molecules. Here also the cation (a Cd(II) atom) lies on a crystallographic inversion center and adopts a slightly distorted octahedral geometry. Each ans anion serves as a bridging ligand linking two Cd(II) atoms into one-dimensional infinite chains along the [010] direction, with each Cd(II) center coordinated by four ans ligands via O and N atoms and by two aqua ligands. In both structures, there are significant pi-pi stacking interactions between adjacent ligands and hydrogen bonds contribute to the formation of two- and three-dimensional networks.

Isozyme-specific ligands for O-acetylserine sulfhydrylase, a novel antibiotic target.

Directory of Open Access Journals (Sweden)

Francesca Spyrakis

Full Text Available The last step of cysteine biosynthesis in bacteria and plants is catalyzed by O-acetylserine sulfhydrylase. In bacteria, two isozymes, O-acetylserine sulfhydrylase-A and O-acetylserine sulfhydrylase-B, have been identified that share similar binding sites, although the respective specific functions are still debated. O-acetylserine sulfhydrylase plays a key role in the adaptation of bacteria to the host environment, in the defense mechanisms to oxidative stress and in antibiotic resistance. Because mammals synthesize cysteine from methionine and lack O-acetylserine sulfhydrylase, the enzyme is a potential target for antimicrobials. With this aim, we first identified potential inhibitors of the two isozymes via a ligand- and structure-based in silico screening of a subset of the ZINC library using FLAP. The binding affinities of the most promising candidates were measured in vitro on purified O-acetylserine sulfhydrylase-A and O-acetylserine sulfhydrylase-B from Salmonella typhimurium by a direct method that exploits the change in the cofactor fluorescence. Two molecules were identified with dissociation constants of 3.7 and 33 µM for O-acetylserine sulfhydrylase-A and O-acetylserine sulfhydrylase-B, respectively. Because GRID analysis of the two isoenzymes indicates the presence of a few common pharmacophoric features, cross binding titrations were carried out. It was found that the best binder for O-acetylserine sulfhydrylase-B exhibits a dissociation constant of 29 µM for O-acetylserine sulfhydrylase-A, thus displaying a limited selectivity, whereas the best binder for O-acetylserine sulfhydrylase-A exhibits a dissociation constant of 50 µM for O-acetylserine sulfhydrylase-B and is thus 8-fold selective towards the former isozyme. Therefore, isoform-specific and isoform-independent ligands allow to either selectively target the isozyme that predominantly supports bacteria during infection and long-term survival or to completely block

Mesoporous organosilica nanotubes containing a chelating ligand in their walls

Energy Technology Data Exchange (ETDEWEB)

Liu, Xiao; Goto, Yasutomo; Maegawa, Yoshifumi; Inagaki, Shinji, E-mail: inagaki@mosk.tytlabs.co.jp [Toyota Central R and D Laboratories, Inc., Nagakute, Aichi 480-1192 (Japan); Japan Science and Technology Agency (JST)/ACT-C, Nagakute, Aichi, 480-1192 (Japan); Ohsuna, Tetsu [Toyota Central R and D Laboratories, Inc., Nagakute, Aichi 480-1192 (Japan)

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 Ce{sup 4+}, due to the ready access of reactants to the active sites in the nanotubes.

Metallogel formation in aqueous DMSO by perfluoroalkyl decorated terpyridine ligands.

Science.gov (United States)

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

2016-08-09

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

Synthesis and characterization of an iron complex bearing a cyclic tetra-N-heterocyclic carbene ligand: An artifical heme analogue?

KAUST Repository

Anneser, Markus R.

2015-04-20

An iron(II) complex with a cyclic tetradentate ligand containing four N-heterocyclic carbenes was synthesized and characterized by means of NMR and IR spectroscopies, as well as by single-crystal X-ray structure analysis. The iron center exhibits an octahedral coordination geometry with two acetonitrile ligands in axial positions, showing structural analogies with porphyrine-ligated iron complexes. The acetonitrile ligands can readily be substituted by other ligands, for instance, dimethyl sulfoxide, carbon monoxide, and nitric oxide. Cyclic voltammetry was used to examine the electronic properties of the synthesized compounds. © 2015 American Chemical Society.

Molecular characterization of the haptoglobin.hemoglobin receptor CD163. Ligand binding properties of the scavenger receptor cysteine-rich domain region

DEFF Research Database (Denmark)

Madsen, Mette; Møller, Holger J; Nielsen, Marianne Jensby

2004-01-01

binding to SRCR domain 3 exhibited effective inhibition of ligand binding. Furthermore, analysis of purified native CD163 revealed that proteolytic cleavage in SRCR domain 3 inactivates ligand binding. Calcium protects against cleavage in this domain. Analysis of the calcium sensitivity of ligand binding...... to CD163 demonstrated that optimal ligand binding requires physiological plasma calcium concentrations, and an immediate ligand release occurs at the low calcium concentrations measured in acidifying endosomes. In conclusion, SRCR domain 3 of CD163 is an exposed domain and a critical determinant...... for the calcium-sensitive coupling of haptoglobin.hemoglobin complexes....

Apo and ligand-bound structures of ModA from the archaeon Methanosarcina acetivorans

International Nuclear Information System (INIS)

Chan, Sum; Giuroiu, Iulia; Chernishof, Irina; Sawaya, Michael R.; Chiang, Janet; Gunsalus, Robert P.; Arbing, Mark A.; Perry, L. Jeanne

2010-01-01

Crystal structures of ModA from M. acetivorans in the apo and ligand-bound conformations confirm domain rotation upon ligand binding. The trace-element oxyanion molybdate, which is required for the growth of many bacterial and archaeal species, is transported into the cell by an ATP-binding cassette (ABC) transporter superfamily uptake system called ModABC. ModABC consists of the ModA periplasmic solute-binding protein, the integral membrane-transport protein ModB and the ATP-binding and hydrolysis cassette protein ModC. In this study, X-ray crystal structures of ModA from the archaeon Methanosarcina acetivorans (MaModA) have been determined in the apoprotein conformation at 1.95 and 1.69 Å resolution and in the molybdate-bound conformation at 2.25 and 2.45 Å resolution. The overall domain structure of MaModA is similar to other ModA proteins in that it has a bilobal structure in which two mixed α/β domains are linked by a hinge region. The apo MaModA is the first unliganded archaeal ModA structure to be determined: it exhibits a deep cleft between the two domains and confirms that upon binding ligand one domain is rotated towards the other by a hinge-bending motion, which is consistent with the ‘Venus flytrap’ model seen for bacterial-type periplasmic binding proteins. In contrast to the bacterial ModA structures, which have tetrahedral coordination of their metal substrates, molybdate-bound MaModA employs octahedral coordination of its substrate like other archaeal ModA proteins

Binding Ligand Prediction for Proteins Using Partial Matching of Local Surface Patches

Directory of Open Access Journals (Sweden)

Lee Sael

2010-12-01

Full Text Available Functional elucidation of uncharacterized protein structures is an important task in bioinformatics. We report our new approach for structure-based function prediction which captures local surface features of ligand binding pockets. Function of proteins, specifically, binding ligands of proteins, can be predicted by finding similar local surface regions of known proteins. To enable partial comparison of binding sites in proteins, a weighted bipartite matching algorithm is used to match pairs of surface patches. The surface patches are encoded with the 3D Zernike descriptors. Unlike the existing methods which compare global characteristics of the protein fold or the global pocket shape, the local surface patch method can find functional similarity between non-homologous proteins and binding pockets for flexible ligand molecules. The proposed method improves prediction results over global pocket shape-based method which was previously developed by our group.

Binding ligand prediction for proteins using partial matching of local surface patches.

Science.gov (United States)

Sael, Lee; Kihara, Daisuke

2010-01-01

Functional elucidation of uncharacterized protein structures is an important task in bioinformatics. We report our new approach for structure-based function prediction which captures local surface features of ligand binding pockets. Function of proteins, specifically, binding ligands of proteins, can be predicted by finding similar local surface regions of known proteins. To enable partial comparison of binding sites in proteins, a weighted bipartite matching algorithm is used to match pairs of surface patches. The surface patches are encoded with the 3D Zernike descriptors. Unlike the existing methods which compare global characteristics of the protein fold or the global pocket shape, the local surface patch method can find functional similarity between non-homologous proteins and binding pockets for flexible ligand molecules. The proposed method improves prediction results over global pocket shape-based method which was previously developed by our group.

Design of a multi-dopamine-modified polymer ligand optimally suited for interfacing magnetic nanoparticles with biological systems.

Science.gov (United States)

Wang, Wentao; Ji, Xin; Na, Hyon Bin; Safi, Malak; Smith, Alexandra; Palui, Goutam; Perez, J Manuel; Mattoussi, Hedi

2014-06-03

We have designed a set of multifunctional and multicoordinating polymer ligands that are optimally suited for surface functionalizing iron oxide and potentially other magnetic nanoparticles (NPs) and promoting their integration into biological systems. The amphiphilic polymers are prepared by coupling (via nucleophilic addition) several amine-terminated dopamine anchoring groups, poly(ethylene glycol) moieties, and reactive groups onto a poly(isobutylene-alt-maleic anhydride) (PIMA) chain. This design greatly benefits from the highly efficient and reagent-free one-step reaction of maleic anhydride groups with amine-containing molecules. The availability of several dopamine groups in the same ligand greatly enhances the ligand affinity, via multiple coordination, to the magnetic NPs, while the hydrophilic and reactive groups promote colloidal stability in buffer media and allow subsequent conjugation with target biomolecules. Iron oxide nanoparticles ligand exchanged with these polymer ligands have a compact hydrodynamic size and exhibit enhanced long-term colloidal stability over the pH range of 4-12 and in the presence of excess electrolytes. Nanoparticles ligated with terminally reactive polymers have been easily coupled to target dyes and tested in live cell imaging with no measurable cytotoxicity. Finally, the resulting hydrophilic nanoparticles exhibit large and size-dependent r2 relaxivity values.

Synthesis and characterization of ligands and bifunctional chelating agents by modification of cysteine for complexation studies with 99mTc

International Nuclear Information System (INIS)

Pillai, M.R.A.; Kothari, K.; Banerjee, S.; Samuel, G.; Suresh, M.; Sarma, H.D.

1998-01-01

The synthesis of four novel ligands using the amino-acid cysteine and its ethyl carboxylate derivative is described. The synthetic method involves a two-step procedure, wherein the intermediate Schiff base formed by the condensation of the amino group of the cysteine substrate and salicylaldehyde is reduced to give the target ligands. The intermediates and the final products are characterised by high resolution NMR spectroscopy. Complexation studies of the ligands with 99m Tc are standardised using stannous tartrate as the reducing agent at varying reaction conditions. The complexes are characterised using standard quality control techniques such as TLC, paper electrophoresis and PC. Lipophilicities of the complexes are estimated by solvent extraction into chloroform. Substantial changes in net charge and lipophilicity in the 99m Tc complexes are observed on substituting the carboxylic acid residue in ligand I and II with the ethyl carboxylate groups (ligands III and IV). All the ligands formed complexes in high yield. While the complexes of ligand I and II are observed to be hydrophilic in nature and are not extractable into CHCl 3 , ligands III and IV gave neutral and lipophilic complexes. Though the distribution ratios of the complexes of ligands III and IV in CHCl 3 /saline system are observed to be very high, considerable differences in lipophilicities are also observed as evidenced by the difference in their respective extractabilities in chloroform. On storage, the complex of ligand III exhibit a tendency to get converted to a hydrophilic and non-extractable species. The bio-distribution of the complexes of ligands I and II showed that they have predominantly renal clearances whereas the complexes of ligands III and IV exhibited a significant hepatobiliary uptake and did not show much uptake in brain in spite of its favourable properties such as neutrality, lipophilicity and conversion into a hydrophilic species. (author)

Analogies and surprising differences between recombinant nitric oxide synthase-like proteins from Staphylococcus aureus and Bacillus anthracis in their interactions with l-arginine analogs and iron ligands.

Science.gov (United States)

Salard, Isabelle; Mercey, Emilie; Rekka, Eleni; Boucher, Jean-Luc; Nioche, Pierre; Mikula, Ivan; Martasek, Pavel; Raman, C S; Mansuy, Daniel

2006-12-01

Genome sequencing has recently shown the presence of genes coding for NO-synthase (NOS)-like proteins in bacteria. The roles of these proteins remain unclear. The interactions of a series of l-arginine (l-arg) analogs and iron ligands with two recombinant NOS-like proteins from Staphylococcus aureus (saNOS) and Bacillus anthracis (baNOS) have been studied by UV-visible spectroscopy. SaNOS and baNOS in their ferric native state, as well as their complexes with l-arg analogs and with various ligands, exhibit spectral characteristics highly similar to the corresponding complexes of heme-thiolate proteins such as cytochromes P450 and NOSs. However, saNOS greatly differs from baNOS at the level of three main properties: (i) native saNOS mainly exists under an hexacoordinated low-spin ferric state whereas native baNOS is mainly high-spin, (ii) the addition of tetrahydrobiopterin (H4B) or H4B analogs leads to an increase of the affinity of l-arg for saNOS but not for baNOS, and (iii) saNOS Fe(II), contrary to baNOS, binds relatively bulky ligands such as nitrosoalkanes and tert-butylisocyanide. Thus, saNOS exhibits properties very similar to those of the oxygenase domain of inducible NOS (iNOS(oxy)) not containing H4B, as expected for a NOSoxy-like protein that does not contain H4B. By contrast, the properties of baNOS which look like those of H4B-containing iNOS(oxy) are unexpected for a NOS-like protein not containing H4B. The origin of these surprising properties of baNOS remains to be determined.

Composition of Overlapping Protein-Protein and Protein-Ligand Interfaces.

Directory of Open Access Journals (Sweden)

Ruzianisra Mohamed

Full Text Available Protein-protein interactions (PPIs play a major role in many biological processes and they represent an important class of targets for therapeutic intervention. However, targeting PPIs is challenging because often no convenient natural substrates are available as starting point for small-molecule design. Here, we explored the characteristics of protein interfaces in five non-redundant datasets of 174 protein-protein (PP complexes, and 161 protein-ligand (PL complexes from the ABC database, 436 PP complexes, and 196 PL complexes from the PIBASE database and a dataset of 89 PL complexes from the Timbal database. In all cases, the small molecule ligands must bind at the respective PP interface. We observed similar amino acid frequencies in all three datasets. Remarkably, also the characteristics of PP contacts and overlapping PL contacts are highly similar.

Ligand Depot: a data warehouse for ligands bound to macromolecules.

Science.gov (United States)

Feng, Zukang; Chen, Li; Maddula, Himabindu; Akcan, Ozgur; Oughtred, Rose; Berman, Helen M; Westbrook, John

2004-09-01

Ligand Depot is an integrated data resource for finding information about small molecules bound to proteins and nucleic acids. The initial release (version 1.0, November, 2003) focuses on providing chemical and structural information for small molecules found as part of the structures deposited in the Protein Data Bank. Ligand Depot accepts keyword-based queries and also provides a graphical interface for performing chemical substructure searches. A wide variety of web resources that contain information on small molecules may also be accessed through Ligand Depot. Ligand Depot is available at http://ligand-depot.rutgers.edu/. Version 1.0 supports multiple operating systems including Windows, Unix, Linux and the Macintosh operating system. The current drawing tool works in Internet Explorer, Netscape and Mozilla on Windows, Unix and Linux.

Radioiodinated ligands for dopamine receptors

International Nuclear Information System (INIS)

Kung, H.F.

1994-01-01

The dopamine receptor system is important for normal brain function; it is also the apparent action site for various neuroleptic drugs for the treatment of schizophrenia and other metal disorders. In the past few years radioiodinated ligands for single photon emission tomography (SPECT) have been successfully developed and tested in humans: [ 123 I]TISCH for D1 dopamine receptors; [ 123 I]IBZM, epidepride, IBF and FIDA2, four iodobenzamide derivatives, for D2/D3 dopamine receptors. In addition, [ 123 I]β-CIT (RTI-55) and IPT, cocaine derivatives, for the dopamine reuptake site are potentially useful for diagnosis of loss of dopamine neurons. The first iodinated ligand, (R)trans-7-OH-PIPAT, for D3 dopamine receptors, was synthesized and characterized with cloned cell lines (Spodoptera frugiperda, Sf9) expressing the D2 and D3 dopamine receptors and with rat basal forebrain membrane preparations. Most of the known iodobenzamides displayed similar potency in binding to both D2 and D3 dopamine receptors expressed in the cell lines. Initial studies appear to suggest that by fine tuning the structures it may be possible to develop agents specific for D2 and D3 dopamine receptors. It is important to investigate D2/D3 selectivity for this series of potent ligands

Reactivity of nitrido complexes of ruthenium(VI), osmium(VI), and manganese(V) bearing Schiff base and simple anionic ligands.

Science.gov (United States)

Man, Wai-Lun; Lam, William W Y; Lau, Tai-Chu

2014-02-18

Nitrido complexes (M≡N) may be key intermediates in chemical and biological nitrogen fixation and serve as useful reagents for nitrogenation of organic compounds. Osmium(VI) nitrido complexes bearing 2,2':6',2″-terpyridine (terpy), 2,2'-bipyridine (bpy), or hydrotris(1-pyrazolyl)borate anion (Tp) ligands are highly electrophilic: they can react with a variety of nucleophiles to generate novel osmium(IV)/(V) complexes. This Account describes our recent results studying the reactivity of nitridocomplexes of ruthenium(VI), osmium(VI), and manganese(V) that bear Schiff bases and other simple anionic ligands. We demonstrate that these nitrido complexes exhibit rich chemical reactivity. They react with various nucleophiles, activate C-H bonds, undergo N···N coupling, catalyze the oxidation of organic compounds, and show anticancer activities. Ruthenium(VI) nitrido complexes bearing Schiff base ligands, such as [Ru(VI)(N)(salchda)(CH3OH)](+) (salchda = N,N'-bis(salicylidene)o-cyclohexyldiamine dianion), are highly electrophilic. This complex reacts readily at ambient conditions with a variety of nucleophiles at rates that are much faster than similar reactions using Os(VI)≡N. This complex also carries out unique reactions, including the direct aziridination of alkenes, C-H bond activation of alkanes and C-N bond cleavage of anilines. The addition of ligands such as pyridine can enhance the reactivity of [Ru(VI)(N)(salchda)(CH3OH)](+). Therefore researchers can tune the reactivity of Ru≡N by adding a ligand L trans to nitride: L-Ru≡N. Moreover, the addition of various nucleophiles (Nu) to Ru(VI)≡N initially generate the ruthenium(IV) imido species Ru(IV)-N(Nu), a new class of hydrogen-atom transfer (HAT) reagents. Nucleophiles also readily add to coordinated Schiff base ligands in Os(VI)≡N and Ru(VI)≡N complexes. These additions are often stereospecific, suggesting that the nitrido ligand has a directing effect on the incoming nucleophile. M≡N is also

Narcissistic self-sorting in self-assembled cages of rare Earth metals and rigid ligands.

Science.gov (United States)

Johnson, Amber M; Wiley, Calvin A; Young, Michael C; Zhang, Xing; Lyon, Yana; Julian, Ryan R; Hooley, Richard J

2015-05-04

Highly selective, narcissistic self-sorting can be achieved in the formation of self-assembled cages of rare earth metals with multianionic salicylhydrazone ligands. The assembly process is highly sensitive to the length of the ligand and the coordination geometry. Most surprisingly, high-fidelity sorting is possible between ligands of identical coordination angle and geometry, differing only in a single functional group on the ligand core, which is not involved in the coordination. Supramolecular effects allow discrimination between pendant functions as similar as carbonyl or methylene groups in a complex assembly process. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Mesoporous organosilica nanotubes containing a chelating ligand in their walls

Directory of Open Access Journals (Sweden)

Xiao Liu

2014-11-01

Full Text Available 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.

Impact of protein and ligand impurities on ITC-derived protein-ligand thermodynamics.

Science.gov (United States)

Grüner, Stefan; Neeb, Manuel; Barandun, Luzi Jakob; Sielaff, Frank; Hohn, Christoph; Kojima, Shun; Steinmetzer, Torsten; Diederich, François; Klebe, Gerhard

2014-09-01

The thermodynamic characterization of protein-ligand interactions by isothermal titration calorimetry (ITC) is a powerful tool in drug design, giving valuable insight into the interaction driving forces. ITC is thought to require protein and ligand solutions of high quality, meaning both the absence of contaminants as well as accurately determined concentrations. Ligands synthesized to deviating purity and protein of different pureness were titrated by ITC. Data curation was attempted also considering information from analytical techniques to correct stoichiometry. We used trypsin and tRNA-guanine transglycosylase (TGT), together with high affinity ligands to investigate the effect of errors in protein concentration as well as the impact of ligand impurities on the apparent thermodynamics. We found that errors in protein concentration did not change the thermodynamic properties obtained significantly. However, most ligand impurities led to pronounced changes in binding enthalpy. If protein binding of the respective impurity is not expected, the actual ligand concentration was corrected for and the thus revised data compared to thermodynamic properties obtained with the respective pure ligand. Even in these cases, we observed differences in binding enthalpy of about 4kJ⋅mol(-1), which is considered significant. Our results indicate that ligand purity is the critical parameter to monitor if accurate thermodynamic data of a protein-ligand complex are to be recorded. Furthermore, artificially changing fitting parameters to obtain a sound interaction stoichiometry in the presence of uncharacterized ligand impurities may lead to thermodynamic parameters significantly deviating from the accurate thermodynamic signature. Copyright © 2014 Elsevier B.V. All rights reserved.

Synthesis and Optical Properties of Thiol Functionalized CdSe/ZnS (Core/Shell Quantum Dots by Ligand Exchange

Directory of Open Access Journals (Sweden)

Huaping Zhu

2014-01-01

Full Text Available The colloidal photoluminescent quantum dots (QDs of CdSe (core and CdSe/ZnS (core/shell were synthesized at different temperatures with different growth periods. Optical properties (i.e., UV/Vis spectra and photoluminescent emission spectra of the resulting QDs were investigated. The shell-protected CdSe/ZnS QDs exhibited higher photoluminescent (PL efficiency and stability than their corresponding CdSe core QDs. Ligand exchange with various thiol molecules was performed to replace the initial surface passivation ligands, that is, trioctylphosphine oxide (TOPO and trioctylphosphine (TOP, and the optical properties of the surface-modified QDs were studied. The thiol ligand molecules in this study included 1,4-benzenedimethanethiol, 1,16-hexadecanedithiol, 1,11-undecanedithiol, biphenyl-4,4′-dithiol, 11-mercapto-1-undecanol, and 1,8-octanedithiol. After the thiol functionalization, the CdSe/ZnS QDs exhibited significantly enhanced PL efficiency and storage stability. Besides surface passivation effect, such enhanced performance of thiol-functionalized QDs could be due to cross-linked assembly formation of dimer/trimer clusters, in which QDs are linked by dithiol molecules. Furthermore, effects of ligand concentration, type of ligand, and heating on the thiol stabilization of QDs were also discussed.

Real-Time Ligand Binding Pocket Database Search Using Local Surface Descriptors

Science.gov (United States)

Chikhi, Rayan; Sael, Lee; Kihara, Daisuke

2010-01-01

Due to the increasing number of structures of unknown function accumulated by ongoing structural genomics projects, there is an urgent need for computational methods for characterizing protein tertiary structures. As functions of many of these proteins are not easily predicted by conventional sequence database searches, a legitimate strategy is to utilize structure information in function characterization. Of a particular interest is prediction of ligand binding to a protein, as ligand molecule recognition is a major part of molecular function of proteins. Predicting whether a ligand molecule binds a protein is a complex problem due to the physical nature of protein-ligand interactions and the flexibility of both binding sites and ligand molecules. However, geometric and physicochemical complementarity is observed between the ligand and its binding site in many cases. Therefore, ligand molecules which bind to a local surface site in a protein can be predicted by finding similar local pockets of known binding ligands in the structure database. Here, we present two representations of ligand binding pockets and utilize them for ligand binding prediction by pocket shape comparison. These representations are based on mapping of surface properties of binding pockets, which are compactly described either by the two dimensional pseudo-Zernike moments or the 3D Zernike descriptors. These compact representations allow a fast real-time pocket searching against a database. Thorough benchmark study employing two different datasets show that our representations are competitive with the other existing methods. Limitations and potentials of the shape-based methods as well as possible improvements are discussed. PMID:20455259

Withanolide D Exhibits Similar Cytostatic Effect in Drug-Resistant and Drug-Sensitive Multiple Myeloma Cells

Directory of Open Access Journals (Sweden)

Mark E. Issa

2017-09-01

Full Text Available In spite of recent therapeutic advances, multiple myeloma (MM remains a malignancy with very low curability. This has been partly attributed to the existence of a drug-resistant subpopulation known as cancer stem cells (CSCs. MM-CSCs are equipped with the necessary tools that render them highly resistant to virtually all conventional therapies. In this study, the growth inhibitory effects of withanolide D (WND, a steroidal lactone isolated from Withania somnifera, on drug-sensitive tumoral plasma cells and drug-resistant MM cells have been investigated. In MTT/XTT assays, WND exhibited similar cytostatic effects between drug-resistant and drug-sensitive cell lines in the nM range. WND also induced cell death and apoptosis in MM-CSCs and RPMI 8226 cells, as examined by the calcein/ethidium homodimer and annexin V/propidium iodide stainings, respectively. To determine whether P-glycoprotein (P-gp efflux affected the cytostatic activity of WND, P-gp was inhibited with verapamil and results indicated that the WND cytostatic effect in MM-CSCs was independent of P-gp efflux. Furthermore, WND did not increase the accumulation of the fluorescent P-gp substrate rhodamine 123 in MM-CSCs, suggesting that WND may not inhibit P-gp at the tested relevant doses. Therefore, the WND-induced cytostatic effect may be independent of P-gp efflux. These findings warrant further investigation of WND in MM-CSC animal models.

Revealing a steroid receptor ligand as a unique PPAR[gamma] agonist

Energy Technology Data Exchange (ETDEWEB)

Lin, Shengchen; Han, Ying; Shi, Yuzhe; Rong, Hui; Zheng, Songyang; Jin, Shikan; Lin, Shu-Yong; Lin, Sheng-Cai; Li, Yong (Pitt); (Xiamen)

2012-06-28

Peroxisome proliferator-activated receptor gamma (PPAR{gamma}) regulates metabolic homeostasis and is a molecular target for anti-diabetic drugs. We report here the identification of a steroid receptor ligand, RU-486, as an unexpected PPAR{gamma} agonist, thereby uncovering a novel signaling route for this steroid drug. Similar to rosiglitazone, RU-486 modulates the expression of key PPAR{gamma} target genes and promotes adipocyte differentiation, but with a lower adipogenic activity. Structural and functional studies of receptor-ligand interactions reveal the molecular basis for a unique binding mode for RU-486 in the PPAR{gamma} ligand-binding pocket with distinctive properties and epitopes, providing the molecular mechanisms for the discrimination of RU-486 from thiazolidinediones (TZDs) drugs. Our findings together indicate that steroid compounds may represent an alternative approach for designing non-TZD PPAR{gamma} ligands in the treatment of insulin resistance.

Ligands in PSI structures

International Nuclear Information System (INIS)

Kumar, Abhinav; Chiu, Hsiu-Ju; Axelrod, Herbert L.; Morse, Andrew; Elsliger, Marc-André; Wilson, Ian A.; Deacon, Ashley

2010-01-01

A survey of the types and frequency of ligands that are bound to PSI structures is analyzed as well as their utility in functional annotation of previously uncharacterized proteins. Approximately 65% of PSI structures report some type of ligand(s) that is bound in the crystal structure. Here, a description is given of how such ligands are handled and analyzed at the JCSG and a survey of the types, variety and frequency of ligands that are observed in the PSI structures is also compiled and analyzed, including illustrations of how these bound ligands have provided functional clues for annotation of proteins with little or no previous experimental characterization. Furthermore, a web server was developed as a tool to mine and analyze the PSI structures for bound ligands and other identifying features

Xanthene and Xanthone Derivatives as G-Quadruplex Stabilizing Ligands

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Alessandro Altieri

2013-10-01

Full Text Available Following previous studies on anthraquinone and acridine-based G-quadruplex ligands, here we present a study of similar aromatic cores, with the specific aim of increasing G-quadruplex binding and selectivity with respect to duplex DNA. Synthesized compounds include two and three-side chain xanthone and xanthene derivatives, as well as a dimeric “bridged” form. ESI and FRET measurements suggest that all the studied molecules are good G-quadruplex ligands, both at telomeres and on G-quadruplex forming sequences of oncogene promoters. The dimeric compound and the three-side chain xanthone derivative have been shown to represent the best compounds emerging from the different series of ligands presented here, having also high selectivity for G-quadruplex structures with respect to duplex DNA. Molecular modeling simulations are in broad agreement with the experimental data.

Molecular dynamics simulations suggest ligand's binding to nicotinamidase/pyrazinamidase.

Science.gov (United States)

Zhang, Ji-Long; Zheng, Qing-Chuan; Li, Zheng-Qiang; Zhang, Hong-Xing

2012-01-01

The research on the binding process of ligand to pyrazinamidase (PncA) is crucial for elucidating the inherent relationship between resistance of Mycobacterium tuberculosis and PncA's activity. In the present study, molecular dynamics (MD) simulation methods were performed to investigate the unbinding process of nicotinamide (NAM) from two PncA enzymes, which is the reverse of the corresponding binding process. The calculated potential of mean force (PMF) based on the steered molecular dynamics (SMD) simulations sheds light on an optimal binding/unbinding pathway of the ligand. The comparative analyses between two PncAs clearly exhibit the consistency of the binding/unbinding pathway in the two enzymes, implying the universality of the pathway in all kinds of PncAs. Several important residues dominating the pathway were also determined by the calculation of interaction energies. The structural change of the proteins induced by NAM's unbinding or binding shows the great extent interior motion in some homologous region adjacent to the active sites of the two PncAs. The structure comparison substantiates that this region should be very important for the ligand's binding in all PncAs. Additionally, MD simulations also show that the coordination position of the ligand is displaced by one water molecule in the unliganded enzymes. These results could provide the more penetrating understanding of drug resistance of M. tuberculosis and be helpful for the development of new antituberculosis drugs.

Engineering of Olfactory Receptor OlfCc1 for Directed Ligand Sensitivity

OpenAIRE

Berke, Allison Paige

2013-01-01

Abstract Engineering of Olfactory Receptor OlfCc1 for Directed Ligand Sensitivityby Allison Paige Berke Joint Doctor of Philosophywith the University of California San FranciscoUniversity of California, Berkeley Professor Song Li, ChairDue to structural similarity, OlfCc1and its mammalian analogue V2R2 are hypothesized to respond to amino acid ligands in a calcium-mediated fashion. By analyzing receptor structure and making targeted mutations, the specificity and sensitivity of the receptor s...

Effects of the η(5)-C5H4(i)Pr Ligand on the Properties Exhibited by Its Tungsten Nitrosyl Complexes.

Science.gov (United States)

Fabulyak, Diana; Baillie, Rhett A; Patrick, Brian O; Legzdins, Peter; Rosenfeld, Devon C

2016-02-15

Reaction of Na[η(5)-C5H4(i)Pr] with W(CO)6 in refluxing THF for 4 days generates a solution of Na[(η(5)-C5H4(i)Pr)W(CO)3] that when treated with N-methyl-N-nitroso-p-toluenesulfonamide at ambient temperatures affords (η(5)-C5H4(i)Pr)W(NO)(CO)2 (1) that is isolable in good yield as an analytically pure orange oil. Treatment of 1 with an equimolar amount of I2 in Et2O at ambient temperatures affords (η(5)-C5H4(i)Pr)W(NO)I2 (2) as a dark brown solid in excellent yield. Sequential treatment at low temperatures of 2 with 0.5 equiv of Mg(CH2CMe3)2 and Mg(CH2CH═CMe2)2 in Et2O produces the alkyl allyl complex, (η(5)-C5H4(i)Pr)W(NO)(CH2CMe3)(η(3)-CH2CHCMe2) (3), as a thermally sensitive yellow liquid. Complex 3 may also be synthesized, albeit in low yield, in one vessel at low temperatures by reacting 1 first with 1 equiv of PCl5 and then with the binary magnesium reagents specified above. Interestingly, similar treatment of 1 in Et2O with PCl5 and only 0.5 equiv of Mg(CH2CH═CMe2)2 results in the formation of the unusual complex (η(5)-C5H4(i)Pr)W(NO)(PCl2CMe2CH═CH2)Cl2 (4), which probably is formed via a metathesis reaction of the binary magnesium reagent with (η(5)-C5H4(i)Pr)W(NO)(PCl3)Cl2. The C-D activation of C6D6 by complex 3 has been investigated and compared to that exhibited by its η(5)-C5Me5, η(5)-C5Me4H, and η(5)-C5Me4(n)Pr analogues. Kinetic analyses of the various activations have established that the presence of the η(5)-C5H4(i)Pr ligand significantly increases the rate of the reaction, an outcome that can be attributed to a combination of steric and electronic factors. In addition, mechanistic studies have established that in solution 3 loses neopentane under ambient conditions to generate exclusively the 16e η(2)-diene intermediate complex (η(5)-C5H4(i)Pr)W(NO)(η(2)-CH2═CMeCH═CH2), which then effects the subsequent C-D activations. This behavior contrasts with that exhibited by the η(5)-C5Me5 analogue of 3 which forms both η(2

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

Science.gov (United States)

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.

Performance of machine learning methods for ligand-based virtual screening.

Science.gov (United States)

Plewczynski, Dariusz; Spieser, Stéphane A H; Koch, Uwe

2009-05-01

Computational screening of compound databases has become increasingly popular in pharmaceutical research. This review focuses on the evaluation of ligand-based virtual screening using active compounds as templates in the context of drug discovery. Ligand-based screening techniques are based on comparative molecular similarity analysis of compounds with known and unknown activity. We provide an overview of publications that have evaluated different machine learning methods, such as support vector machines, decision trees, ensemble methods such as boosting, bagging and random forests, clustering methods, neuronal networks, naïve Bayesian, data fusion methods and others.

Design of a Bioactive Small Molecule that Targets the Myotonic Dystrophy Type 1 RNA Via an RNA Motif-Ligand Database & Chemical Similarity Searching

Science.gov (United States)

Parkesh, Raman; Childs-Disney, Jessica L.; Nakamori, Masayuki; Kumar, Amit; Wang, Eric; Wang, Thomas; Hoskins, Jason; Tran, Tuan; Housman, David; Thornton, Charles A.; Disney, Matthew D.

2012-01-01

Myotonic dystrophy type 1 (DM1) is a triplet repeating disorder caused by expanded CTG repeats in the 3′ untranslated region of the dystrophia myotonica protein kinase (DMPK) gene. The transcribed repeats fold into an RNA hairpin with multiple copies of a 5′CUG/3′GUC motif that binds the RNA splicing regulator muscleblind-like 1 protein (MBNL1). Sequestration of MBNL1 by expanded r(CUG) repeats causes splicing defects in a subset of pre-mRNAs including the insulin receptor, the muscle-specific chloride ion channel, Sarco(endo)plasmic reticulum Ca2+ ATPase 1 (Serca1/Atp2a1), and cardiac troponin T (cTNT). Based on these observations, the development of small molecule ligands that target specifically expanded DM1 repeats could serve as therapeutics. In the present study, computational screening was employed to improve the efficacy of pentamidine and Hoechst 33258 ligands that have been shown previously to target the DM1 triplet repeat. A series of inhibitors of the RNA-protein complex with low micromolar IC50’s, which are >20-fold more potent than the query compounds, were identified. Importantly, a bis-benzimidazole identified from the Hoechst query improves DM1-associated pre-mRNA splicing defects in cell and mouse models of DM1 (when dosed with 1 mM and 100 mg/kg, respectively). Since Hoechst 33258 was identified as a DM1 binder through analysis of an RNA motif-ligand database, these studies suggest that lead ligands targeting RNA with improved biological activity can be identified by using a synergistic approach that combines analysis of known RNA-ligand interactions with virtual screening. PMID:22300544

Complexation of biological ligands with lanthanides(III) for MRI: Structure, thermodynamic and methods; Complexation des cations lanthanides trivalents par des ligands d'origine biologique pour l'IRM: Structure, thermodynamique et methodes

Energy Technology Data Exchange (ETDEWEB)

Bonnet, C

2006-07-15

New cyclic ligands derived from sugars and amino-acids form a scaffold carrying a coordination sphere of oxygen atoms suitable to complex Ln(III) ions. In spite of their rather low molecular weights, the complexes display surprisingly high relaxivity values, especially at high field. The ACX and BCX ligands, which are acidic derivatives of modified and cyclo-dextrins, form mono and bimetallic complexes with Ln(III). The LnACX and LnBCX complexes show affinities towards Ln(III) similar to those of tri-acidic ligands. In the bimetallic Lu2ACX complex, the cations are deeply embedded in the cavity of the ligand, as shown by the X-ray structure. In aqueous solution, the number of water molecules coordinated to the cation in the LnACX complex depends on the nature and concentration of the alkali ions of the supporting electrolyte, as shown by luminescence and relaxometric measurements. There is only one water molecule coordinated in the LnBCX complex, which enables us to highlight an important second sphere contribution to relaxivity. The NMR study of the RAFT peptidic ligand shows the complexation of Ln(III), with an affinity similar to those of natural ligands derived from calmodulin. The relaxometric study also shows an important second sphere contribution to relaxivity. To better understand the intricate molecular factors affecting relaxivity, we developed new relaxometric methods based on probe solutes. These methods allow us to determine the charge of the complex, weak affinity constants, trans-metallation constants, and the electronic relaxation rate. (author)

Synthesis and antimalarial activity of metal complexes of cross-bridged tetraazamacrocyclic ligands.

Science.gov (United States)

Hubin, Timothy J; Amoyaw, Prince N-A; Roewe, Kimberly D; Simpson, Natalie C; Maples, Randall D; Carder Freeman, TaRynn N; Cain, Amy N; Le, Justin G; Archibald, Stephen J; Khan, Shabana I; Tekwani, Babu L; Khan, M O Faruk

2014-07-01

Using transition metals such as manganese(II), iron(II), cobalt(II), nickel(II), copper(II), and zinc(II), several new metal complexes of cross-bridged tetraazamacrocyclic chelators namely, cyclen- and cyclam-analogs with benzyl groups, were synthesized and screened for in vitro antimalarial activity against chloroquine-resistant (W2) and chloroquine-sensitive (D6) strains of Plasmodium falciparum. The metal-free chelators tested showed little or no antimalarial activity. All the metal complexes of the dibenzyl cross-bridged cyclam ligand exhibited potent antimalarial activity. The Mn(2+) complex of this ligand was the most potent with IC50s of 0.127 and 0.157μM against the chloroquine-sensitive (D6) and chloroquine-resistant (W2) P. falciparum strains, respectively. In general, the dibenzyl hydrophobic ligands showed better anti-malarial activity compared to the activity of monobenzyl ligands, potentially because of their higher lipophilicity and thus better cell penetration ability. The higher antimalarial activity displayed by the manganese complex for the cyclam ligand in comparison to that of the cyclen, correlates with the larger pocket of cyclam compared to that of cyclen which produces a more stable complex with the Mn(2+). Few of the Cu(2+) and Fe(2+) complexes also showed improvement in activity but Ni(2+), Co(2+) and Zn(2+) complexes did not show any improvement in activity upon the metal-free ligands for anti-malarial development. Published by Elsevier Ltd.

Screening the efficient biological prospects of triazole allied mixed ligand metal complexes

Science.gov (United States)

Utthra, Ponnukalai Ponya; Kumaravel, Ganesan; Raman, Natarajan

2017-12-01

Triazole appended mixed ligand complexes (1-8) of the general formula [ML (bpy/phen)2]Cl2, where M = Cu(II), Co(II), Ni(II) and Zn(II), L = triazole appended Schiff base (E)sbnd N-(4-nitrobenzylidene)-1H-1,2,4-triazol-3-amine and bpy/phen = 2,2‧-bipyridine/1,10-phenanthroline, have been synthesized. The design and synthesis of this elaborate ligand has been performed with the aim of increasing stability and conjugation of 1,2,4 triazole, whose Schiff base derivatives are known as biologically active compounds thereby exploring their DNA binding affinity and other biological applications. The compounds have been comprehensively characterized by elemental analysis, spectroscopic methods (IR, UV-Vis, EPR, 1H and 13C NMR spectroscopy), ESI mass spectrometry and magnetic susceptibility measurements. The complexes were found to exhibit octahedral geometry. The complexes 1-8 were subjected to DNA binding techniques evaluated using UV-Vis absorption, CV, CD, Fluorescence spectroscopy and hydrodynamic measurements. Complex 5 showed a Kb value of 3.9 × 105 M-1. The DNA damaging efficacy for the complexes was observed to be high compared to the ligand. The antimicrobial screening of the compounds against bacterial and fungal strains indicates that the complexes possess excellent antimicrobial activity than the ligand. The overall biological activity of the complexes with phen as a co-ligand possessed superior potential than the ligand.

Molecular dynamics simulations suggest ligand's binding to nicotinamidase/pyrazinamidase.

Directory of Open Access Journals (Sweden)

Ji-Long Zhang

Full Text Available The research on the binding process of ligand to pyrazinamidase (PncA is crucial for elucidating the inherent relationship between resistance of Mycobacterium tuberculosis and PncA's activity. In the present study, molecular dynamics (MD simulation methods were performed to investigate the unbinding process of nicotinamide (NAM from two PncA enzymes, which is the reverse of the corresponding binding process. The calculated potential of mean force (PMF based on the steered molecular dynamics (SMD simulations sheds light on an optimal binding/unbinding pathway of the ligand. The comparative analyses between two PncAs clearly exhibit the consistency of the binding/unbinding pathway in the two enzymes, implying the universality of the pathway in all kinds of PncAs. Several important residues dominating the pathway were also determined by the calculation of interaction energies. The structural change of the proteins induced by NAM's unbinding or binding shows the great extent interior motion in some homologous region adjacent to the active sites of the two PncAs. The structure comparison substantiates that this region should be very important for the ligand's binding in all PncAs. Additionally, MD simulations also show that the coordination position of the ligand is displaced by one water molecule in the unliganded enzymes. These results could provide the more penetrating understanding of drug resistance of M. tuberculosis and be helpful for the development of new antituberculosis drugs.

Ligand-mediated adhesive mechanics of two static, deformed spheres.

Science.gov (United States)

Sircar, Sarthok; Nguyen, Giang; Kotousov, Andrei; Roberts, Anthony J

2016-10-01

A self-consistent model is developed to investigate attachment/detachment kinetics of two static, deformable microspheres with irregular surface and coated with flexible binding ligands. The model highlights how the microscale binding kinetics of these ligands as well as the attractive/repulsive potential of the charged surface affects the macroscale static deformed configuration of the spheres. It is shown that in the limit of smooth, neutrally charged surface (i.e., the dimensionless inverse Debye length, [Formula: see text]), interacting via elastic binders (i.e., the dimensionless stiffness coefficient, [Formula: see text]) the adhesion mechanics approaches the regime of application of the JKR theory, and in this particular limit, the contact radius, R c , scales with the particle radius, R, according to the scaling law, [Formula: see text]. We show that static, deformed, highly charged, ligand-coated surface of micro-spheres exhibit strong adhesion. Normal stress distribution within the contact area adjusts with the binder stiffness coefficient, from a maximum at the center to a maximum at the periphery of the region. Although reported in some in vitro experiments involving particle adhesion, until now a physical interpretation for this variation of the stress distribution for deformable, charged, ligand-coated microspheres is missing. Surface roughness results in a diminished adhesion with a distinct reduction in the pull-off force, larger separation gap, weaker normal stress and limited area of adhesion. These results are in agreement with the published experimental findings.

Structural and Electrochemical Consequences of [Cp*] Ligand Protonation.

Science.gov (United States)

Peng, Yun; Ramos-Garcés, Mario V; Lionetti, Davide; Blakemore, James D

2017-09-05

There are few examples of the isolation of analogous metal complexes bearing [η 5 -Cp*] and [η 4 -Cp*H] (Cp* = pentamethylcyclopentadienyl) complexes within the same metal/ligand framework, despite the relevance of such structures to catalytic applications. Recently, protonation of Cp*Rh(bpy) (bpy = 2,2'-bipyridyl) has been shown to yield a complex bearing the uncommon [η 4 -Cp*H] ligand, rather than generating a [Rh III -H] complex. We now report the purification and isolation of this protonated species, as well as characterization of analogous complexes of 1,10-phenanthroline (phen). Specifically, reaction of Cp*Rh(bpy) or Cp*Rh(phen) with 1 equiv of Et 3 NH + Br - affords rhodium compounds bearing endo-η 4 -pentamethylcyclopentadiene (η 4 -Cp*H) as a ligand. NMR spectroscopy and single-crystal X-ray diffraction studies confirm protonation of the Cp* ligand, rather than formation of metal hydride complexes. Analysis of new structural data and electronic spectra suggests that phen is significantly reduced in Cp*Rh(phen), similar to the case of Cp*Rh(bpy). Backbonding interactions with olefinic motifs are activated by formation of [η 4 -Cp*H]; protonation of [Cp*] stabilizes the low-valent metal center and results in loss of reduced character on the diimine ligands. In accord with these changes in electronic structure, electrochemical studies reveal a distinct manifold of redox processes that are accessible in the [Cp*H] complexes in comparison with their [Cp*] analogues; these processes suggest new applications in catalysis for the complexes bearing endo-η 4 -Cp*H.

Role of the T cell receptor ligand affinity in T cell activation by bacterial superantigens

DEFF Research Database (Denmark)

Andersen, P S; Geisler, C; Buus, S

2001-01-01

Similar to native peptide/MHC ligands, bacterial superantigens have been found to bind with low affinity to the T cell receptor (TCR). It has been hypothesized that low ligand affinity is required to allow optimal TCR signaling. To test this, we generated variants of Staphylococcus enterotoxin C3...... (SEC3) with up to a 150-fold increase in TCR affinity. By stimulating T cells with SEC3 molecules immobilized onto plastic surfaces, we demonstrate that increasing the affinity of the SEC3/TCR interaction caused a proportional increase in the ability of SEC3 to activate T cells. Thus, the potency...... correlation between ligand affinity and ligand potency indicating that it is the density of receptor-ligand complexes in the T cell contact area that determines TCR signaling strength....

Crystallization of protein–ligand complexes

International Nuclear Information System (INIS)

Hassell, Anne M.; An, Gang; Bledsoe, Randy K.; Bynum, Jane M.; Carter, H. Luke III; Deng, Su-Jun J.; Gampe, Robert T.; Grisard, Tamara E.; Madauss, Kevin P.; Nolte, Robert T.; Rocque, Warren J.; Wang, Liping; Weaver, Kurt L.; Williams, Shawn P.; Wisely, G. Bruce; Xu, Robert; Shewchuk, Lisa M.

2007-01-01

Methods presented for growing protein–ligand complexes fall into the categories of co-expression of the protein with the ligands of interest, use of the ligands during protein purification, cocrystallization and soaking the ligands into existing crystals. Obtaining diffraction-quality crystals has long been a bottleneck in solving the three-dimensional structures of proteins. Often proteins may be stabilized when they are complexed with a substrate, nucleic acid, cofactor or small molecule. These ligands, on the other hand, have the potential to induce significant conformational changes to the protein and ab initio screening may be required to find a new crystal form. This paper presents an overview of strategies in the following areas for obtaining crystals of protein–ligand complexes: (i) co-expression of the protein with the ligands of interest, (ii) use of the ligands during protein purification, (iii) cocrystallization and (iv) soaks

Synthesis, Crystal Structure and Luminescent Property of A Novel Cd(II) Coordination Polymer with Bis-imidazole Ligand

International Nuclear Information System (INIS)

Zhou, Yong Hong

2013-01-01

The key to the successful design of metal-organic coordination polymers is the judicious selection of organic ligand. Recently, polydentate aromatic nitrogen heterocyclic ligands with five-membered rings have been well-studied in the construction of supramolecular structure for their N-coordinated sites apt to coordinating to transition metals. Similar to six-membered N-heterocyclic ligands, the azole-based five-membered N-heterocyclic ligands, such as imidazoles, triazoles and tetrazoles have been extensively employed in the construction of various coordination polymers with diverse topologies and interesting properties. The bis(azole) ligands in which N-donor azole rings (imidazole, triazole, or tetrazole) are separated by alkyl, (CH 2 ) n , spacers are good choices for flexible bridging ligands. The conformational flexibility of the spacers makes the ligands adaptable to various coordination networks with one-, two-, and three dimensional structures

Structural Diversity of Metallosupramolecular Assemblies Based on the Bent Bridging Ligand 4,4′-Dithiodipyridine

Directory of Open Access Journals (Sweden)

Rüdiger W. Seidel

2013-05-01

Full Text Available 4,4′-Dithiodipyridine (dtdp, also termed 4,4′-dipyridyldisulfide, is a bridging ligand of the 4,4′-bipyridine type. The introduction of the disulfide moiety inevitably leads to a relatively rigid angular structure, which exhibits axial chirality. More than 90 metal complexes containing the dtdp ligand have been crystallographically characterised until now. This review focuses on the preparation and structural diversity of discrete and polymeric metallosupramolecular assemblies constructed from dtdp as bridging ligands. These encompass metallamacrocycles with M2L2 topology and coordination polymers with periodicity in one or two dimensions. One-dimensional coordination polymers represent the vast majority of the metallosupramolecular structures obtained from dtdp. These include repeated rhomboids, zigzag, helical and arched chains among other types. In this contribution, we make an attempt to provide a comprehensive account of the structural data that are currently available for metallosupramolecular assemblies based on the bent bridging ligand dtdp.

Ligand-dependent exciton dynamics and photovoltaic properties of PbS quantum dot heterojunction solar cells.

Science.gov (United States)

Chang, Jin; Ogomi, Yuhei; Ding, Chao; Zhang, Yao Hong; Toyoda, Taro; Hayase, Shuzi; Katayama, Kenji; Shen, Qing

2017-03-01

The surface chemistry of colloidal quantum dots (QDs) plays an important role in determining the photoelectric properties of QD films and the corresponding quantum dot heterojunction solar cells (QDHSCs). To investigate the effects of the ligand structure on the photovoltaic performance and exciton dynamics of QDHSCs, PbS QDHSCs were fabricated by the solid state ligand exchange method with mercaptoalkanoic acid as the cross-linking ligand. Temperature-dependent photoluminescence and ultrafast transient absorption spectra show that the electronic coupling and charge transfer rate within QD ensembles were monotonically enhanced as the ligand length decreased. However, in practical QDHSCs, the second shortest ligand 3-mercaptopropionic acid (MPA) showed higher power conversion efficiency than the shortest ligand thioglycolic acid (TGA). This could be attributed to the difference in their surface trap states, supported by thermally stimulated current measurements. Moreover, compared with the non-conjugated ligand MPA, the conjugated ligand 4-mercaptobenzoic acid (MBA) introduces less trap states and has a similar charge transfer rate in QD ensembles, but has poor photovoltaic properties. This unexpected result could be contributed by the QD-ligand orbital mixing, leading to the charge transfer from QDs to ligands instead of charge transfer between adjacent QDs. This work highlights the significant effects of ligand structures on the photovoltaic properties and exciton dynamics of QDHSCs, which would shed light on the further development of QD-based photoelectric devices.

Consensus of sample-balanced classifiers for identifying ligand-binding residue by co-evolutionary physicochemical characteristics of amino acids

KAUST Repository

Chen, Peng

2013-01-01

Protein-ligand binding is an important mechanism for some proteins to perform their functions, and those binding sites are the residues of proteins that physically bind to ligands. So far, the state-of-the-art methods search for similar, known

Complexation of biological ligands with lanthanides(III) for MRI: Structure, thermodynamic and methods; Complexation des cations lanthanides trivalents par des ligands d'origine biologique pour l'IRM: Structure, thermodynamique et methodes

Energy Technology Data Exchange (ETDEWEB)

Bonnet, C

2006-07-15

New cyclic ligands derived from sugars and amino-acids form a scaffold carrying a coordination sphere of oxygen atoms suitable to complex Ln(III) ions. In spite of their rather low molecular weights, the complexes display surprisingly high relaxivity values, especially at high field. The ACX and BCX ligands, which are acidic derivatives of modified and cyclo-dextrins, form mono and bimetallic complexes with Ln(III). The LnACX and LnBCX complexes show affinities towards Ln(III) similar to those of tri-acidic ligands. In the bimetallic Lu2ACX complex, the cations are deeply embedded in the cavity of the ligand, as shown by the X-ray structure. In aqueous solution, the number of water molecules coordinated to the cation in the LnACX complex depends on the nature and concentration of the alkali ions of the supporting electrolyte, as shown by luminescence and relaxometric measurements. There is only one water molecule coordinated in the LnBCX complex, which enables us to highlight an important second sphere contribution to relaxivity. The NMR study of the RAFT peptidic ligand shows the complexation of Ln(III), with an affinity similar to those of natural ligands derived from calmodulin. The relaxometric study also shows an important second sphere contribution to relaxivity. To better understand the intricate molecular factors affecting relaxivity, we developed new relaxometric methods based on probe solutes. These methods allow us to determine the charge of the complex, weak affinity constants, trans-metallation constants, and the electronic relaxation rate. (author)

A two-dimensional layered Cd(II) coordination polymer with a three-dimensional supramolecular architecture incorporating mixed multidentate N- and O-donor ligands.

Science.gov (United States)

Huang, Qiu-Ying; Su, Ming-Yang; Meng, Xiang-Ru

2015-06-01

The combination of N-heterocyclic and multicarboxylate ligands is a good choice for the construction of metal-organic frameworks. In the title coordination polymer, poly[bis{μ2-1-[(1H-benzimidazol-2-yl)methyl]-1H-tetrazole-κ(2)N(3):N(4)}(μ4-butanedioato-κ(4)O(1):O(1'):O(4):O(4'))(μ2-butanedioato-κ(2)O(1):O(4))dicadmium], [Cd(C4H4O4)(C9H8N6)]n, each Cd(II) ion exhibits an irregular octahedral CdO4N2 coordination geometry and is coordinated by four O atoms from three carboxylate groups of three succinate (butanedioate) ligands and two N atoms from two 1-[(1H-benzimidazol-2-yl)methyl]-1H-tetrazole (bimt) ligands. Cd(II) ions are connected by two kinds of crystallographically independent succinate ligands to generate a two-dimensional layered structure with bimt ligands located on each side of the layer. Adjacent layers are further connected by hydrogen bonding, leading to a three-dimensional supramolecular architecture in the solid state. Thermogravimetric analysis of the title polymer shows that it is stable up to 529 K and then loses weight from 529 to 918 K, corresponding to the decomposition of the bimt ligands and succinate groups. The polymer exhibits a strong fluorescence emission in the solid state at room temperature.

Excited state redox properties of phthalocyanines: influence of the axial ligand on the rates of relaxation and electron-transfer quenching of the lowest /sup 3/. pi pi. /sup */ excited state

Energy Technology Data Exchange (ETDEWEB)

Ferraudi, G J; Prasad, D R

1874-01-01

Laser flash excitations at 640 nm have been used to generate the transient spectra of the lowest-lying /sup 3/..pi pi../sup */ state of phthalocyaninatoruthenium(II) complexes. The properties of this excited state such as the properties of the maxima, lambda/sub max/ = 500 +/- 30 nm, and lifetimes, t/sub 1/2/ = 70-4500 ns, exhibit a large dependence on the electron-accepting and electron-withdrawing tendencies of the axial ligands. A similar influence was observed upon the rate of electron-transfer quenching of the /sup 3/..pi pi../sup */ state. Values between 10/sup 6/ and 10/sup 7/ dm/sup 3/ mol/sup -1/ s/sup -1/ for the self-exchange rate constant have been obtained, according to Marcus-Hush theoretical treatments, for (Ru(pc.)LL')/sup +//(/sup 3/..pi pi../sup */)(Ru(pc)LL') (L and L' = neutral axial ligands; pc = phthalocyaninate (2-)) and isoelectronic cobalt(III) and rhodium(III) couples. The redox properties of the ground and excited states are correlated with axial ligand-induced perturbations of the electronic structure.

Autoreactive effector/memory CD4+ and CD8+ T cells infiltrating grafted and endogenous islets in diabetic NOD mice exhibit similar T cell receptor usage.

Directory of Open Access Journals (Sweden)

Ramiro Diz

Full Text Available Islet transplantation provides a "cure" for type 1 diabetes but is limited in part by recurrent autoimmunity mediated by β cell-specific CD4(+ and CD8(+ T cells. Insight into the T cell receptor (TCR repertoire of effector T cells driving recurrent autoimmunity would aid the development of immunotherapies to prevent islet graft rejection. Accordingly, we used a multi-parameter flow cytometry strategy to assess the TCR variable β (Vβ chain repertoires of T cell subsets involved in autoimmune-mediated rejection of islet grafts in diabetic NOD mouse recipients. Naïve CD4(+ and CD8(+ T cells exhibited a diverse TCR repertoire, which was similar in all tissues examined in NOD recipients including the pancreas and islet grafts. On the other hand, the effector/memory CD8(+ T cell repertoire in the islet graft was dominated by one to four TCR Vβ chains, and specific TCR Vβ chain usage varied from recipient to recipient. Similarly, islet graft- infiltrating effector/memory CD4(+ T cells expressed a limited number of prevalent TCR Vβ chains, although generally TCR repertoire diversity was increased compared to effector/memory CD8(+ T cells. Strikingly, the majority of NOD recipients showed an increase in TCR Vβ12-bearing effector/memory CD4(+ T cells in the islet graft, most of which were proliferating, indicating clonal expansion. Importantly, TCR Vβ usage by effector/memory CD4(+ and CD8(+ T cells infiltrating the islet graft exhibited greater similarity to the repertoire found in the pancreas as opposed to the draining renal lymph node, pancreatic lymph node, or spleen. Together these results demonstrate that effector/memory CD4(+ and CD8(+ T cells mediating autoimmune rejection of islet grafts are characterized by restricted TCR Vβ chain usage, and are similar to T cells that drive destruction of the endogenous islets.

Simple knowledge-based descriptors to predict protein-ligand interactions. Methodology and validation

Science.gov (United States)

Nissink, J. Willem M.; Verdonk, Marcel L.; Klebe, Gerhard

2000-11-01

A new type of shape descriptor is proposed to describe the spatial orientation for non-covalent interactions. It is built from simple, anisotropic Gaussian contributions that are parameterised by 10 adjustable values. The descriptors have been used to fit propensity distributions derived from scatter data stored in the IsoStar database. This database holds composite pictures of possible interaction geometries between a common central group and various interacting moieties, as extracted from small-molecule crystal structures. These distributions can be related to probabilities for the occurrence of certain interaction geometries among different functional groups. A fitting procedure is described that generates the descriptors in a fully automated way. For this purpose, we apply a similarity index that is tailored to the problem, the Split Hodgkin Index. It accounts for the similarity in regions of either high or low propensity in a separate way. Although dependent on the division into these two subregions, the index is robust and performs better than the regular Hodgkin index. The reliability and coverage of the fitted descriptors was assessed using SuperStar. SuperStar usually operates on the raw IsoStar data to calculate propensity distributions, e.g., for a binding site in a protein. For our purpose we modified the code to have it operate on our descriptors instead. This resulted in a substantial reduction in calculation time (factor of five to eight) compared to the original implementation. A validation procedure was performed on a set of 130 protein-ligand complexes, using four representative interacting probes to map the properties of the various binding sites: ammonium nitrogen, alcohol oxygen, carbonyl oxygen, and methyl carbon. The predicted `hot spots' for the binding of these probes were compared to the actual arrangement of ligand atoms in experimentally determined protein-ligand complexes. Results indicate that the version of SuperStar that applies to

Electrical and Plasmonic Properties of Ligand-Free Sn(4+) -Doped In2 O3 (ITO) Nanocrystals.

Science.gov (United States)

Jagadeeswararao, Metikoti; Pal, Somnath; Nag, Angshuman; Sarma, D D

2016-03-03

Sn(4+) -doped In2 O3 (ITO) is a benchmark transparent conducting oxide material. We prepared ligand-free but colloidal ITO (8 nm, 10 % Sn(4+) ) nanocrystals (NCs) by using a post-synthesis surface-modification reaction. (CH3 )3 OBF4 removes the native oleylamine ligand from NC surfaces to give ligand-free, positively charged NCs that form a colloidal dispersion in polar solvents. Both oleylamine-capped and ligand-free ITO NCs exhibit intense absorption peaks, due to localized surface plasmon resonance (LSPR) at around λ=1950 nm. Compared with oleylamine-capped NCs, the electrical resistivity of ligand-free ITO NCs is lower by an order of magnitude (≈35 mΩ cm(-1) ). Resistivity over a wide range of temperatures can be consistently described as a composite of metallic ITO grains embedded in an insulating matrix by using a simple equivalent circuit, which provides an insight into the conduction mechanism in these systems. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Why does the disorder of R-pn and rac-pn ligands in the quasi-one-dimensional bromo-bridged NiIII complexes, [Ni(pn)2Br]Br2 (pn=1,2-diaminopropane) afford similar STM patterns?

Science.gov (United States)

Wu, Hashen; Kawakami, Daisuke; Sasaki, Mari; Xie, Jimin; Takaishi, Shinya; Kajiwara, Takashi; Miyasaka, Hitoshi; Yamashita, Masahiro; Matsuzaki, Hiroyuki; Okamoto, Hiroshi

2007-09-03

The disordered patterns of R- and rac-1,2-diaminopropane (pn) in quasi-one-dimensional bromo-bridged Ni(III) complexes, [NiIII(pn)2Br]Br2, have been investigated by single-crystal X-ray structure determination and scanning tunneling microscopy (STM). X-ray structure determination shows that the methyl moieties are disordered on the right- and left-hand sides with half occupancies in both compounds, while the carbon atoms of the ethylene moieties of pn ligands are disordered in [Ni(rac-pn)2Br]Br2 and not disordered in [Ni(R-pn)2Br]Br2. In the STM images of both compounds, the bright spots are not straight but fluctuated with the similar patterns. We have concluded that tunnel current from the STM tip to metal ions are detected via methyl groups of pn ligands.

Structural diversification and photocatalytic properties of three Cd(II) coordination polymers decorated with different auxiliary ligands

Energy Technology Data Exchange (ETDEWEB)

Yin, Wen-Yu; Zhuang, Guo-Yong; Huang, Zuo-Long; Cheng, Hong-Jian; Zhou, Li; Ma, Man-Hong; Wang, Hao; Tang, Xiao-Yan, E-mail: xytang@cslg.edu.cn; Ma, Yun-Sheng; Yuan, Rong-Xin, E-mail: yuanrx@cslg.edu.cn

2016-03-15

Three cadmium coordination polymers, [Cd(bismip)]{sub n} (1), {[Cd(bismip)(phen)]·H_2O}{sub n} (2) and {[Cd_2(bismip)_2(4,4′-bipy)]·2H_2O}{sub n} (3) (H{sub 2}bismip=5-(1H-benzoimidazol-2-ylsulfanylmethyl)-isophthalic acid, phen=1,10-phenanthroline, 4,4′-bipy=4,4′-bipyridine) have been prepared under solvothermal conditions. In 1, the [Cd{sub 4}(bismip){sub 3}] units are jointed by bismip ligands to afford a three-dimensional (3D) architecture. Complex 2 exhibits a 3D supramolecular framework based on the interconnection of 1D chains through hydrogen bonding interactions and π-π packing interactions. 3 is a two-fold interpenetrating 3D architecture with a (4·8{sup 2})(4{sup 2}·8{sup 4}) Schläfli symbol in which 2D layers are interlinked by 4,4′-bipy ligands. The diverse structures of compounds 1–3 indicate that the auxiliary ligands have significant effects on the final structures. The photoluminescent properties and photocatalytic properties of these coordination polymers in the solid state were also investigated. Remarkably, 3 shows the wide gap semiconductor nature and exhibit excellent photocatalytic performance. - Graphical abstract: Three cadmium coordination polymers with different architectures based on 5-(1H-benzoimidazol-2-ylsulfanylmethyl)-isophthalic acid have been prepared. Their photoluminescent properties were also investigated. - Highlights: • Three new Cd(II) Cps were synthesized based on H{sub 2}bismip. • Compounds 1 and 3 show 3D networks and 2 exhibits a 1D chain. • Compoud 3 exhibits good catalytic activity of methylene blue photodegradation.

LigandRFs: random forest ensemble to identify ligand-binding residues from sequence information alone

KAUST Repository

Chen, Peng; Huang, Jianhua Z; Gao, Xin

2014-01-01

Protein-ligand binding is important for some proteins to perform their functions. Protein-ligand binding sites are the residues of proteins that physically bind to ligands. Despite of the recent advances in computational prediction

Lanthanide and actinide complexation studies with tetradentate 'N' donor ligands

International Nuclear Information System (INIS)

Bhattacharyya, A.; Mohapatra, M.; Mohapatra, P.K.; Rawat, N.; Tomar, B.S.; Gadly, T.; Ghosh, S.K.; Manna, D.; Ghanty, T.K.

2014-01-01

Because of their similar charge and chemical behaviour separation of trivalent actinides and lanthanides is an important and challenging task in nuclear fuel cycle. Soft (S,N) donor ligands show selectivity towards the trivalent actinides over the lanthanides. Out of various 'N' donor ligands studied, bis(1,2,4)triazinyl bipyridine (BTBP) and bis(1,2,4)triazinyl phenanthroline (BTPhen) were found to be most promising. In order to understand the separation behaviour of these ligands, their complexation studies with these 'f' block elements are essential. In the present work, complexation studies of various lanthanide ions (La 3+ , Eu 3+ and Er 3+ ) was studied with ethyl derivatives of BTBP (C 2 BTBP) and BTBPhen (C 2 BTPhen) and pentyl derivative of BTBP (C 5 BTBP) in acetonitrile medium using UV-Vis spectrophotometry, fluorescence spectroscopy and solution calorimetry. Computational studies were also carried out to understand the experimental results

Architecture effects on multivalent interactions by polypeptide-based multivalent ligands

Science.gov (United States)

Liu, Shuang

Multivalent interactions are characterized by the simultaneous binding between multiple ligands and multiple binding sites, either in solutions or at interfaces. In biological systems, most multivalent interactions occur between protein receptors and carbohydrate ligands through hydrogen-bonding and hydrophobic interactions. Compared with weak affinity binding between one ligand and one binding site, i.e. monovalent interaction, multivalent interactioins provide greater avidity and specificity, and therefore play unique roles in a broad range of biological activities. Moreover, the studies of multivalent interactions are also essential for producing effective inhibitors and effectors of biological processes that could have important therapeutic applications. Synthetic multivalent ligands have been designed to mimic the biological functions of natural multivalent interactions, and various types of scaffolds have been used to display multiple ligands, including small molecules, linear polymers, dendrimers, nanoparticle surfaces, monolayer surfaces and liposomes. Studies have shown that multivalent interactions can be highly affected by various architectural parameters of these multivalent ligands, including ligand identities, valencies, spacing, ligand densities, nature of linker arms, scaffold length and scaffold conformation. Most of these multivalent ligands are chemically synthesized and have limitations of controlling over sequence and conformation, which is a barrier for mimicking ordered and controlled natural biological systems. Therefore, multivalent ligands with precisely controlled architecture are required for improved structure-function relationship studies. Protein engineering methods with subsequent chemical coupling of ligands provide significant advantages of controlling over backbone conformation and functional group placement, and therefore have been used to synthesize recombinant protein-based materials with desired properties similar to natural

Crystal structure of a mixed-ligand terbium(III coordination polymer containing oxalate and formate ligands, having a three-dimensional fcu topology

Directory of Open Access Journals (Sweden)

Chainok Kittipong

2016-01-01

Full Text Available The title compound, poly[(μ3-formato(μ4-oxalatoterbium(III], [Tb(CHO2(C2O4]n, is a three-dimensional coordination polymer, and is isotypic with the LaIII, CeIII and SmIII analogues. The asymmetric unit contains one TbIII ion, one formate anion (CHO2− and half of an oxalate anion (C2O42−, the latter being completed by application of inversion symmetry. The TbIII ion is nine-coordinated in a distorted tricapped trigonal–prismatic manner by two chelating carboxylate groups from two C2O42− ligands, two carboxylate oxygen atoms from another two C2O42− ligands and three oxygen atoms from three CHO2− ligands, with the Tb—O bond lengths and the O—Tb—O bond angles ranging from 2.4165 (19 to 2.478 (3 Å and 64.53 (6 to 144.49 (4°, respectively. The CHO2− and C2O42− anions adopt μ3-bridging and μ4-chelating-bridging coordination modes, respectively, linking adjacent TbIII ions into a three-dimensional 12-connected fcu topology with point symbol (324.436.56. The title compound exhibits thermal stability up to 623 K, and also displays strong green photoluminescence in the solid state at room temperature.

Solution NMR characterization of magnetic/electronic properties of azide and cyanide-inhibited substrate complexes of human heme oxygenase: implications for steric ligand tilt.

Science.gov (United States)

Peng, Dungeng; Ogura, Hiroshi; Ma, Li-Hua; Evans, John P; de Montellano, Paul R Ortiz; La Mar, Gerd N

2013-04-01

Solution 2D (1)H NMR was carried out on the azide-ligated substrate complex of human heme oxygenase, hHO, to provide information on the active site molecular structure, chromophore electronic/magnetic properties, and the distal H-bond network linked to the exogenous ligand by catalytically relevant oriented water molecules. While 2D NMR exhibited very similar patterns of two-dimensional nuclear Overhauser spectroscopy cross peaks of residues with substrate and among residues as the previously characterized cyanide complex, significant, broadly distributed chemical shift differences were observed for both labile and non-labile protons. The anisotropy and orientation of the paramagnetic susceptibility tensor, χ, were determined for both the azide and cyanide complexes. The most significant difference observed is the tilt of the major magnetic axes from the heme normal, which is only half as large for the azide than cyanide ligand, with each ligand tilted toward the catalytically cleaved α-meso position. The difference in chemical shifts is quantitatively correlated with differences in dipolar shifts in the respective complexes for all but the distal helix. The necessity of considering dipolar shifts, and hence determination of the orientation/anisotropy of χ, in comparing chemical shifts involving paramagnetic complexes, is emphasized. The analysis shows that the H-bond network cannot detect significant differences in H-bond acceptor properties of cyanide versus azide ligands. Lastly, significant retardation of distal helix labile proton exchange upon replacing cyanide with azide indicates that the dynamic stability of the distal helix is increased upon decreasing the steric interaction of the ligand with the distal helix. Copyright © 2013. Published by Elsevier Inc.

1,2-Ferrocenediylazaphosphinines 3: a new class of planar chiral ligands for Cu-catalyzed cyclopropanation

Energy Technology Data Exchange (ETDEWEB)

Paek, Seung Hwan; Co, Thanh Thien; Lee, Dong Ho; Park, Yu Chul; Kim, Tae Jeong [Kyungpook National Univ., Daegu (Korea, Republic of)

2002-12-01

The synthesis and catalytic application of a new class of planar chiral ferrocenes, 1,2-ferrocenediylazaphos-phinines (1 and 2) are described. They are powerful ligands for the copper(I)-catalyzed asymmetric cyclopropanation of a range of alkenes with diazo esters to exhibit an exceptionally high degree of diastereoselectivity ({approx}100%) in favor of trans isomers, regardless the structure of the olefins and the diazo compounds. Comparative studies between 1 and 2 reveal that the former works better in terms of diastereocontrol. In contrast, however, enantioselectivity is low with both 1 and 2 as a whole although, in certain cases with a proper combination of the olefin and the diazo ester, high optical yields (up to 100% ee) can be achieved. Other reaction parameters such as the reaction temperature and the structure of the ligand do exhibit some influence, although infinitesimal, on both chemical and optical yields.

1,2-Ferrocenediylazaphosphinines 3: a new class of planar chiral ligands for Cu-catalyzed cyclopropanation

International Nuclear Information System (INIS)

Paek, Seung Hwan; Co, Thanh Thien; Lee, Dong Ho; Park, Yu Chul; Kim, Tae Jeong

2002-01-01

The synthesis and catalytic application of a new class of planar chiral ferrocenes, 1,2-ferrocenediylazaphos-phinines (1 and 2) are described. They are powerful ligands for the copper(I)-catalyzed asymmetric cyclopropanation of a range of alkenes with diazo esters to exhibit an exceptionally high degree of diastereoselectivity (∼100%) in favor of trans isomers, regardless the structure of the olefins and the diazo compounds. Comparative studies between 1 and 2 reveal that the former works better in terms of diastereocontrol. In contrast, however, enantioselectivity is low with both 1 and 2 as a whole although, in certain cases with a proper combination of the olefin and the diazo ester, high optical yields (up to 100% ee) can be achieved. Other reaction parameters such as the reaction temperature and the structure of the ligand do exhibit some influence, although infinitesimal, on both chemical and optical yields

Virtual screening using the ligand ZINC database for novel lipoxygenase-3 inhibitors.

Science.gov (United States)

Monika; Kour, Janmeet; Singh, Kulwinder

2013-01-01

The leukotrienes constitute a group of arachidonic acid-derived compounds with biologic activities suggesting important roles in inflammation and immediate hypersensitivity. Epidermis-type lipoxygenase-3 (ALOXE3), a distinct subclass within the multigene family of mammalian lipoxygenases, is a novel isoenzyme involved in the metabolism of leukotrienes and plays a very important role in skin barrier functions. Lipoxygenase selective inhibitors such as azelastine and zileuton are currently used to reduce inflammatory response. Nausea, pharyngolaryngeal pain, headache, nasal burning and somnolence are the most frequently reported adverse effects of these drugs. Therefore, there is still a need to develop more potent lipoxygenase inhibitors. In this paper, we report the screening of various compounds from the ZINC database (contains over 21 million compounds) using the Molegro Virtual Docker software against the ALOXE3 protein. Screening was performed using molecular constraints tool to filter compounds with physico-chemical properties similar to the 1N8Q bound ligand protocatechuic acid. The analysis resulted in 4319 Lipinski compliant hits which are docked and scored to identify structurally novel ligands that make similar interactions to those of known ligands or may have different interactions with other parts of the binding site. Our screening approach identified four molecules ZINC84299674; ZINC76643455; ZINC84299122 & ZINC75626957 with MolDock score of -128.901, -120.22, -116.873 & - 102.116 kcal/mol, respectively. Their energy scores were better than the 1N8Q bound co-crystallized ligand protocatechuic acid (with MolDock score of -77.225 kcal/mol). All the ligands were docked within the binding pocket forming interactions with amino acid residues.

Study on the optical properties of CdSe QDs with different ligands in specific matrix

International Nuclear Information System (INIS)

Lin Wei; Zou Wei; Du Zhongjie; Li Hangquan; Zhang Chen

2013-01-01

Different ligand structures of CdSe quantum dots were designed and synthesized for the specific matrix and the effect of the ligands on the photoluminescence and optical properties were further investigated. Ligand exchange reaction was used to synthesize thioglycolic acid-capped CdSe QDs and the process was characterized by FT-IR and titration. The influence of environmental pH value and storing time on the properties of thioglycolic acid-capped CdSe QDs in aqueous solution were studied by absorption and photoluminescence spectra. It was found that alkaline environment was more beneficial for the application of CdSe QDs. Therefore, the amino ligands with different molecular weight were grafted onto CdSe QDs for improving the compatibility with epoxy matrix and then amino-capped CdSe QDs/epoxy nanocomposites were fabricated. The morphologies and properties of the nanocomposites were characterized by DLS, HR-TEM, UV–Vis spectra, and photoluminescence spectra. As a result, amino ligands with short-molecular chain-capped CdSe QDs/epoxy nanocomposites exhibited good dispersion, high transparency and photoluminescence, and would be suitable for potential application in light-emitting diode device.

Synthesis, crystal structures, and luminescent properties of Cd(II) coordination polymers assembled from semi-rigid multi-dentate N-containing ligand

Energy Technology Data Exchange (ETDEWEB)

Yuan, Gang; Shao, Kui-Zhan; Chen, Lei; Liu, Xin-Xin [Institute of Functional Material Chemistry, Faculty of Chemistry, Northeast Normal University, Changchun 130024, Jilin (China); Su, Zhong-Min, E-mail: zmsu@nenu.edu.cn [Institute of Functional Material Chemistry, Faculty of Chemistry, Northeast Normal University, Changchun 130024, Jilin (China); Ma, Jian-Fang [Institute of Functional Material Chemistry, Faculty of Chemistry, Northeast Normal University, Changchun 130024, Jilin (China)

2012-12-15

Three new polymers, [Cd(L){sub 2}(H{sub 2}O){sub 2}]{sub n} (1), [Cd{sub 3}(L){sub 2}({mu}{sub 3}-OH){sub 2}({mu}{sub 2}-Cl){sub 2}(H{sub 2}O){sub 2}]{sub n} (2), {l_brace}[Cd{sub 2}(L){sub 2}(nic){sub 2}(H{sub 2}O){sub 2}]{center_dot}H{sub 2}O{r_brace}{sub n} (3) (HL=5-(4-((1H-1,2,4-triazol-1-yl)methyl)phenyl)-1H-tetrazole, Hnic=nicotinic acid) have been prepared and structurally characterized. Compounds 1 and 2 display 2D monomolecular layers built by the inter-linking single helical chains and L{sup -} ligands connecting chain-like [Cd({mu}{sub 3}-OH)({mu}{sub 2}-Cl)]{sub n} secondary building units, respectively. Compound 3 is constructed from the mixed ligands and possesses a (3,4)-connected framework with (4{center_dot}8{sup 2})(4{center_dot}8{sup 2}{center_dot}10{sup 3}) topology. Moreover, the fluorescent properties of HL ligand and compounds 1-3 are also been investigated. - Graphical abstract: Three new coordination polymers based on the semi-rigid multidentate N-donor ligand have been successfully synthesized by hydrothermal reaction. Complexes 1 and 2 exhibit the 2D layers formed by inter-linking single helices and L{sup -} anions bridging 1D chain-like SBUs, respectively. Complex 3 is buit by L{sup -} and assistant nic{sup -} ligands connecting metal centers and possesses a (3,4)-connected framework with (4 Multiplication-Sign 8{sup 2})(4 Multiplication-Sign 8{sup 2} Multiplication-Sign 10{sup 3}) topology. Moreover, these complexes display fluorescent properties indicating that they may have potential applications as optical materials. Highlights: Black-Right-Pointing-Pointer Three Cd-compounds were prepared from semi-rigid HL ligand with different N-containing groups. Black-Right-Pointing-Pointer They exhibit diverse structures from 2D monomolecular layer to 3D covalent framework. Black-Right-Pointing-Pointer The HL ligands displayed various coordination modes under different reaction conditions. Black-Right-Pointing-Pointer These compounds exhibit

Integration of a semi-rigid proline ligand and 4,4'-bipyridine in the synthesis of homochiral metal-organic frameworks with helices.

Science.gov (United States)

Xu, Zhong-Xuan; Kang, Yao; Han, Min-Le; Li, Dong-Sheng; Zhang, Jian

2015-06-28

A pair of 3-D homochiral metal-organic frameworks (HMOFs) based on a mixed semi-rigid 5-(2-carboxypyrrolidine-1-carbonyl)isophthalate (PIA) ligand and rigid 4,4'-bipyridine (bipy), [Co3((R)-PIA)2(bipy)3]·6H2O (1-D) and [Co3((S)-PIA)2(bipy)3]·6H2O (1-L) are synthesized and structurally characterized. They are enantiomers and exhibit three-dimensional open frameworks. In each structure, the PIA ligands link the Co centers into homochiral frameworks with large open channels that are occupied by the bipy ligands. Interesting helical chains built from the connectivity between PIA ligands and Co centers are presented. Antiferromagnetic coupling is observed in 1-D. These results demonstrated that the mixed ligand approach is successful for the construction of HMOFs.

A new class of PN3-pincer ligands for metal–ligand cooperative catalysis

KAUST Repository

Li, Huaifeng

2014-12-01

Work on a new class of PN3-pincer ligands for metal-ligand cooperative catalysis is reviewed. While the field of the pyridine-based PN3-transition metal pincer complexes is still relatively young, many important applications of these complexes have already emerged. In several cases, the PN3-pincer complexes for metal-ligand cooperative catalysis result in significantly improved or unprecedented activities. The synthesis and coordination chemistry of PN3-pincer ligands are briefly summarized first to cover the synthetic routes for their preparation, followed by a focus review on their applications in catalysis. A specific emphasis is placed on the later section about the role of PN3-pincer ligands\\' dearomatization-rearomatization steps during the catalytic cycles. The mechanistic insights from density functional theory (DFT) calculations are also discussed.

A new class of PN3-pincer ligands for metal–ligand cooperative catalysis

KAUST Repository

Li, Huaifeng; Zheng, Bin; Huang, Kuo-Wei

2014-01-01

Work on a new class of PN3-pincer ligands for metal-ligand cooperative catalysis is reviewed. While the field of the pyridine-based PN3-transition metal pincer complexes is still relatively young, many important applications of these complexes have already emerged. In several cases, the PN3-pincer complexes for metal-ligand cooperative catalysis result in significantly improved or unprecedented activities. The synthesis and coordination chemistry of PN3-pincer ligands are briefly summarized first to cover the synthetic routes for their preparation, followed by a focus review on their applications in catalysis. A specific emphasis is placed on the later section about the role of PN3-pincer ligands' dearomatization-rearomatization steps during the catalytic cycles. The mechanistic insights from density functional theory (DFT) calculations are also discussed.

Crystal structures and luminescence of two cadmium-carboxylate cluster-based compounds with mixed ligands

Energy Technology Data Exchange (ETDEWEB)

Ma, Hui-Fang; Lei, Qian; Wang, Yu-Ling; Yin, Shun-Gao; Liu, Qing-Yan [College of Chemistry and Chemical Engineering and Key Lab. of Functional Small Organic Molecule of Ministry of Education, Jiangxi Normal Univ., Nanchang (China)

2017-04-04

Reactions of Cd(NO{sub 3}){sub 2}.4H{sub 2}O with 2-quinolinecarboxylic acid (H-QLC) in the presence of 1,4-benzenedicarboxylic acid (H{sub 2}-BDC) or 1,3,5-benzenetricarboxylic acid (H-BTC) in DMF/H{sub 2}O solvent afforded two compounds, namely, [Cd(QLC)(BDC){sub 1/2}(H{sub 2}O)]{sub n} (1) and [Cd(QLC)(BTC){sub 1/3}]{sub n} (2). Both compounds are two-dimensional (2D) frameworks but feature different cadmium-carboxylate clusters as a result of the presence of the polycarboxylate ligands with different geometries and coordination preference. The dinuclear Cd{sub 2}(QLC){sub 2} units in 1 are bridged by the pairs of bridging water ligands to give a one-dimensional (1D) chain, which is further linked by the second ligand of BDC{sup 2-} to form a 2D structure. Compound 2 is constructed from unique hexanuclear macrometallacyclic Cd{sub 6}(QLC){sub 6} clusters, which are linked by the surrounding BTC{sup 3-} ligands to generate a 2D structure. Photoluminescence studies showed both compounds exhibit ligand-centered luminescent emissions with emission maxima at 405 and 401 nm, respectively. (copyright 2017 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim)

GalaxyDock BP2 score: a hybrid scoring function for accurate protein-ligand docking

Science.gov (United States)

Baek, Minkyung; Shin, Woong-Hee; Chung, Hwan Won; Seok, Chaok

2017-07-01

Protein-ligand docking is a useful tool for providing atomic-level understanding of protein functions in nature and design principles for artificial ligands or proteins with desired properties. The ability to identify the true binding pose of a ligand to a target protein among numerous possible candidate poses is an essential requirement for successful protein-ligand docking. Many previously developed docking scoring functions were trained to reproduce experimental binding affinities and were also used for scoring binding poses. However, in this study, we developed a new docking scoring function, called GalaxyDock BP2 Score, by directly training the scoring power of binding poses. This function is a hybrid of physics-based, empirical, and knowledge-based score terms that are balanced to strengthen the advantages of each component. The performance of the new scoring function exhibits significant improvement over existing scoring functions in decoy pose discrimination tests. In addition, when the score is used with the GalaxyDock2 protein-ligand docking program, it outperformed other state-of-the-art docking programs in docking tests on the Astex diverse set, the Cross2009 benchmark set, and the Astex non-native set. GalaxyDock BP2 Score and GalaxyDock2 with this score are freely available at http://galaxy.seoklab.org/softwares/galaxydock.html.

PL-PatchSurfer: A Novel Molecular Local Surface-Based Method for Exploring Protein-Ligand Interactions

Directory of Open Access Journals (Sweden)

Bingjie Hu

2014-08-01

Full Text Available Structure-based computational methods have been widely used in exploring protein-ligand interactions, including predicting the binding ligands of a given protein based on their structural complementarity. Compared to other protein and ligand representations, the advantages of a surface representation include reduced sensitivity to subtle changes in the pocket and ligand conformation and fast search speed. Here we developed a novel method named PL-PatchSurfer (Protein-Ligand PatchSurfer. PL-PatchSurfer represents the protein binding pocket and the ligand molecular surface as a combination of segmented surface patches. Each patch is characterized by its geometrical shape and the electrostatic potential, which are represented using the 3D Zernike descriptor (3DZD. We first tested PL-PatchSurfer on binding ligand prediction and found it outperformed the pocket-similarity based ligand prediction program. We then optimized the search algorithm of PL-PatchSurfer using the PDBbind dataset. Finally, we explored the utility of applying PL-PatchSurfer to a larger and more diverse dataset and showed that PL-PatchSurfer was able to provide a high early enrichment for most of the targets. To the best of our knowledge, PL-PatchSurfer is the first surface patch-based method that treats ligand complementarity at protein binding sites. We believe that using a surface patch approach to better understand protein-ligand interactions has the potential to significantly enhance the design of new ligands for a wide array of drug-targets.

PL-PatchSurfer: a novel molecular local surface-based method for exploring protein-ligand interactions.

Science.gov (United States)

Hu, Bingjie; Zhu, Xiaolei; Monroe, Lyman; Bures, Mark G; Kihara, Daisuke

2014-08-27

Structure-based computational methods have been widely used in exploring protein-ligand interactions, including predicting the binding ligands of a given protein based on their structural complementarity. Compared to other protein and ligand representations, the advantages of a surface representation include reduced sensitivity to subtle changes in the pocket and ligand conformation and fast search speed. Here we developed a novel method named PL-PatchSurfer (Protein-Ligand PatchSurfer). PL-PatchSurfer represents the protein binding pocket and the ligand molecular surface as a combination of segmented surface patches. Each patch is characterized by its geometrical shape and the electrostatic potential, which are represented using the 3D Zernike descriptor (3DZD). We first tested PL-PatchSurfer on binding ligand prediction and found it outperformed the pocket-similarity based ligand prediction program. We then optimized the search algorithm of PL-PatchSurfer using the PDBbind dataset. Finally, we explored the utility of applying PL-PatchSurfer to a larger and more diverse dataset and showed that PL-PatchSurfer was able to provide a high early enrichment for most of the targets. To the best of our knowledge, PL-PatchSurfer is the first surface patch-based method that treats ligand complementarity at protein binding sites. We believe that using a surface patch approach to better understand protein-ligand interactions has the potential to significantly enhance the design of new ligands for a wide array of drug-targets.

Ligand fishing from Dioscorea nipponica extract using human serum albumin functionalized magnetic nanoparticles.

Science.gov (United States)

Qinga, Lin-Sen; Xue, Ying; Zheng, Yi; Xiong, Jing; Liao, Xun; Ding, Li-Sheng; Li, Bo-Gang; Liu, Yi-Ming

2010-07-09

Dioscorea nipponica and the preparations made from it have been used for long to prevent and treat coronary heart disease in traditional Chinese medicine. A group of steroidal saponins present in the plant are believed to be the active ingredients. It has been a challenge to study the individual saponins separately due to the similarities in their chemical and physical properties. In this work, human serum albumin (HSA) functionalized magnetic nanoparticles (MNPs) were used to isolate and identify saponin ligands that bind to HSA from D. nipponica extract. Electrospray ionization mass spectrometry (ESI-MS) was used for compound identification and semi-quantification. Three saponins, i.e. dioscin, gracillin, and pseudo-protodioscin showed affinity to HSA-MNPs and thus isolated effectively from the extract. The other two saponins detected in the extract (i.e. protodioscin and 26-O-β-D-glucopyranosyl-3β,20α,26-triol-25(R)-Δ(5,22)-dienofurostan-3-O-α-L-rhamnopyranosyl (1→2)-[α-L-rhamnopyranosyl (1→4)]-β-D-glucopyranoside) exhibited no affinity at all. Among the three saponins fished out, dioscin bound to HSA much stronger than gracillin and pseudo-protodioscin did. The results indicated that affinity interaction between HSA immobilized on MNPs and small molecule compounds were highly dependent on chemical structures and, potentially, medicinal usefulness. The present work demonstrates a facile and effective way to isolate and identify ligands of receptors from medicinal plants.

Effect of capping ligands on the optical properties and electronic energies of iron pyrite FeS2 nanocrystals and solid thin films

International Nuclear Information System (INIS)

Zhai, Guangmei; Xie, Rongwei; Wang, Heng; Zhang, Jitao; Yang, Yongzhen; Wang, Hua; Li, Xuemin; Liu, Xuguang; Xu, Bingshe

2016-01-01

In this work, the optical and electronic properties of iron pyrite FeS 2 nanocrystals and solid thin films with various capping ligands were systematically investigated by UV–Vis–NIR absorption spectroscopy, cyclic voltammetry and current density–voltage characteristic measurements. The iron pyrite nanocrystals with various ligands have an indirect band gap of around 1.05 eV and broad absorption spanning into the near-infrared region, exhibiting favorable optical properties for their photovoltaic applications. The electron affinities and ionization potentials of FeS 2 nanocrystals determined through cyclic voltammetry measurements show strong ligand dependence. An energy level shift of up to 190 meV was obtained among the pyrite nanocrystals capped with the ligands employed in this work. The iron pyrite nanocrystal films capped with iodide and 1,2-ethanedithiol exhibit the largest band edge energy shift and conductivity, respectively. Our results not only provide several useful optical and electronic parameters of pyrite nanocrystals for their further use in optoelectronic devices as active layers and/or infrared optical absorption materials, but also highlight the relationship between their surface chemistry and electronic energies. - Highlights: • The energy levels of FeS 2 nanocrystals with various ligands were determined via electrochemical measurements. • The energy levels of FeS 2 nanocrystals showed strong ligand-dependence. • An energy level shift of up to 190 meV was obtained for the pyrite nanocrystals studied in the work. • The conductivities of FeS 2 nanocrystals with different ligands were obtained by current density–voltage measurements.

Combination of 2D/3D ligand-based similarity search in rapid virtual screening from multimillion compound repositories. Selection and biological evaluation of potential PDE4 and PDE5 inhibitors.

Science.gov (United States)

Dobi, Krisztina; Hajdú, István; Flachner, Beáta; Fabó, Gabriella; Szaszkó, Mária; Bognár, Melinda; Magyar, Csaba; Simon, István; Szisz, Dániel; Lőrincz, Zsolt; Cseh, Sándor; Dormán, György

2014-05-28

Rapid in silico selection of target focused libraries from commercial repositories is an attractive and cost effective approach. If structures of active compounds are available rapid 2D similarity search can be performed on multimillion compound databases but the generated library requires further focusing by various 2D/3D chemoinformatics tools. We report here a combination of the 2D approach with a ligand-based 3D method (Screen3D) which applies flexible matching to align reference and target compounds in a dynamic manner and thus to assess their structural and conformational similarity. In the first case study we compared the 2D and 3D similarity scores on an existing dataset derived from the biological evaluation of a PDE5 focused library. Based on the obtained similarity metrices a fusion score was proposed. The fusion score was applied to refine the 2D similarity search in a second case study where we aimed at selecting and evaluating a PDE4B focused library. The application of this fused 2D/3D similarity measure led to an increase of the hit rate from 8.5% (1st round, 47% inhibition at 10 µM) to 28.5% (2nd round at 50% inhibition at 10 µM) and the best two hits had 53 nM inhibitory activities.

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

Science.gov (United States)

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.

Novel chalcone-based fluorescent human histamine H3 receptor ligands as pharmacological tools

Directory of Open Access Journals (Sweden)

Holger eStark

2012-03-01

Full Text Available Novel fluorescent chalcone-based ligands at human histamine H3 receptors (hH3R have been designed, synthesized and characterized. Compounds described are non-imidazole analogues of ciproxifan with a tetralone motif. Tetralones as chemical precursors and related fluorescent chalcones exhibit affinities at hH3R in the same concentration range like that of the reference antagonist ciproxifan (hH3R pKi value of 7.2. Fluorescence characterization of our novel ligands shows emission maxima about 570 nm for yellow fluorescent chalcones and ≥600 nm for the red fluorescent derivatives. Interferences to cellular autofluorescence could be excluded. All synthesized chalcone compounds could be taken to visualize hH3R proteins in stably transfected HEK-293 cells using confocal laser scanning fluorescence microscopy. These novel fluorescent ligands possess high potential to be used as pharmacological tools for hH3R visualization in different tissues.

Reduction of dinitrogen ligands

International Nuclear Information System (INIS)

Richards, R.L.

1983-01-01

Processes of dinitrogen ligand reduction in complexes of transition metals are considered. The basic character of the dinitrogen ligand is underlined. Data on X-ray photoelectronic spectroscopy and intensities of bands ν (N 2 ) in IR-spectra of nitrogen complexes are given. The mechanism of protonation of an edge dinitrogen ligand is discussed. Model systems and mechanism of nitrogenogenase are compared

Constructing two new crystalline metal–organic frameworks based on a mixed-donor ligand

KAUST Repository

Wang, Xiaofang; Xue, Ming; Wu, Gang; Pan, Ying; Qiu, Shilun

2016-01-01

© 2015 Elsevier B.V. All Rights Reserved. The self-assembly of a prominent ligand, 5-(4-(1H-tetrazolyl)phen)isophthalic acid (H3TZPI), with Zn2 +/Cu2 + centres generates two new MOFs, [Zn2(TZPI)(μ3-OH)(H2O)2]·2H2O (JUC-161) and [Cu(HTZPI)(μ2-H2O)0.5(H2O)1.5]·5(H2O) (JUC-162). JUC-161 exhibits fascinating three-dimensional structures containing rectangular channels with dimensions of 6.5 × 3.0 Å2, and JUC-162 displays 3D supramolecular structures with 12.5 × 14.6 Å2 hexagonal channels. The observed structural diversity in these frameworks is due to the two distinct coordinating moieties of the H3TZPI ligand. The photoluminescence of JUC-161 and the magnetic properties of JUC-162 are also measured at room temperature. Photoluminescence investigations reveal that JUC-161 displays a strong main emission spectrum peak at 388 nm. JUC-162 is found to exhibit an antiferromagnetic interaction between Cu2 + ions.

Constructing two new crystalline metal–organic frameworks based on a mixed-donor ligand

KAUST Repository

Wang, Xiaofang

2016-02-01

© 2015 Elsevier B.V. All Rights Reserved. The self-assembly of a prominent ligand, 5-(4-(1H-tetrazolyl)phen)isophthalic acid (H3TZPI), with Zn2 +/Cu2 + centres generates two new MOFs, [Zn2(TZPI)(μ3-OH)(H2O)2]·2H2O (JUC-161) and [Cu(HTZPI)(μ2-H2O)0.5(H2O)1.5]·5(H2O) (JUC-162). JUC-161 exhibits fascinating three-dimensional structures containing rectangular channels with dimensions of 6.5 × 3.0 Å2, and JUC-162 displays 3D supramolecular structures with 12.5 × 14.6 Å2 hexagonal channels. The observed structural diversity in these frameworks is due to the two distinct coordinating moieties of the H3TZPI ligand. The photoluminescence of JUC-161 and the magnetic properties of JUC-162 are also measured at room temperature. Photoluminescence investigations reveal that JUC-161 displays a strong main emission spectrum peak at 388 nm. JUC-162 is found to exhibit an antiferromagnetic interaction between Cu2 + ions.

Unusual metal coordination chemistry from an amino-amide derivative of 4-nitrophenol, a surprising ligand

DEFF Research Database (Denmark)

McGinley, John; McKee, Vickie; Toftlund, Hans

2009-01-01

The simple ligand N-(2-aminoethyl)-2-hydroxy-5-nitrobenzamide () exhibits several coordination modes depending on the reaction conditions, acting as a zwitterion on its own or being ionic in the presence of acid and depending on the concentration of metal present in a reaction, it can coordinate...... to the metal in either a 1:1 or a 1:2 metal:ligand mode. Furthermore, the role of solvent plays an important role in these complexation reactions with both four and six coordinate copper complexes being obtained using water as solvent but only six coordinate copper complexes obtained using acetonitrile...

Construction of three metal-organic frameworks based on multifunctional T-shaped tripodal ligands, H3PyImDC

KAUST Repository

Jing, Xuemin

2010-08-04

Three novel metal-organic frameworks (MOFs), |(C3H 7NO)2(H2O)|[Zn3(C10H 5N3O4)3(C3H 7NO)2] (1), |(H2O)5(H 3O)(NO3)|[Nd2(C10H5N 3O4)3(H2O)4] (2), and |(H2O)2|[Nd3(C10H5N 3O4)3(C10H4N 3O4)] (3), based on the T-shaped tripodal ligands 2-(pyridine-4-yl)-1H-4,5-imidazoledicarboxylic acid and 2-(pyridine-3-yl)-1H-4, 5-imidazoledicarboxylic acid (H3PyImDC), have been constructed under solvo-/hydrothermal conditions. The diverse coordination modes of H 3PyImDC ligands have afforded the assembly of three novel compounds. In compound 1, two oxygen atoms and three nitrogen atoms of the H 3PyImDC ligand, a T-shaped linker, coordinate to two zinc centers to form a novel bbm net with two distinct channels along the [100] and [001] directions. In compound 2, H3PyImDC ligands coordinate to neodymium centers to form a ladder-like chain which then interacts with a water molecules chain via hydrogen-bondings to construct a 3D supermolecular structure. In compound 3, H3PyImDC ligands, a T-shaped linker, coordinate to neodymium centers to form a (3,6)-connected net with an ant topology. In compounds 1-3, the two H3PyImDC ligands exhibit different coordination modes with zinc and neodymium centers, which afforded the expected structural diversity. Additionally, all three compounds exhibit strong fluorescence emissions in the solid state at room temperature. © 2010 American Chemical Society.

Evaluation of several two-step scoring functions based on linear interaction energy, effective ligand size, and empirical pair potentials for prediction of protein-ligand binding geometry and free energy.

Science.gov (United States)

Rahaman, Obaidur; Estrada, Trilce P; Doren, Douglas J; Taufer, Michela; Brooks, Charles L; Armen, Roger S

2011-09-26

The performances of several two-step scoring approaches for molecular docking were assessed for their ability to predict binding geometries and free energies. Two new scoring functions designed for "step 2 discrimination" were proposed and compared to our CHARMM implementation of the linear interaction energy (LIE) approach using the Generalized-Born with Molecular Volume (GBMV) implicit solvation model. A scoring function S1 was proposed by considering only "interacting" ligand atoms as the "effective size" of the ligand and extended to an empirical regression-based pair potential S2. The S1 and S2 scoring schemes were trained and 5-fold cross-validated on a diverse set of 259 protein-ligand complexes from the Ligand Protein Database (LPDB). The regression-based parameters for S1 and S2 also demonstrated reasonable transferability in the CSARdock 2010 benchmark using a new data set (NRC HiQ) of diverse protein-ligand complexes. The ability of the scoring functions to accurately predict ligand geometry was evaluated by calculating the discriminative power (DP) of the scoring functions to identify native poses. The parameters for the LIE scoring function with the optimal discriminative power (DP) for geometry (step 1 discrimination) were found to be very similar to the best-fit parameters for binding free energy over a large number of protein-ligand complexes (step 2 discrimination). Reasonable performance of the scoring functions in enrichment of active compounds in four different protein target classes established that the parameters for S1 and S2 provided reasonable accuracy and transferability. Additional analysis was performed to definitively separate scoring function performance from molecular weight effects. This analysis included the prediction of ligand binding efficiencies for a subset of the CSARdock NRC HiQ data set where the number of ligand heavy atoms ranged from 17 to 35. This range of ligand heavy atoms is where improved accuracy of predicted ligand

Analysis of the HIV-2 protease's adaptation to various ligands: characterization of backbone asymmetry using a structural alphabet.

Science.gov (United States)

Triki, Dhoha; Cano Contreras, Mario Enrique; Flatters, Delphine; Visseaux, Benoit; Descamps, Diane; Camproux, Anne-Claude; Regad, Leslie

2018-01-15

The HIV-2 protease (PR2) is a homodimer of 99 residues with asymmetric assembly and binding various ligands. We propose an exhaustive study of the local structural asymmetry between the two monomers of all available PR2 structures complexed with various inhibitors using a structural alphabet approach. On average, PR2 exhibits asymmetry in 31% of its positions-i.e., exhibiting different backbone local conformations in the two monomers. This asymmetry was observed all along its structure, particularly in the elbow and flap regions. We first differentiated structural asymmetry conserved in most PR2 structures from the one specific to some PR2. Then, we explored the origin of the detected asymmetry in PR2. We localized asymmetry that could be induced by PR2's flexibility, allowing transition from the semi-open to closed conformations and the asymmetry potentially induced by ligand binding. This latter could be important for the PR2's adaptation to diverse ligands. Our results highlighted some differences between asymmetry of PR2 bound to darunavir and amprenavir that could explain their differences of affinity. This knowledge is critical for a better description of PR2's recognition and adaptation to various ligands and for a better understanding of the resistance of PR2 to most PR2 inhibitors, a major antiretroviral class.

Ligand modeling and design

Energy Technology Data Exchange (ETDEWEB)

Hay, B.P. [Pacific Northwest National Lab., Richland, WA (United States)

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.

Ligand and proton exchange dynamics in recombinant human myoglobin mutants.

Science.gov (United States)

Lambright, D G; Balasubramanian, S; Boxer, S G

1989-05-05

Site-specific mutants of human myoglobin have been prepared in which lysine 45 is replaced by arginine (K45R) and aspartate 60 by glutamate (D60E), in order to examine the influence of these residues and their interaction on the dynamics of the protein. These proteins were studied by a variety of methods, including one and two-dimensional proton nuclear magnetic resonance spectroscopy, exchange kinetics for the distal and proximal histidine NH protons as a function of pH in the met cyano forms, flash photolysis of the CO forms, and ligand replacement kinetics. The electronic absorption and proton nuclear magnetic resonance spectra of the CO forms of these proteins are virtually identical, indicating that the structure of the heme pocket is unaltered by these mutations. There are, however, substantial changes in the dynamics of both CO binding and proton exchange for the mutant K45R, whereas the mutant D60E exhibits behavior indistinguishable from the reference human myoglobin. K45R has a faster CO bimolecular recombination rate and slower CO off-rate relative to the reference. The kinetics for CO binding are independent of pH (6.5 to 10) as well as ionic strength (0 to 1 M-NaCl). The exchange rate for the distal histidine NH is substantially lower for K45R than the reference, whereas the proximal histidine NH exchange rate is unaltered. The exchange behavior of the human proteins is similar to that reported for a comparison of the exchange rates for myoglobins having lysine at position 45 with sperm whale myoglobin, which has arginine at this position. This indicates that the differences in exchange rates reflects largely the Lys----Arg substitution. The lack of a simple correlation for the CO kinetics with this substitution means that these are sensitive to other factors as well. Specific kinetic models, whereby substitution of arginine for lysine at position 45 can affect ligand binding dynamics, are outlined. These experiments demonstrate that a relatively

PatchSurfers: Two methods for local molecular property-based binding ligand prediction.

Science.gov (United States)

Shin, Woong-Hee; Bures, Mark Gregory; Kihara, Daisuke

2016-01-15

Protein function prediction is an active area of research in computational biology. Function prediction can help biologists make hypotheses for characterization of genes and help interpret biological assays, and thus is a productive area for collaboration between experimental and computational biologists. Among various function prediction methods, predicting binding ligand molecules for a target protein is an important class because ligand binding events for a protein are usually closely intertwined with the proteins' biological function, and also because predicted binding ligands can often be directly tested by biochemical assays. Binding ligand prediction methods can be classified into two types: those which are based on protein-protein (or pocket-pocket) comparison, and those that compare a target pocket directly to ligands. Recently, our group proposed two computational binding ligand prediction methods, Patch-Surfer, which is a pocket-pocket comparison method, and PL-PatchSurfer, which compares a pocket to ligand molecules. The two programs apply surface patch-based descriptions to calculate similarity or complementarity between molecules. A surface patch is characterized by physicochemical properties such as shape, hydrophobicity, and electrostatic potentials. These properties on the surface are represented using three-dimensional Zernike descriptors (3DZD), which are based on a series expansion of a 3 dimensional function. Utilizing 3DZD for describing the physicochemical properties has two main advantages: (1) rotational invariance and (2) fast comparison. Here, we introduce Patch-Surfer and PL-PatchSurfer with an emphasis on PL-PatchSurfer, which is more recently developed. Illustrative examples of PL-PatchSurfer performance on binding ligand prediction as well as virtual drug screening are also provided. Copyright © 2015 Elsevier Inc. All rights reserved.

Ligand identification using electron-density map correlations

International Nuclear Information System (INIS)

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

2007-01-01

An automated ligand-fitting procedure is applied to (F o − F c )exp(iϕ 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 o − F c )exp(iϕ 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

Effect of capping ligands on the optical properties and electronic energies of iron pyrite FeS{sub 2} nanocrystals and solid thin films

Energy Technology Data Exchange (ETDEWEB)

Zhai, Guangmei, E-mail: zhaiguangmei@tyut.edu.cn [Key Laboratory of Interface Science and Engineering in Advanced Materials of Ministry of Education of the People' s Republic of China, Research Centre of Advanced Materials Science and Technology of Taiyuan University of Technology, Taiyuan, Shanxi 030024 (China); Jiangsu Key Laboratory for Solar Cell Materials and Technology, Changzhou University, Changzhou, Jiangsu 213164 (China); State Key Laboratory of Electronic Thin Films and Integrated Devices, University of Electronic Science and Technology of China, Chengdu, Sichuan 610054 (China); Xie, Rongwei; Wang, Heng; Zhang, Jitao; Yang, Yongzhen; Wang, Hua; Li, Xuemin [Key Laboratory of Interface Science and Engineering in Advanced Materials of Ministry of Education of the People' s Republic of China, Research Centre of Advanced Materials Science and Technology of Taiyuan University of Technology, Taiyuan, Shanxi 030024 (China); Liu, Xuguang [Key Laboratory of Interface Science and Engineering in Advanced Materials of Ministry of Education of the People' s Republic of China, Research Centre of Advanced Materials Science and Technology of Taiyuan University of Technology, Taiyuan, Shanxi 030024 (China); College of Chemistry and Chemical Engineering, Taiyuan University of Technology, Taiyuan, Shanxi 030024 (China); Xu, Bingshe [Key Laboratory of Interface Science and Engineering in Advanced Materials of Ministry of Education of the People' s Republic of China, Research Centre of Advanced Materials Science and Technology of Taiyuan University of Technology, Taiyuan, Shanxi 030024 (China)

2016-07-25

In this work, the optical and electronic properties of iron pyrite FeS{sub 2} nanocrystals and solid thin films with various capping ligands were systematically investigated by UV–Vis–NIR absorption spectroscopy, cyclic voltammetry and current density–voltage characteristic measurements. The iron pyrite nanocrystals with various ligands have an indirect band gap of around 1.05 eV and broad absorption spanning into the near-infrared region, exhibiting favorable optical properties for their photovoltaic applications. The electron affinities and ionization potentials of FeS{sub 2} nanocrystals determined through cyclic voltammetry measurements show strong ligand dependence. An energy level shift of up to 190 meV was obtained among the pyrite nanocrystals capped with the ligands employed in this work. The iron pyrite nanocrystal films capped with iodide and 1,2-ethanedithiol exhibit the largest band edge energy shift and conductivity, respectively. Our results not only provide several useful optical and electronic parameters of pyrite nanocrystals for their further use in optoelectronic devices as active layers and/or infrared optical absorption materials, but also highlight the relationship between their surface chemistry and electronic energies. - Highlights: • The energy levels of FeS{sub 2} nanocrystals with various ligands were determined via electrochemical measurements. • The energy levels of FeS{sub 2} nanocrystals showed strong ligand-dependence. • An energy level shift of up to 190 meV was obtained for the pyrite nanocrystals studied in the work. • The conductivities of FeS{sub 2} nanocrystals with different ligands were obtained by current density–voltage measurements.

Long-lived charge-separated states in ligand-stabilized silver clusters

KAUST Repository

Pelton, Matthew; Tang, Yun; Bakr, Osman; Stellacci, Francesco

2012-01-01

Recently developed synthesis methods allow for the production of atomically monodisperse clusters of silver atoms stabilized in solution by aromatic thiol ligands, which exhibit intense absorption peaks throughout the visible and near-IR spectral regions. Here we investigated the time-dependent optical properties of these clusters. We observed two kinetic processes following ultrafast laser excitation of any of the absorption peaks: a rapid decay, with a time constant of 1 ps or less, and a slow decay, with a time constant that can be longer than 300 ns. Both time constants decrease as the polarity of the solvent increases, indicating that the two processes correspond to the formation and recombination, respectively, of a charge-separated state. The long lifetime of this state and the broad optical absorption spectrum mean that the ligand-stabilized silver clusters are promising materials for solar energy harvesting. © 2012 American Chemical Society.

Long-lived charge-separated states in ligand-stabilized silver clusters

KAUST Repository

Pelton, Matthew

2012-07-25

Recently developed synthesis methods allow for the production of atomically monodisperse clusters of silver atoms stabilized in solution by aromatic thiol ligands, which exhibit intense absorption peaks throughout the visible and near-IR spectral regions. Here we investigated the time-dependent optical properties of these clusters. We observed two kinetic processes following ultrafast laser excitation of any of the absorption peaks: a rapid decay, with a time constant of 1 ps or less, and a slow decay, with a time constant that can be longer than 300 ns. Both time constants decrease as the polarity of the solvent increases, indicating that the two processes correspond to the formation and recombination, respectively, of a charge-separated state. The long lifetime of this state and the broad optical absorption spectrum mean that the ligand-stabilized silver clusters are promising materials for solar energy harvesting. © 2012 American Chemical Society.

Novel aza-analogous ergoline derived scaffolds as potent serotonin 5-HT6 and dopamine D2 receptor ligands

DEFF Research Database (Denmark)

Krogsgaard-Larsen, Niels; Jensen, Anders A.; Schrøder, T.J.

2014-01-01

By introducing distal substituents on a tetracyclic scaffold resembling the ergoline structure, two series of analogues were achieved exhibiting subnanomolar receptor binding affinities for the dopamine D2 and serotonin 5-HT6 receptor subtype, respectively. While the 5-HT6 ligands were antagonists......, the D2 ligands displayed intrinsic activities ranging from full agonism to partial agonism with low intrinsic activity. These structures could potentially be interesting for treatment of neurological diseases such as schizophrenia, Parkinson’s disease, and cognitive deficits....

Schiff base ligand

Indian Academy of Sciences (India)

Unknown

Low-temperature stoichiometric Schiff base reaction in air in 3 : 1 mole ratio between benz- aldehyde and triethylenetetramine (trien) in methanol yields a novel tetraaza µ-bis(bidentate) acyclic ligand L. It was .... electrochemical work was performed as reported in ..... change in ligand shape through change in oxidation.

Acetylcholine receptors and cholinergic ligands: biochemical and genetic aspects in Torpedo californica and Drosophila melanogaster

International Nuclear Information System (INIS)

Rosenthal, L.S.

1987-01-01

This study evaluates the biochemical and genetic aspects of the acetylcholine receptor proteins and cholinergic ligands in Drosophila melanogaster and Torpedo californica. Included are (1) a comparative study of nicotinic ligand-induced cation release from acetylcholine receptors isolated from Torpedo californica and from Drosophila melanogaster, (2) solution studies of the cholinergic ligands, nikethamide and ethamivan, aimed at measuring internal molecular rotational barriers in solvents of different polarity; and (3) the isolation and characterization of the gene(s) for the acetylcholine receptor in Drosophila melasogaster. Acetylcholine receptor proteins isolated from Drosphila melanogaster heads were found to behave kinetically similar (with regards to cholinergic ligand-induced 155 Eu: 3+ displacement from prelabeled proteins) to receptor proteins isolated from Torpedo californica electric tissue, providing additional biochemical evidence for the existence of a Drosophila acetylcholine receptor

Incorporation of protein flexibility and conformational energy penalties in docking screens to improve ligand discovery

Science.gov (United States)

Fischer, Marcus; Coleman, Ryan G.; Fraser, James S.; Shoichet, Brian K.

2014-07-01

Proteins fluctuate between alternative conformations, which presents a challenge for ligand discovery because such flexibility is difficult to treat computationally owing to problems with conformational sampling and energy weighting. Here we describe a flexible docking method that samples and weights protein conformations using experimentally derived conformations as a guide. The crystallographically refined occupancies of these conformations, which are observable in an apo receptor structure, define energy penalties for docking. In a large prospective library screen, we identified new ligands that target specific receptor conformations of a cavity in cytochrome c peroxidase, and we confirm both ligand pose and associated receptor conformation predictions by crystallography. The inclusion of receptor flexibility led to ligands with new chemotypes and physical properties. By exploiting experimental measures of loop and side-chain flexibility, this method can be extended to the discovery of new ligands for hundreds of targets in the Protein Data Bank for which similar experimental information is available.

Meso-Helical Ag(I) Coordination Polymer Based on a Pyridylimidazole Ligand

International Nuclear Information System (INIS)

Kang, Youngjin; Kim, Jinho; Lee, Eunji; Park, Ki-Min; Moon, Suk-Hee

2016-01-01

In the fields of material science and metallosupramolecular chemistry, coordination polymers with various helical types have been extensively explored because of their charming structures, and their potential applications in material chemistry. Among them, meso-helical coordination polymers consisting of achiral 1D strands, which are generally constructed by a crystallographic inversion symmetry, are relatively rare. The coordination polymer 1 exhibits a rare one-dimensional meso-helical chain topology constructed by its internal inversion symmetry. The skeleton of this meso-helical chain is preserved up to 300°C. The complexation of silver(I) ion to the free pyim ligand give rise to the enhanced photoluminescence intensity and slightly blue-shifted emission maximum, originated from intraligand (IL) π[BOND]π* transition and rigidochromic effect. Further exploration of complexation of this ligand with other transition metal ions is currently in progress

Solution stabilities of some mixed ligand complexes of UO22+ and Th4+ with complexones and salicylic acids

International Nuclear Information System (INIS)

Singh, R.K.; Saxena, M.C.

1991-01-01

Formation constants (log Ksub(MAL)sup(MA)) of mixed ligands complexes (MAL), where M = UO 2 2+ or Th 4+ , A = IMDA, NTA, HEDTA, EDTA, CDTA or DTPA, L = salicylic acid (SA) or 5-sulphosalicylic acid (SSA), have been determined by pH titrations using Irving-Rossotti approach at 25 o C and at I =0.2 (mol dm -3 , KNO 3 ). The solution stabilities exhibit the sequence (i) Th 4+ >UO 2 2+ , (ii) IMDA>NTA>HEDTA>EDTA>CDTA>DTPA, and (iii) SA>SSA with respect to metal ions, primary ligands and secondary ligands, respectively. The formation constants log Ksub(ML)sup(M) and log Ksub(ML 2 )sup(ML) have also been determined. The Δlog K values have been found to be negative-increasing numerically with the negative charge on the deprotonated primary ligand (A n- ). (author). 17 refs., 1 tab

Synthesis, crystal structure and luminescence properties of lanthanide coordination polymers with a new semirigid bridging thenylsalicylamide ligand

International Nuclear Information System (INIS)

Song, Xue-Qin; Wang, Li; Zhao, Meng-Meng; Wang, Xiao-Run; Peng, Yun-Qiao; Cheng, Guo-Quan

2013-01-01

Two new lanthanide coordination polymers based on a semirigid bridging thenylsalicylamide ligand ([Ln 2 L 3 (NO 3 ) 6 ]·(C 4 H 8 O 2 ) 2 ) ∞ were obtained and characterized by elemental analysis, X-ray diffraction, IR and TGA measurements. The two compounds are isostructure and possess one dimensional trapezoid ladder-like chain built up from the connection of isolated LnO 3 (NO 3 ) 3 polyhedra (distorted monocapped antisquare prism) through the ligand. The photoluminescence analysis suggest that there is an efficient ligand-to-Ln(III) energy transfer in Tb(III) complex and the ligand is an efficient “antenna” for Tb(III). From a more general perspective, the results demonstrated herein provide the possibility of controlling the formation of the desired lanthanide coordination structure to enrich the crystal engineering strategy and enlarge the arsenal for developing excellent luminescent lanthanide coordination polymers. - Graphical abstract: We present herein one dimensional lanthanide coordination polymers of a new semirigid exo-bidentate ligand which not only display interesting structures but also possess strong luminescence properties. Display Omitted - Highlights: • We present lanthanide coordination polymers of a new semirigid exo-bidentate ligand. • The lanthanide coordination polymers exhibit interesting structures. • The luminescent properties of Tb(III) complexes are discussed in detail

Complexes of technetium with polyhydric ligands

International Nuclear Information System (INIS)

Hwang, L.L.Y.; Ronca, N.; Solomon, N.A.; Steigman, J.

1985-01-01

Polyhydric complexes of Tc(V) show absorption bands near 500 nm, with molar absorptivity coefficients of about 100. The shorter-chain compounds like ethylene glycol produce complexes which quickly disproportionate to Tc(IV) (as TcO 2 ) and Tc(VII) (as TcO 4 - ) on acidification. The longer-chain ligands like mannitol and gluconate do not. However, while the mannitol complex shows no change in spectrum from pH 12 to pH 3, the gluconate and glucoheptonate compounds show a definite spectral change on acidification, starting at pH 5. Electrophoresis similarity showed a change in mobility with pH for Tc-glucoheptonate, but none for Tc-mannitol. It was concluded that the carboxylic acid group of glucoheptonate was not binding the technetium. In 25 molal choline chloride the glucoheptonate-Tc mole ratio was 1:1 or less. A similar result emerged from a similar experiment in methylcellosolve as solvent. (author)

NMR studies of DNA oligomers and their interactions with minor groove binding ligands

Energy Technology Data Exchange (ETDEWEB)

Fagan, Patricia A. [Univ. of California, Berkeley, CA (United States). Dept. of Chemistry

1996-05-01

The cationic peptide ligands distamycin and netropsin bind noncovalently to the minor groove of DNA. The binding site, orientation, stoichiometry, and qualitative affinity of distamycin binding to several short DNA oligomers were investigated by NMR spectroscopy. The oligomers studied contain A,T-rich or I,C-rich binding sites, where I = 2-desaminodeoxyguanosine. I•C base pairs are functional analogs of A•T base pairs in the minor groove. The different behaviors exhibited by distamycin and netropsin binding to various DNA sequences suggested that these ligands are sensitive probes of DNA structure. For sites of five or more base pairs, distamycin can form 1:1 or 2:1 ligand:DNA complexes. Cooperativity in distamycin binding is low in sites such as AAAAA which has narrow minor grooves, and is higher in sites with wider minor grooves such as ATATAT. The distamycin binding and base pair opening lifetimes of I,C-containing DNA oligomers suggest that the I,C minor groove is structurally different from the A,T minor groove. Molecules which direct chemistry to a specific DNA sequence could be used as antiviral compounds, diagnostic probes, or molecular biology tools. The author studied two ligands in which reactive groups were tethered to a distamycin to increase the sequence specificity of the reactive agent.

Slow magnetic relaxation in carbonato-bridged dinuclear lanthanide(III) complexes with 2,3-quinoxalinediolate ligands.

Science.gov (United States)

Vallejo, Julia; Cano, Joan; Castro, Isabel; Julve, Miguel; Lloret, Francesc; Fabelo, Oscar; Cañadillas-Delgado, Laura; Pardo, Emilio

2012-08-11

The coordination chemistry of the 2,3-quinoxalinediolate ligand with different lanthanide(III) ions in basic media in air affords a new family of carbonato-bridged M(2)(III) compounds (M = Pr, Gd and Dy), the Dy(2)(III) analogue exhibiting slow magnetic relaxation behaviour typical of single-molecule magnets.

Mono- and Dinuclear Manganese Carbonyls Supported by 1,8-Disubstituted (L = Py, SMe, SH) Anthracene Ligand Scaffolds.

Science.gov (United States)

Manes, Taylor A; Rose, Michael J

2016-06-06

Presented herein is a synthetic scheme to generate symmetric and asymmetric ligands based on a 1,8-disubstituted anthracene scaffold. The metal-binding scaffolds were prepared by aryl chloride activation of 1,8-dichloroanthracene using Suzuki-type couplings facilitated by [Pd(dba)2] as a Pd source; the choice of cocatalyst (XPhos or SPhos) yielded symmetrically or asymmetrically substituted scaffolds (respectively): namely, Anth-SMe2 (3), Anth-N2 (4), and Anth-NSMe (6). The ligands exhibit a nonplanar geometry in the solid state (X-ray), owing to steric hindrance between the anthracene scaffold and the coupled aryl units. To determine the flexibility and binding characteristics of the anthracene-based ligands, the symmetric scaffolds were complexed with [Mn(CO)5Br] to afford the mononuclear species [(Anth-SMe2)Mn(CO)3Br] (8) and [(Anth-N2)Mn(CO)3Br] (9), in which the donor moieties chelate the Mn center in a cis fashion. The asymmetric ligand Anth-NSMe (6) binds preferentially through the py moieties, affording the bis-ligated complex [(Anth-NSMe)2Mn(CO)3Br] (10), wherein the thioether-S donors remain unbound. Alternatively, deprotection of the thioether in 6 affords the free thiol ligand Anth-NSH (7), which more readily binds the Mn center. Complexation of 7 ultimately affords the mixed-valence Mn(I)/Mn(II) dimer of formula [(Anth-NS)3Mn2(CO)3] (11), which exhibits a fac-{Mn(CO)3} unit supported by a triad of bridging thiolates, which are in turn ligated to a supporting Mn(II) center (EPR: |D| = 0.053 cm(-1), E/|D| = 0.3, Aiso = -150 MHz). All of the metal complexes have been characterized by single-crystal X-ray diffraction, IR spectroscopy and NMR/EPR measurements-all of which demonstrate that the meta-linked, anthracene-based ligand scaffold is a viable approach for the coordination of metal carbonyls.

Selective extraction of americium(III) over europium(III) ions with pyridylpyrazole ligands. Structure-property relationships

Energy Technology Data Exchange (ETDEWEB)

Su, Dongping; Liu, Ying; Li, Shimeng; Ding, Songdong; Jin, Yongdong; Wang, Zhipeng; Hu, Xiaoyang; Zhang, Lirong [Department of chemistry, Sichuan University, Chengdu (China)

2017-01-18

To clarify the structure-property relationships of pyridylpyrazole ligands and provide guidance for the design of new and more efficient ligands for the selective extraction of actinides over lanthanides, a series of alkyl-substituted pyridylpyrazole ligands with different branched chains at different positions of the pyrazole ring were synthesized. Extraction experiments showed that the pyridylpyrazole ligands exhibited good selective extraction abilities for Am{sup III} ions, and the steric effects of the branched chain had a significant impact on the distribution ratios of Am{sup III} and Eu{sup III} ions as well as the separation factor. Moreover, both slope analyses and UV/Vis spectrometry titrations indicated the formation of a 1:1 complex of 2-(1-octyl-1H-pyrazol-3-yl)pyridine (C8-PypzH) with Eu{sup III} ions. The stability constant (log K) for this complex obtained from the UV/Vis titration was 4.45 ± 0.04. Single crystals of the complexes of 3-(2-pyridyl)pyrazole (PypzH) with Eu(NO{sub 3}){sub 3} and Sm(NO{sub 3}){sub 3} were obtained; PypzH acts as a bidentate ligand in the crystal structures, and the N atom with a bound H atom did not participate in the coordination. In general, this study revealed some interesting findings on the effects of the alkyl-chain structure and the special complexation between pyridylpyrazole ligands and Ln{sup III} ions. (copyright 2017 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim)

Solvent-Controlled Assembly of ionic Metal-Organic Frameworks Based on Indium and Tetracarboxylate Ligand: Topology Variety and Gas Sorption Properties

KAUST Repository

Zheng, Bing

2016-07-15

Four Metal-Organic Frameworks (MOFs) based on Indium and tetracarboxylate ligand have been synthesized through regulation of the solvent conditions, the resulted compounds not only exhibited rich structural topologies (pts, soc and unique topologies), but also interesting charge reversal framework features. By regulating the solvent, different building units (indium monomer, trimer) have been generated in situ, and they are connected with the ligand to form ionic frameworks 1-4, respectively. Among the synthesized four ionic frameworks, compounds 3 and 4 could keep their crystallinity upon heating temperature up to 300oC after fully removal of solvent guest molecules, they also exhibit the charge reversal framework features (3 adopts an overall cationic framework, while 4 has an anionic framework). Both compounds 3 and 4 exhibit significant uptake capacity for CO2 and H2, besides that, compounds 3 and 4 also present excellent selective adsorption of CO2 over N2 and CH4.

Solvent-Controlled Assembly of ionic Metal-Organic Frameworks Based on Indium and Tetracarboxylate Ligand: Topology Variety and Gas Sorption Properties

KAUST Repository

Zheng, Bing; Sun, Xiaodong; Li, Guanghua; Cairns, Amy; Kravtsov, Victor; Huo, Qisheng; Liu, Yunling; Eddaoudi, Mohamed

2016-01-01

Four Metal-Organic Frameworks (MOFs) based on Indium and tetracarboxylate ligand have been synthesized through regulation of the solvent conditions, the resulted compounds not only exhibited rich structural topologies (pts, soc and unique topologies), but also interesting charge reversal framework features. By regulating the solvent, different building units (indium monomer, trimer) have been generated in situ, and they are connected with the ligand to form ionic frameworks 1-4, respectively. Among the synthesized four ionic frameworks, compounds 3 and 4 could keep their crystallinity upon heating temperature up to 300oC after fully removal of solvent guest molecules, they also exhibit the charge reversal framework features (3 adopts an overall cationic framework, while 4 has an anionic framework). Both compounds 3 and 4 exhibit significant uptake capacity for CO2 and H2, besides that, compounds 3 and 4 also present excellent selective adsorption of CO2 over N2 and CH4.

Calreticulin discriminates the proximal region at the N-glycosylation site of Glc1Man9GlcNAc2 ligand

Energy Technology Data Exchange (ETDEWEB)

Hirano, Makoto; Adachi, Yuka [Department of Materials and Life Science, Seikei University, 3-3-1 Kichijoji-kita, Musashino, Tokyo 180-8633 (Japan); Ito, Yukishige [Synthetic Cellular Chemistry Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198 (Japan); ERATO, Japan Science and Technology Agency, Ito Glycotrilogy Project, 2-1 Hirosawa, Wako, Saitama 351-0198 (Japan); Totani, Kiichiro, E-mail: ktotani@st.seikei.ac.jp [Department of Materials and Life Science, Seikei University, 3-3-1 Kichijoji-kita, Musashino, Tokyo 180-8633 (Japan)

2015-10-23

Calreticulin (CRT) is well known as a lectin-like chaperone that recognizes Glc1Man9GlcNAc2 (G1M9)-glycoproteins in the endoplasmic reticulum (ER). However, whether CRT can directly interact with the aglycone moiety (protein portion) of the glycoprotein remains controversial. To improve our understanding of CRT interactions, structure-defined G1M9-derivatives with different aglycones (–OH, –Gly–NH{sub 2}, and –Gly–Glu–{sup t}Bu) were used as CRT ligands, and their interactions with recombinant CRT were analyzed using thermal shift analysis. The results showed that CRT binds strongly to a G1M9-ligand in the order –Gly–Glu–{sup t}Bu > –Gly–NH{sub 2} > –OH, which is the same as that of the reglucosylation of Man9GlcNAc2 (M9)-derivatives by the folding sensor enzyme UGGT (UDP-glucose: glycoprotein glucosyltransferase). Our results indicate that, similar to UGGT, CRT discriminates the proximal region at the N-glycosylation site, suggesting a similar mechanism mediating the recognition of aglycone moieties in the ER glycoprotein quality control system. - Highlights: • Glc1Man9GlcNAc2 (G1M9) ligands with different aglycones were chemically prepared. • Calreticulin (CRT) discriminates the aglycone of Glc1Man9GlcNAc2 (G1M9) ligand. • CRT binds with G1M9 ligands in a similar manner to folding sensor enzyme.

Bitopic Ligands and Metastable Binding Sites

DEFF Research Database (Denmark)

Fronik, Philipp; Gaiser, Birgit I; Sejer Pedersen, Daniel

2017-01-01

of orthosteric binding sites. Bitopic ligands have been employed to address the selectivity problem by combining (linking) an orthosteric ligand with an allosteric modulator, theoretically leading to high-affinity subtype selective ligands. However, it remains a challenge to identify suitable allosteric binding...... that have been reported to date, this type of bitopic ligands would be composed of two identical pharmacophores. Herein, we outline the concept of bitopic ligands, review metastable binding sites, and discuss their potential as a new source of allosteric binding sites....

Consensus of sample-balanced classifiers for identifying ligand-binding residue by co-evolutionary physicochemical characteristics of amino acids

KAUST Repository

Chen, Peng

2013-01-01

Protein-ligand binding is an important mechanism for some proteins to perform their functions, and those binding sites are the residues of proteins that physically bind to ligands. So far, the state-of-the-art methods search for similar, known structures of the query and predict the binding sites based on the solved structures. However, such structural information is not commonly available. In this paper, we propose a sequence-based approach to identify protein-ligand binding residues. Due to the highly imbalanced samples between the ligand-binding sites and non ligand-binding sites, we constructed several balanced data sets, for each of which a random forest (RF)-based classifier was trained. The ensemble of these RF classifiers formed a sequence-based protein-ligand binding site predictor. Experimental results on CASP9 targets demonstrated that our method compared favorably with the state-of-the-art. © Springer-Verlag Berlin Heidelberg 2013.

Toehold-Mediated Displacement of an Adenosine-Binding Aptamer from a DNA Duplex by its Ligand.

Science.gov (United States)

Monserud, Jon H; Macri, Katherine M; Schwartz, Daniel K

2016-10-24

DNA is increasingly used to engineer dynamic nanoscale circuits, structures, and motors, many of which rely on DNA strand-displacement reactions. The use of functional DNA sequences (e.g., aptamers, which bind to a wide range of ligands) in these reactions would potentially confer responsiveness on such devices, and integrate DNA computation with highly varied molecular stimuli. By using high-throughput single-molecule FRET methods, we compared the kinetics of a putative aptamer-ligand and aptamer-complement strand-displacement reaction. We found that the ligands actively disrupted the DNA duplex in the presence of a DNA toehold in a similar manner to complementary DNA, with kinetic details specific to the aptamer structure, thus suggesting that the DNA strand-displacement concept can be extended to functional DNA-ligand systems. © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Large-scale binding ligand prediction by improved patch-based method Patch-Surfer2.0.

Science.gov (United States)

Zhu, Xiaolei; Xiong, Yi; Kihara, Daisuke

2015-03-01

Ligand binding is a key aspect of the function of many proteins. Thus, binding ligand prediction provides important insight in understanding the biological function of proteins. Binding ligand prediction is also useful for drug design and examining potential drug side effects. We present a computational method named Patch-Surfer2.0, which predicts binding ligands for a protein pocket. By representing and comparing pockets at the level of small local surface patches that characterize physicochemical properties of the local regions, the method can identify binding pockets of the same ligand even if they do not share globally similar shapes. Properties of local patches are represented by an efficient mathematical representation, 3D Zernike Descriptor. Patch-Surfer2.0 has significant technical improvements over our previous prototype, which includes a new feature that captures approximate patch position with a geodesic distance histogram. Moreover, we constructed a large comprehensive database of ligand binding pockets that will be searched against by a query. The benchmark shows better performance of Patch-Surfer2.0 over existing methods. http://kiharalab.org/patchsurfer2.0/ CONTACT: dkihara@purdue.edu Supplementary data are available at Bioinformatics online. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Distinct roles of beta1 metal ion-dependent adhesion site (MIDAS), adjacent to MIDAS (ADMIDAS), and ligand-associated metal-binding site (LIMBS) cation-binding sites in ligand recognition by integrin alpha2beta1.

Science.gov (United States)

Valdramidou, Dimitra; Humphries, Martin J; Mould, A Paul

2008-11-21

Integrin-ligand interactions are regulated in a complex manner by divalent cations, and previous studies have identified ligand-competent, stimulatory, and inhibitory cation-binding sites. In collagen-binding integrins, such as alpha2beta1, ligand recognition takes place exclusively at the alpha subunit I domain. However, activation of the alphaI domain depends on its interaction with a structurally similar domain in the beta subunit known as the I-like or betaI domain. The top face of the betaI domain contains three cation-binding sites: the metal-ion dependent adhesion site (MIDAS), the ADMIDAS (adjacent to MIDAS), and LIMBS (ligand-associated metal-binding site). The role of these sites in controlling ligand binding to the alphaI domain has yet to be elucidated. Mutation of the MIDAS or LIMBS completely blocked collagen binding to alpha2beta1; in contrast mutation of the ADMIDAS reduced ligand recognition but this effect could be overcome by the activating monoclonal antibody TS2/16. Hence, the MIDAS and LIMBS appear to be essential for the interaction between alphaI and betaI, whereas occupancy of the ADMIDAS has an allosteric effect on the conformation of betaI. An activating mutation in the alpha2 I domain partially restored ligand binding to the MIDAS and LIMBS mutants. Analysis of the effects of Ca(2+), Mg(2+), and Mn(2+) on ligand binding to these mutants showed that the MIDAS is a ligand-competent site through which Mn(2+) stimulates ligand binding, whereas the LIMBS is a stimulatory Ca(2+)-binding site, occupancy of which increases the affinity of Mg(2+) for the MIDAS.

Hydrophilic 2,9-bis-triazolyl-1,10-phenanthroline ligands enable selective Am(iii) separation: a step further towards sustainable nuclear energy.

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Edwards, Alyn C; Mocilac, Pavle; Geist, Andreas; Harwood, Laurence M; Sharrad, Clint A; Burton, Neil A; Whitehead, Roger C; Denecke, Melissa A

2017-05-02

The first hydrophilic, 1,10-phenanthroline derived ligands consisting of only C, H, O and N atoms for the selective extraction of Am(iii) from spent nuclear fuel are reported herein. One of these 2,9-bis-triazolyl-1,10-phenanthroline (BTrzPhen) ligands combined with a non-selective extracting agent, was found to exhibit process-suitable selectivity for Am(iii) over Eu(iii) and Cm(iii), providing a clear step forward.

From undefined red smear cheese consortia to minimal model communities both exhibiting similar anti-listerial activity on a cheese-like matrix.

Science.gov (United States)

Imran, M; Desmasures, N; Vernoux, J-P

2010-12-01

Starting from one undefined cheese smear consortium exhibiting anti-listerial activity (signal) at 15 °C, 50 yeasts and 39 bacteria were identified by partial rDNA sequencing. Construction of microbial communities was done either by addition or by erosion approach with the aim to obtain minimal communities having similar signal to that of the initial smear. The signal of these microbial communities was monitored in cheese microcosm for 14 days under ripening conditions. In the addition scheme, strains having significant signals were mixed step by step. Five-member communities, obtained by addition of a Gram negative bacterium to two yeasts and two Gram positive bacteria, enhanced the signal dramatically contrary to six-member communities including two Gram negative bacteria. In the erosion approach, a progressive reduction of 89 initial strains was performed. While intermediate communities (89, 44 and 22 members) exhibited a lower signal than initial smear consortium, eleven- and six-member communities gave a signal almost as efficient. It was noteworthy that the final minimal model communities obtained by erosion and addition approaches both had anti-listerial activity while consisting of different strains. In conclusion, some minimal model communities can have higher anti-listerial effectiveness than individual strains or the initial 89 micro-organisms from smear. Thus, microbial interactions are involved in the production and modulation of anti-listerial signals in cheese surface communities. Copyright © 2010 Elsevier Ltd. All rights reserved.

Heterogeneity and dynamics of the ligand recognition mode in purine-sensing riboswitches.

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Jain, Niyati; Zhao, Liang; Liu, John D; Xia, Tianbing

2010-05-04

High-resolution crystal structures and biophysical analyses of purine-sensing riboswitches have revealed that a network of hydrogen bonding interactions appear to be largey responsible for discrimination of cognate ligands against structurally related compounds. Here we report that by using femtosecond time-resolved fluorescence spectroscopy to capture the ultrafast decay dynamics of the 2-aminopurine base as the ligand, we have detected the presence of multiple conformations of the ligand within the binding pockets of one guanine-sensing and two adenine-sensing riboswitches. All three riboswitches have similar conformational distributions of the ligand-bound state. The known crystal structures represent the global minimum that accounts for 50-60% of the population, where there is no significant stacking interaction between the ligand and bases of the binding pocket, but the hydrogen-bonding cage collectively provides an electronic environment that promotes an ultrafast ( approximately 1 ps) charge transfer pathway. The ligand also samples multiple conformations in which it significantly stacks with either the adenine or the uracil bases of the A21-U75 and A52-U22 base pairs that form the ceiling and floor of the binding pocket, respectively, but favors the larger adenine bases. These alternative conformations with well-defined base stacking interactions are approximately 1-1.5 kcal/mol higher in DeltaG degrees than the global minimum and have distinct charge transfer dynamics within the picosecond to nanosecond time regime. Inside the pocket, the purine ligand undergoes dynamic motion on the low nanosecond time scale, sampling the multiple conformations based on time-resolved anisotropy decay dynamics. These results allowed a description of the energy landscape of the bound ligand with intricate details and demonstrated the elastic nature of the ligand recognition mode by the purine-sensing riboswitches, where there is a dynamic balance between hydrogen bonding

Ligand size is a major determinant of specificity in periplasmic oxyanion-binding proteins: the 1.2 A resolution crystal structure of Azotobacter vinelandii ModA.

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Lawson, D M; Williams, C E; Mitchenall, L A; Pau, R N

1998-12-15

. Periplasmic receptors constitute a diverse class of binding proteins that differ widely in size, sequence and ligand specificity. Nevertheless, almost all of them display a common beta/alpha folding motif and have similar tertiary structures consisting of two globular domains. The ligand is bound at the bottom of a deep cleft, which lies at the interface between these two domains. The oxyanion-binding proteins are notable in that they can discriminate between very similar ligands. . Azotobacter vinelandii is unusual in that it possesses two periplasmic molybdate-binding proteins. The crystal structure of one of these with bound ligand has been determined at 1.2 A resolution. It superficially resembles the structure of sulphate-binding protein (SBP) from Salmonella typhimurium and uses a similar constellation of hydrogen-bonding interactions to bind its ligand. However, the detailed interactions are distinct from those of SBP and the more closely related molybdate-binding protein of Escherichia coli. . Despite differences in the residues involved in binding, the volumes of the binding pockets in the A. vinelandii and E. coli molybdate-binding proteins are similar and are significantly larger than that of SBP. We conclude that the discrimination between molybdate and sulphate shown by these binding proteins is largely dependent upon small differences in the sizes of these two oxyanions.

Virtual drug screen schema based on multiview similarity integration and ranking aggregation.

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Kang, Hong; Sheng, Zhen; Zhu, Ruixin; Huang, Qi; Liu, Qi; Cao, Zhiwei

2012-03-26

The current drug virtual screen (VS) methods mainly include two categories. i.e., ligand/target structure-based virtual screen and that, utilizing protein-ligand interaction fingerprint information based on the large number of complex structures. Since the former one focuses on the one-side information while the later one focuses on the whole complex structure, they are thus complementary and can be boosted by each other. However, a common problem faced here is how to present a comprehensive understanding and evaluation of the various virtual screen results derived from various VS methods. Furthermore, there is still an urgent need for developing an efficient approach to fully integrate various VS methods from a comprehensive multiview perspective. In this study, our virtual screen schema based on multiview similarity integration and ranking aggregation was tested comprehensively with statistical evaluations, providing several novel and useful clues on how to perform drug VS from multiple heterogeneous data sources. (1) 18 complex structures of HIV-1 protease with ligands from the PDB were curated as a test data set and the VS was performed with five different drug representations. Ritonavir ( 1HXW ) was selected as the query in VS and the weighted ranks of the query results were aggregated from multiple views through four similarity integration approaches. (2) Further, one of the ranking aggregation methods was used to integrate the similarity ranks calculated by gene ontology (GO) fingerprint and structural fingerprint on the data set from connectivity map, and two typical HDAC and HSP90 inhibitors were chosen as the queries. The results show that rank aggregation can enhance the result of similarity searching in VS when two or more descriptions are involved and provide a more reasonable similarity rank result. Our study shows that integrated VS based on multiple data fusion can achieve a remarkable better performance compared to that from individual ones and

Allosteric ligands and their binding sites define γ-aminobutyric acid (GABA) type A receptor subtypes.

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Olsen, Richard W

2015-01-01

GABAA receptors (GABA(A)Rs) mediate rapid inhibitory transmission in the brain. GABA(A)Rs are ligand-gated chloride ion channel proteins and exist in about a dozen or more heteropentameric subtypes exhibiting variable age and brain regional localization and thus participation in differing brain functions and diseases. GABA(A)Rs are also subject to modulation by several chemotypes of allosteric ligands that help define structure and function, including subtype definition. The channel blocker picrotoxin identified a noncompetitive channel blocker site in GABA(A)Rs. This ligand site is located in the transmembrane channel pore, whereas the GABA agonist site is in the extracellular domain at subunit interfaces, a site useful for low energy coupled conformational changes of the functional channel domain. Two classes of pharmacologically important allosteric modulatory ligand binding sites reside in the extracellular domain at modified agonist sites at other subunit interfaces: the benzodiazepine site and the high-affinity, relevant to intoxication, ethanol site. The benzodiazepine site is specific for certain GABA(A)R subtypes, mainly synaptic, while the ethanol site is found at a modified benzodiazepine site on different, extrasynaptic, subtypes. In the transmembrane domain are allosteric modulatory ligand sites for diverse chemotypes of general anesthetics: the volatile and intravenous agents, barbiturates, etomidate, propofol, long-chain alcohols, and neurosteroids. The last are endogenous positive allosteric modulators. X-ray crystal structures of prokaryotic and invertebrate pentameric ligand-gated ion channels, and the mammalian GABA(A)R protein, allow homology modeling of GABA(A)R subtypes with the various ligand sites located to suggest the structure and function of these proteins and their pharmacological modulation. © 2015 Elsevier Inc. All rights reserved.

Ligand combination strategy for the preparation of novel low-dimensional and open-framework metal cluster materials

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Anokhina, Ekaterina V.

Low-dimensional and open-framework materials containing transition metals have a wide range of applications in redox catalysis, solid-state batteries, and electronic and magnetic devices. This dissertation reports on research carried out with the goal to develop a strategy for the preparation of low-dimensional and open-framework materials using octahedral metal clusters as building blocks. Our approach takes its roots from crystal engineering principles where the desired framework topologies are achieved through building block design. The key idea of this work is to induce directional bonding preferences in the cluster units using a combination of ligands with a large difference in charge density. This investigation led to the preparation and characterization of a new family of niobium oxychloride cluster compounds with original structure types exhibiting 1ow-dimensional or open-framework character. Most of these materials have framework topologies unprecedented in compounds containing octahedral clusters. Comparative analysis of their structural features indicates that the novel cluster connectivity patterns in these systems are the result of complex interplay between the effects of anisotropic ligand arrangement in the cluster unit and optimization of ligand-counterion electrostatic interactions. The important role played by these factors sets niobium oxychloride systems apart from cluster compounds with one ligand type or statistical ligand distribution where the main structure-determining factor is the total number of ligands. These results provide a blueprint for expanding the ligand combination strategy to other transition metal cluster systems and for the future rational design of cluster-based materials.

Investigation on biomolecular interactions of nickel(II) complexes with monoanionic bidentate ligands

Science.gov (United States)

Jayamani, Arumugam; Sethupathi, Murugan; Ojwach, Stephen O.; Sengottuvelan, Nallathambi

2018-01-01

Reactions of monoanionic bidentate ligands 5-methylsalicylaldehyde (5-msal), 5-bromosalicylaldehyde (5-brsal), 5-nitrosalicylaldehyde (5-nsal) and 2-hydroxy-1-naphthaldehyde (2-hnap) with nickel perchlorate hexahydrate produced nickel(II) complexes 1-4, respectively. Single crystal X-ray analyses of complexes 1 and 2 confirmed bidentate mode of the ligands with O˄O coordination to give square planar geometry around nickel atoms. Complexes 1-4 showed one quasi-reversible redox peak at cathodic region (-0.67 to -0.80 V) and one redox peak at anodic region (+1.08 to +1.44 V) assignable to the Ni(II)/Ni(I) and Ni(II)/Ni(III) redox couples, respectively. The complexes exhibited good bovine serum albumin (BSA) binding abilities with a maximum binding constant of 1.96 × 105 M-1. The binding of complexes with calf thymus DNA (ctDNA) showed that the binding affinity is consistent with an increase in steric bulk of the ligands. The nuclease activity of the complexes showed efficient oxidative cleavage in the presence of hydrogen peroxide as an oxidizing agent. The complexes showed higher zone of inhibition when screened for antimicrobial activity against bacteria and human pathogenic fungi.

Synthesis, Photophysical and Electrochemical Properties of a Mixed Bipyridyl-Phenanthrolyl Ligand Ru(II Heteroleptic Complex Having trans-2-Methyl-2-butenoic Acid Functionalities

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Adewale O. Adeloye

2011-09-01

Full Text Available In this work, two ligands: 4-(trans-2-Methyl-2-butenoic acid-2,2'-bipyridine (L1 and 5-(trans-2-methyl-2-butenoic acid-1,10-phenanthroline (L2, with the corresponding mixed-ligand heteroleptic Ru(II complex were synthesized and characterized by FT-IR, 1H-, 13C-NMR spectroscopy and elemental analysis. The influence of the mixed functionalized polypyridyl ruthenium(II complex on the photophysical and electrochemical properties were investigated and compared to individual single-ligand homoleptic complexes. Interestingly, the mixed-ligand complex formulated as [RuL1L2(NCS2] exhibits broad and intense metal-to-ligand charge transfer (MLCT absorption with a high molar extinction coefficient (λmax = 514 nm, ε = 69,700 M−1 cm−1, better than those of individual single-ligand complexes, [Ru(L12(NCS2] and [Ru(L22(NCS2], and a strong photoluminescence intensity ratio in the red region at λem = 686 nm. The electrochemical properties of the complex indicated that the redox processes are ligand-based.

Spectrophotometric method for determination of bifunctional macrocyclic ligands in macrocyclic ligand-protein conjugates

International Nuclear Information System (INIS)

Dadachova, E.; Chappell, L.L.; Brechbiel, M.W.

1999-01-01

A simple spectrophotometric assay for determination of bifunctional polyazacarboxylate-macrocyclic ligands of different sizes that are conjugated to proteins has been developed for: 12-membered macrocycle DOTA (2-[4-nitrobenzyl]-1, 4, 7, 10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid) and analogs, the 15-membered PEPA macrocycle (2-[4-nitrobenzyl]-1,4,7,10,13-pentaazacyclopentadecane-N,N',N'',N''',N'''' -pentaacetic acid), and the large 18-membered macrocycle HEHA (1,4,7,10,13,16-hexaazacyclooctadecane-N,N',N'',N''',N''''-hexaacetic acid). The method is based on titration of the blue-colored 1:1 Pb(II)-Arsenazo III (AAIII) complex with the polyazacarboxylate macrocyclic ligand in the concentration range of 0-2.5 μM, wherein color change occurring upon transchelation of the Pb(II) from the AAIII to the polyazamacrocyclic ligand is monitored at 656 nm. The assay is performed at ambient temperature within 20 min without any interfering interaction between the protein and Pb(II)-AA(III) complex. Thus, this method also provides a ligand-to-protein ratio (L/P ratio) that reflects the effective number of ligands per protein molecule available to radiolabeling. The method is not suitable for 14-membered TETA macrocycle (2-[4-nitrobenzyl]-1, 4, 8, 11-tetraazacyclotetradecane N,N',N'',N'''-tetraacetic acid) because of low stability constant of Pb(II)-TETA complex. The method is rapid, simple and may be customized for other polyazacarboxylate macrocyclic ligands

Rosetta Ligand docking with flexible XML protocols.

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Lemmon, Gordon; Meiler, Jens

2012-01-01

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

Simple Ligand-Receptor Interaction Descriptor (SILIRID) for alignment-free binding site comparison.

Science.gov (United States)

Chupakhin, Vladimir; Marcou, Gilles; Gaspar, Helena; Varnek, Alexandre

2014-06-01

We describe SILIRID (Simple Ligand-Receptor Interaction Descriptor), a novel fixed size descriptor characterizing protein-ligand interactions. SILIRID can be obtained from the binary interaction fingerprints (IFPs) by summing up the bits corresponding to identical amino acids. This results in a vector of 168 integer numbers corresponding to the product of the number of entries (20 amino acids and one cofactor) and 8 interaction types per amino acid (hydrophobic, aromatic face to face, aromatic edge to face, H-bond donated by the protein, H-bond donated by the ligand, ionic bond with protein cation and protein anion, and interaction with metal ion). Efficiency of SILIRID to distinguish different protein binding sites has been examined in similarity search in sc-PDB database, a druggable portion of the Protein Data Bank, using various protein-ligand complexes as queries. The performance of retrieval of structurally and evolutionary related classes of proteins was comparable to that of state-of-the-art approaches (ROC AUC ≈ 0.91). SILIRID can efficiently be used to visualize chemogenomic space covered by sc-PDB using Generative Topographic Mapping (GTM): sc-PDB SILIRID data form clusters corresponding to different protein types.

Systematic Introduction of Aromatic Rings to Diphosphine Ligands for Emission Color Tuning of Dinuclear Copper(I) Iodide Complexes.

Science.gov (United States)

Okano, Yuka; Ohara, Hiroki; Kobayashi, Atsushi; Yoshida, Masaki; Kato, Masako

2016-06-06

We have newly synthesized two solution-stable luminescent dinuclear copper(I) complexes, [Cu2(μ-I)2(dpppy)2] (Cu-py) and [Cu2(μ-I)2(dpppyz)2] (Cu-pyz), where dpppy = 2,3-bis(diphenylphosphino)pyridine and dpppyz = 2,3-bis(diphenylphosphino)pyrazine, using chelating diphosphine ligands composed of N-heteroaromatic rings. X-ray analysis clearly indicates that the molecular structures of Cu-py and Cu-pyz are almost identical with that of the parent complex, [Cu2(μ-I)2(dppb)2] [Cu-bz; dppb = 2,3-bis(diphenylphosphino)benzene]. Complexes Cu-py and Cu-pyz exhibit luminescence [emission quantum yield (Φem) = 0.48 and 0.02, respectively] in the solid state at 298 K. A wide emission color tuning, from 497 to 638 nm (energy = 0.55 eV, with an emission color ranging from green to reddish-orange), was achieved in the solid state by the introduction of pyridinic N atoms into the bridging phenyl group between the two diphenylphosphine groups. Density functional theory calculations suggest that the emission could originate from the effective combination of the metal-to-ligand charge-transfer excited state with the halide-to-ligand charge-transfer excited state. Thus, the emission color change is due to stabilization of the π* levels of the central aryl group in the diphosphine ligand. Furthermore, these copper(I) complexes exhibit thermally activated delayed fluorescence at 298 K because of the small singlet-triplet energy difference (ΔE = 523 and 564 cm(-1) for Cu-py and Cu-pyz, respectively). The stability of these complexes in chloroform, due to the rigid bonds between the diphosphine ligands and the Cu(I) ions, enables the preparation of emissive poly(methyl methacrylate) films by the solution-doping technique.

Ligand-receptor Interactions by NMR Spectroscopy

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Novak. P.

2008-04-01

Full Text Available Today NMR spectroscopy is a method of choice for elucidation of interactions between biomolecules and the potential ligands. Knowledge on these interactions is an essential prerequisite for the rational drug design. The most important contribution of NMR to drug design a few years ago was the 3D structure determination of proteins. Besides delivering the 3D structures of the free proteins as a raw material for the modeling studies on ligand binding, NMR can directly yield valuable experimental data on the biologically important protein-ligand complexes. In addition to X-ray diffraction, NMR spectroscopy can provide information on the internal protein dynamics ordynamics of intermolecular interactions. Changes in NMR parameters allow us to detect ("SAR by NMR" and quantitatively determine binding affinities (titration, diffusion NMR experiments, etc. of potential ligands. Also, it is possible to determine the binding site and conformations of ligands, receptors and receptor-ligand complexes with the help of NMR methods such as tr-NOESY. Epitopes or functional groups responsible for binding of ligands to the receptor can be identified by employing STD or WaterLOGSY experiments. In this review are described some of the most frequent NMR methods for the characterization of the interactions between biomolecules and ligands, together with their advantages and disadvantages.

Comparison of the kinetics of different Markov models for ligand binding under varying conditions

International Nuclear Information System (INIS)

Martini, Johannes W. R.; Habeck, Michael

2015-01-01

We recently derived a Markov model for macromolecular ligand binding dynamics from few physical assumptions and showed that its stationary distribution is the grand canonical ensemble [J. W. R. Martini, M. Habeck, and M. Schlather, J. Math. Chem. 52, 665 (2014)]. The transition probabilities of the proposed Markov process define a particular Glauber dynamics and have some similarity to the Metropolis-Hastings algorithm. Here, we illustrate that this model is the stochastic analog of (pseudo) rate equations and the corresponding system of differential equations. Moreover, it can be viewed as a limiting case of general stochastic simulations of chemical kinetics. Thus, the model links stochastic and deterministic approaches as well as kinetics and equilibrium described by the grand canonical ensemble. We demonstrate that the family of transition matrices of our model, parameterized by temperature and ligand activity, generates ligand binding kinetics that respond to changes in these parameters in a qualitatively similar way as experimentally observed kinetics. In contrast, neither the Metropolis-Hastings algorithm nor the Glauber heat bath reflects changes in the external conditions correctly. Both converge rapidly to the stationary distribution, which is advantageous when the major interest is in the equilibrium state, but fail to describe the kinetics of ligand binding realistically. To simulate cellular processes that involve the reversible stochastic binding of multiple factors, our pseudo rate equation model should therefore be preferred to the Metropolis-Hastings algorithm and the Glauber heat bath, if the stationary distribution is not of only interest

Comparison of the kinetics of different Markov models for ligand binding under varying conditions

Energy Technology Data Exchange (ETDEWEB)

Martini, Johannes W. R., E-mail: jmartin2@gwdg.de [Max Planck Institute for Developmental Biology, Tübingen (Germany); Felix Bernstein Institute for Mathematical Statistics in the Biosciences, University of Göttingen, Göttingen (Germany); Habeck, Michael, E-mail: mhabeck@gwdg.de [Felix Bernstein Institute for Mathematical Statistics in the Biosciences, University of Göttingen, Göttingen (Germany); Max Planck Institute for Biophysical Chemistry, Göttingen (Germany)

2015-03-07

We recently derived a Markov model for macromolecular ligand binding dynamics from few physical assumptions and showed that its stationary distribution is the grand canonical ensemble [J. W. R. Martini, M. Habeck, and M. Schlather, J. Math. Chem. 52, 665 (2014)]. The transition probabilities of the proposed Markov process define a particular Glauber dynamics and have some similarity to the Metropolis-Hastings algorithm. Here, we illustrate that this model is the stochastic analog of (pseudo) rate equations and the corresponding system of differential equations. Moreover, it can be viewed as a limiting case of general stochastic simulations of chemical kinetics. Thus, the model links stochastic and deterministic approaches as well as kinetics and equilibrium described by the grand canonical ensemble. We demonstrate that the family of transition matrices of our model, parameterized by temperature and ligand activity, generates ligand binding kinetics that respond to changes in these parameters in a qualitatively similar way as experimentally observed kinetics. In contrast, neither the Metropolis-Hastings algorithm nor the Glauber heat bath reflects changes in the external conditions correctly. Both converge rapidly to the stationary distribution, which is advantageous when the major interest is in the equilibrium state, but fail to describe the kinetics of ligand binding realistically. To simulate cellular processes that involve the reversible stochastic binding of multiple factors, our pseudo rate equation model should therefore be preferred to the Metropolis-Hastings algorithm and the Glauber heat bath, if the stationary distribution is not of only interest.

Singular Value Decomposition and Ligand Binding Analysis

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André Luiz Galo

2013-01-01

Full Text Available Singular values decomposition (SVD is one of the most important computations in linear algebra because of its vast application for data analysis. It is particularly useful for resolving problems involving least-squares minimization, the determination of matrix rank, and the solution of certain problems involving Euclidean norms. Such problems arise in the spectral analysis of ligand binding to macromolecule. Here, we present a spectral data analysis method using SVD (SVD analysis and nonlinear fitting to determine the binding characteristics of intercalating drugs to DNA. This methodology reduces noise and identifies distinct spectral species similar to traditional principal component analysis as well as fitting nonlinear binding parameters. We applied SVD analysis to investigate the interaction of actinomycin D and daunomycin with native DNA. This methodology does not require prior knowledge of ligand molar extinction coefficients (free and bound, which potentially limits binding analysis. Data are acquired simply by reconstructing the experimental data and by adjusting the product of deconvoluted matrices and the matrix of model coefficients determined by the Scatchard and McGee and von Hippel equation.

Diverse CdII coordination complexes derived from bromide isophthalic acid binding with auxiliary N-donor ligands

International Nuclear Information System (INIS)

Tang, Meng; Dong, Bao-Xia; Wu, Yi-Chen; Yang, Fang; Liu, Wen-Long; Teng, Yun-Lei

2016-01-01

The coordination characteristics of 4-bromoisophthalic acid (4-Br-H 2 ip) have been investigated in a series of Cd II -based frameworks. Hydrothermal reactions of Cd II salts and 4-Br-H 2 ip together with flexible or semiflexible N-donor auxiliary ligands resulted in the formation of four three-dimensional coordination complexes with diverse structures: (Cd(bix) 0.5 (bix) 0.5 (4-Br-ip)]·H 2 O) n (1), [Cd(bbi) 0.5 (bbi) 0.5 (4-Br-ip)] n (2), ([Cd(btx) 0.5 (4-Br-ip)(H 2 O)]·0.5CH 3 OH·H 2 O) n (3) and ([Cd(bbt) 0.5 (4-Br-ip)(H 2 O)]·3·5H 2 O) n (4). These compounds were characterized by elemental analyses, IR spectra, single-crystal and powder X-ray diffraction. They displayed diverse structures depending on the configuration of the 4-connected metal node, the coordination mode of the 4-Br-H 2 ip, the coordination ability and conformationally flexibility of the N-donor auxiliary. Compound 1 exhibits 3-fold interpenetrated 6 6 topology and compound 2 has a 4 12 topology. Compounds 3–4 have similar 3D pillar-layered structures based on 3,4-connected binodal net with the Schläfli symbol of (4·3 8 ). The thermal stabilities and photoluminescence properties of them were discussed in detail. - Graphical abstract: Four 3D Cd II coordination complexes on the basis of 4-bromoisophthalic acid (4-Br-H 2 ip) and two types of flexible (bbi, bbt) and semiflexible (bix, btx) N-donor ligands are prepared. They displayed diverse topology structures of 6 6 (1), 4 12 (2) and 4·3 8 (3−4), depending on the configuration of the 4-connected metal node, the coordination mode of the 4-Br-H 2 ip, the coordination ability and conformationally flexibility of the N-donor auxiliary ligand. - Highlights: • Four 3D Cd II coordination complexes based on 4-Br-H 2 ip and flexible/semiflexible N-donor ligands have been synthesized. • They displayed diverse topology structures of 6 6 for 1, 4 12 for 2 and 4·3 8 for 3–4. • The structural diversity depends on the configuration of 4-Br

A Ferrocene-Based Catecholamide Ligand: the Consequences of Ligand Swivel for Directed Supramolecular Self-Assembly

Energy Technology Data Exchange (ETDEWEB)

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.

Increased precision for analysis of protein-ligand dissociation constants determined from chemical shift titrations

Energy Technology Data Exchange (ETDEWEB)

Markin, Craig J.; Spyracopoulos, Leo, E-mail: leo.spyracopoulos@ualberta.ca [University of Alberta, Department of Biochemistry (Canada)

2012-06-15

NMR is ideally suited for the analysis of protein-protein and protein ligand interactions with dissociation constants ranging from {approx}2 {mu}M to {approx}1 mM, and with kinetics in the fast exchange regime on the NMR timescale. For the determination of dissociation constants (K{sub D}) of 1:1 protein-protein or protein-ligand interactions using NMR, the protein and ligand concentrations must necessarily be similar in magnitude to the K{sub D}, and nonlinear least squares analysis of chemical shift changes as a function of ligand concentration is employed to determine estimates for the parameters K{sub D} and the maximum chemical shift change ({Delta}{delta}{sub max}). During a typical NMR titration, the initial protein concentration, [P{sub 0}], is held nearly constant. For this condition, to determine the most accurate parameters for K{sub D} and {Delta}{delta}{sub max} from nonlinear least squares analyses requires initial protein concentrations that are {approx}0.5 Multiplication-Sign K{sub D}, and a maximum concentration for the ligand, or titrant, of {approx}10 Multiplication-Sign [P{sub 0}]. From a practical standpoint, these requirements are often difficult to achieve. Using Monte Carlo simulations, we demonstrate that co-variation of the ligand and protein concentrations during a titration leads to an increase in the precision of the fitted K{sub D} and {Delta}{delta}{sub max} values when [P{sub 0}] > K{sub D}. Importantly, judicious choice of protein and ligand concentrations for a given NMR titration, combined with nonlinear least squares analyses using two independent variables (ligand and protein concentrations) and two parameters (K{sub D} and {Delta}{delta}{sub max}) is a straightforward approach to increasing the accuracy of measured dissociation constants for 1:1 protein-ligand interactions.

Effect of ligand activation of peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) in human lung cancer cell lines

International Nuclear Information System (INIS)

He Pengfei; Borland, Michael G.; Zhu Bokai; Sharma, Arun K.; Amin, Shantu; El-Bayoumy, Karam; Gonzalez, Frank J.; Peters, Jeffrey M.

2008-01-01

There is compelling evidence that peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) mediates terminal differentiation and is associated with inhibition of cell growth. However, it was recently suggested that growth of two human lung cancer cell lines is enhanced by PPARβ/δ. The goal of the present study was to provide insight in resolving this controversy. Therefore, the effect of ligand activation of PPARβ/δ in A549 and H1838 human lung cancer cell lines was examined using two high affinity PPARβ/δ ligands. Ligand activation of PPARβ/δ caused up-regulation of a known PPARβ/δ target gene, angiopoietin-like 4 (Angptl4) but did not influence expression of phosphatase and tensin homolog (PTEN) or phosphorylation of protein kinase B (Akt), and did not affect cell growth. Results from this study demonstrate that two human lung cancer cell lines respond to ligand activation of PPARβ/δ by modulation of target gene expression (Angptl4), but fail to exhibit significant modulation of cell proliferation

Nanoparticles of novel organotin(IV) complexes bearing phosphoric triamide ligands

Science.gov (United States)

Asadi, Ebadullah; Tavasolinasab, Vahid; Gholivand, Khodayar

2013-01-01

Summary Four novel organotin(IV) complexes containing phosphoric triamide ligands were synthesized and characterized by multinuclear (1H, 31P, 13C) NMR, infrared, ultraviolet and fluorescence spectroscopy as well as elemental analysis. The 1H NMR spectra of complexes 1–4 proved that the Sn atoms adopt octahedral configurations. The nanoparticles of the complexes were also prepared by ultrasonication, and their SEM micrographs indicated identical spherical morphologies with particles sizes about 20–25 nm. The fluorescence spectra exhibited blue shifts for the maximum wavelength of emission upon complexation. PMID:23504649

Pentameric ligand-gated ion channels exhibit distinct transmembrane domain archetypes for folding/expression and function.

Science.gov (United States)

Therien, J P Daniel; Baenziger, John E

2017-03-27

Although transmembrane helix-helix interactions must be strong enough to drive folding, they must still permit the inter-helix movements associated with conformational change. Interactions between the outermost M4 and adjacent M1 and M3 α-helices of pentameric ligand-gated ion channels have been implicated in folding and function. Here, we evaluate the role of different physical interactions at this interface in the function of two prokaryotic homologs, GLIC and ELIC. Strikingly, disruption of most interactions in GLIC lead to either a reduction or a complete loss of expression and/or function, while analogous disruptions in ELIC often lead to gains in function. Structural comparisons suggest that GLIC and ELIC represent distinct transmembrane domain archetypes. One archetype, exemplified by GLIC, the glycine and GABA receptors and the glutamate activated chloride channel, has extensive aromatic contacts that govern M4-M1/M3 interactions and that are essential for expression and function. The other archetype, exemplified by ELIC and both the nicotinic acetylcholine and serotonin receptors, has relatively few aromatic contacts that are detrimental to function. These archetypes likely have evolved different mechanisms to balance the need for strong M4 "binding" to M1/M3 to promote folding/expression, and the need for weaker interactions that allow for greater conformational flexibility.

Macrocyclic G-quadruplex ligands

DEFF Research Database (Denmark)

Nielsen, M C; Ulven, Trond

2010-01-01

are macrocyclic structures which have been modeled after the natural product telomestatin or from porphyrin-based ligands discovered in the late 1990s. These two structural classes of G-quadruplex ligands are reviewed here with special attention to selectivity and structure-activity relationships, and with focus...

IsoCleft Finder – a web-based tool for the detection and analysis of protein binding-site geometric and chemical similarities [v2; ref status: indexed, http://f1000r.es/13y

Directory of Open Access Journals (Sweden)

Natalja Kurbatova

2013-05-01

Full Text Available IsoCleft Finder is a web-based tool for the detection of local geometric and chemical similarities between potential small-molecule binding cavities and a non-redundant dataset of ligand-bound known small-molecule binding-sites. The non-redundant dataset developed as part of this study is composed of 7339 entries representing unique Pfam/PDB-ligand (hetero group code combinations with known levels of cognate ligand similarity. The query cavity can be uploaded by the user or detected automatically by the system using existing PDB entries as well as user-provided structures in PDB format. In all cases, the user can refine the definition of the cavity interactively via a browser-based Jmol 3D molecular visualization interface. Furthermore, users can restrict the search to a subset of the dataset using a cognate-similarity threshold. Local structural similarities are detected using the IsoCleft software and ranked according to two criteria (number of atoms in common and Tanimoto score of local structural similarity and the associated Z-score and p-value measures of statistical significance. The results, including predicted ligands, target proteins, similarity scores, number of atoms in common, etc., are shown in a powerful interactive graphical interface. This interface permits the visualization of target ligands superimposed on the query cavity and additionally provides a table of pairwise ligand topological similarities. Similarities between top scoring ligands serve as an additional tool to judge the quality of the results obtained. We present several examples where IsoCleft Finder provides useful functional information. IsoCleft Finder results are complementary to existing approaches for the prediction of protein function from structure, rational drug design and x-ray crystallography. IsoCleft Finder can be found at: http://bcb.med.usherbrooke.ca/isocleftfinder.

A single-ligand ultra-microporous MOF for precombustion CO2 capture and hydrogen purification.

Science.gov (United States)

Nandi, Shyamapada; De Luna, Phil; Daff, Thomas D; Rother, Jens; Liu, Ming; Buchanan, William; Hawari, Ayman I; Woo, Tom K; Vaidhyanathan, Ramanathan

2015-12-01

Metal organic frameworks (MOFs) built from a single small ligand typically have high stability, are rigid, and have syntheses that are often simple and easily scalable. However, they are normally ultra-microporous and do not have large surface areas amenable to gas separation applications. We report an ultra-microporous (3.5 and 4.8 Å pores) Ni-(4-pyridylcarboxylate)2 with a cubic framework that exhibits exceptionally high CO2/H2 selectivities (285 for 20:80 and 230 for 40:60 mixtures at 10 bar, 40°C) and working capacities (3.95 mmol/g), making it suitable for hydrogen purification under typical precombustion CO2 capture conditions (1- to 10-bar pressure swing). It exhibits facile CO2 adsorption-desorption cycling and has CO2 self-diffusivities of ~3 × 10(-9) m(2)/s, which is two orders higher than that of zeolite 13X and comparable to other top-performing MOFs for this application. Simulations reveal a high density of binding sites that allow for favorable CO2-CO2 interactions and large cooperative binding energies. Ultra-micropores generated by a small ligand ensures hydrolytic, hydrostatic stabilities, shelf life, and stability toward humid gas streams.

Synthesis, structure and luminescence properties of zinc (II) complexes with terpyridine derivatives as ligands

International Nuclear Information System (INIS)

Chen Xuegang; Zhou Quanguo; Cheng Yanxiang; Geng Yanhou; Ma Dongge; Xie Zhiyuan; Wang Lixiang

2007-01-01

Five zinc (II) complexes (1-5) with 4'-phenyl-2,2':6',2''-terpyridine (ptpy) derivatives as ligands have been synthesized and fully characterized. The para-position of phenyl in ptpy is substituted by the group (R), i.e. tert-butyl (t-Bu), hexyloxy (OHex), carbazole-9-yl (Cz), naphthalen-1-yl-phenyl-amine-N-yl (NPA) and diphenyl amine-N-yl (DPA), with different electron-donating ability. With increasing donor ability of the R, the emission color of the complexes in film was modulated from violet (392 nm) to reddish orange (604 nm). The photoexcited luminescence exhibits significant solvatochromism because the emission of the complexes involves the intra-ligand charge transfer (ILCT) excited state. The electrochemical investigations show that the complexes with stronger electro-donating substituent have lower oxidation potential and then higher HOMO level. The electroluminescence (EL) properties of these zinc (II) complexes were studied with the device structure of ITO/PEDOT/Zn (II) complex: PBD:PMMA/BCP/AlQ/LiF/Al. Complexes 3, 4 and 5 exhibit EL wavelength at 552, 600 and 609 nm with maximum current efficiency of 5.28, 2.83 and 2.00 cd/A, respectively

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

Science.gov (United States)

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

Identification of ligands for DAF-12 that govern dauer formation and reproduction in C. elegans.

Science.gov (United States)

Motola, Daniel L; Cummins, Carolyn L; Rottiers, Veerle; Sharma, Kamalesh K; Li, Tingting; Li, Yong; Suino-Powell, Kelly; Xu, H Eric; Auchus, Richard J; Antebi, Adam; Mangelsdorf, David J

2006-03-24

In response to environmental and dietary cues, the C. elegans orphan nuclear receptor, DAF-12, regulates dauer diapause, reproductive development, fat metabolism, and life span. Despite strong evidence for hormonal control, the identification of the DAF-12 ligand has remained elusive. In this work, we identified two distinct 3-keto-cholestenoic acid metabolites of DAF-9, a cytochrome P450 involved in hormone production, that function as ligands for DAF-12. At nanomolar concentrations, these steroidal ligands (called dafachronic acids) bind and transactivate DAF-12 and rescue the hormone deficiency of daf-9 mutants. Interestingly, DAF-9 has a biochemical activity similar to mammalian CYP27A1 catalyzing addition of a terminal acid to the side chain of sterol metabolites. Together, these results define the first steroid hormones in nematodes as ligands for an invertebrate orphan nuclear receptor and demonstrate that steroidal regulation of reproduction, from biology to molecular mechanism, is conserved from worms to humans.

Novel photoaffinity ligands for the GA-receptor

International Nuclear Information System (INIS)

Suttle, J.C.; Hultstrand, J.F.; Tanaka, F.S.

1990-01-01

Previous studies from this laboratory have shown that certain N-substituted phthalimides (NSPs) exhibit GA-like activity in a range of specific bioassays and that bioactive NSPs compete with [ 3 H]-GA 4 for soluble binding sites in cucumber homogenates. As such, these compounds may prove useful in the purification and characterization of GA receptor proteins. To this end, five azido-NSPs have been synthesized and are currently being screened for biological activity and photochemical stability. Three azido-NSPs elicit α-amylase production in barley half-seeds and stimulate tissue elongation in d 5 maize, lettuce, sunflower, and soybean. Further evaluations are in progress and these data as well as the utility of these compounds as photo-affinity ligands will be discussed

Contribution of Adsorbed Protein Films to Nanoscopic Vibrations Exhibited by Bacteria Adhering through Ligand-Receptor Bonds

NARCIS (Netherlands)

Song, Lei; Sjollema, Jelmer; Norde, Willem; Busscher, Henk J.; van der Mei, Henny C.

2015-01-01

Bacteria adhering to surfaces exhibit nanoscopic vibrations that depend on the viscoelasticity of the bond. The quantification of the nanoscopic vibrations of bacteria adhering to surfaces provides new opportunities to better understand the properties of the bond through which bacteria adhere and

Ligand-mediated negative regulation of a chimeric transmembrane receptor tyrosine phosphatase

DEFF Research Database (Denmark)

Desai, D M; Sap, J; Schlessinger, J

1993-01-01

CD45, a transmembrane protein tyrosine phosphatase (PTPase), is required for TCR signaling. Multiple CD45 isoforms, differing in the extracellular domain, are expressed in a tissue- and activation-specific manner, suggesting an important function for this domain. We report that a chimeric protein...... that ligand-mediated regulation of receptor-PTPases may have mechanistic similarities with receptor tyrosine kinases....

Specific ability of sulfur-ligands on removal of 203Hg-labeled organomercury from hemoglobin in comparison with nitrogen-ligands

International Nuclear Information System (INIS)

Hojo, Yasuji; Sugiura, Yukio; Tanaka, Hisashi

1975-01-01

Removal of 203 Hg-labeled organomercurials, bound to sulfhydryl groups of hemoglobin, by various chelating agents was investigated by the use of equilibrium dialysis. Organomercurials employed were chlormerodrin, methylmercury, ethylmercury and phenylmercury compounds. Higher and more specific effects of the sulfur-ligands, such as penicillamine and glutathione, on removal of organomercurial were found as compared with those of the nitrogen-ligands such as EDTA, glycine and polymethylenediamines. Linear correlation was observed between the degree of organomercury elimination from hemoglobin and the stability constant (log K 1 ) of 1:1 organomercury complex in both the sulfur- and nitrogen-ligand systems and at the same value of log K 1 , the elimination-effect of sulfur-ligands was extremely greater than that of the nitrogen-ligands. The relationship between the average percentage of removal and the Taft's polar substituent constant of organic moiety of the metal was also linear among the organomercury compounds other than chlormerodrin. The average removal percentage by sulfur-ligands increased in the order, ethylmercury>methylmercury>phenylmercury, while that of the nitrogen-ligands was not different among the organomercurials investigated. In addition, direct ligand-exchange reaction between hemoglobin-SH and the ligand coordinating-atom (S or N) against organomercurials rather than Ssub(N2) reaction via the ternary complex, hemoglobin-S-RHg-ligand, is postulated. (auth.)

Nonlinear absorbing cationic iridium(III) complexes bearing benzothiazolylfluorene motif on the bipyridine (N∧N) ligand: synthesis, photophysics and reverse saturable absorption.

Science.gov (United States)

Li, Yuhao; Dandu, Naveen; Liu, Rui; Hu, Lei; Kilina, Svetlana; Sun, Wenfang

2013-07-24

Four new heteroleptic cationic Ir(III) complexes bearing benzothiazolylfluorene motif on the bipyridine (N∧N) (1 and 2) and phenylpyridine (C∧N) (3 and 4) ligands are synthesized and characterized. The influence of the position of the substituent and the extent of π-conjugation on the photophysics of these complexes is systematically investigated by spectroscopic methods and simulated by time-dependent density functional theory (TDDFT). The complexes exhibit ligand-centered (1)π,π* transitions with admixtures of (1)ILCT (π(benzothiazolylfluorene) → π*(bpy)) and (1)MLCT (metal-to-ligand charge transfer) characters below 475 nm, and very weak (1,3)MLCT and (1,3)LLCT (ligand-to-ligand charge transfer) transitions above 475 nm. The emission of these complexes at room temperature in CH2Cl2 solutions is ascribed to be predominantly from the (3)MLCT/(3)LLCT states for 1 and from the (3)π,π* state for 2, while the emitting state of 3 and 4 are assigned to be an admixture of (3)MLCT, (3)LLCT, and (3)π,π* characters. The variations of the photophysical properties of 1-4 are attributed to different degrees of π-conjugation in the bipyridine and phenylpyridine ligands induced by different positions of the benzothiazolylfluorenyl substituents on the bipyridine ligand and different extents of π-conjugation in the phenylpyridine ligands, which alters the energy and lifetime of the lowest singlet and triplet excited states. 1-4 all possess broadband transient absorption (TA) upon nanosecond laser excitation, which extends from the visible to the NIR region. Therefore, 1-4 all exhibit strong reverse saturable absorption (RSA) at 532 nm for ns laser pulses. However, the TA of complexes 1, 2, and 3 are much stronger than that of 4. This feature, combined with the difference in ground-state absorption and triplet excited-state quantum yield, result in the difference in RSA strength, which follows this trend: 1 ≈ 2 ≈ 3 > 4. Therefore, complexes 1-3 are strong

ReFlexIn: a flexible receptor protein-ligand docking scheme evaluated on HIV-1 protease.

Directory of Open Access Journals (Sweden)

Simon Leis

Full Text Available For many targets of pharmaceutical importance conformational changes of the receptor protein are relevant during the ligand binding process. A new docking approach, ReFlexIn (Receptor Flexibility by Interpolation, that combines receptor flexibility with the computationally efficient potential grid representation of receptor molecules has been evaluated on the retroviral HIV-1 (Human Immunodeficiency Virus 1 protease system. An approximate inclusion of receptor flexibility is achieved by using interpolation between grid representations of individual receptor conformations. For the retroviral protease the method was tested on an ensemble of protease structures crystallized in the presence of different ligands and on a set of structures obtained from morphing between the unbound and a ligand-bound protease structure. Docking was performed on ligands known to bind to the protease and several non-binders. For the binders the ReFlexIn method yielded in almost all cases ligand placements in similar or closer agreement with experiment than docking to any of the ensemble members without degrading the discrimination with respect to non-binders. The improved docking performance compared to docking to rigid receptors allows for systematic virtual screening applications at very small additional computational cost.

Immobilisation of ligands by radio-derivatized polymers; Immobilisering av ligander med radioderiverte polymerer

Energy Technology Data Exchange (ETDEWEB)

Varga, J.M.; Fritsch, P.

1995-01-30

The invention relates to radio-derivatized polymers and a method of producing them by contacting non-polymerizable conjugands with radiolysable polymers in the presence of irradiation. The resulting radio-derivatized polymers can be further linked with ligand of organic or inorganic nature to immobilize such ligands. 2 figs., 5 tabs.

Stable Toll-Like Receptor 10 Knockdown in THP-1 Cells Reduces TLR-Ligand-Induced Proinflammatory Cytokine Expression

Directory of Open Access Journals (Sweden)

Hai Van Le

2016-06-01

Full Text Available Toll-like receptor 10 (TLR10 is the only orphan receptor whose natural ligand and function are unknown among the 10 human TLRs. In this study, to test whether TLR10 recognizes some known TLR ligands, we established a stable TLR10 knockdown human monocytic cell line THP-1 using TLR10 short hairpin RNA lentiviral particle and puromycin selection. Among 60 TLR10 knockdown clones that were derived from each single transduced cell, six clones were randomly selected, and then one of those clones, named E7, was chosen for the functional study. E7 exhibited approximately 50% inhibition of TLR10 mRNA and protein expression. Of all the TLRs, only the expression of TLR10 changed significantly in this cell line. Additionally, phorbol 12-myristate 13-acetate-induced macrophage differentiation of TLR10 knockdown cells was not affected in the knockdown cells. When exposed to TLR ligands, such as synthetic diacylated lipoprotein (FSL-1, lipopolysaccharide (LPS, and flagellin, significant induction of proinflammatory cytokine gene expression including Interleukin-8 (IL-8, Interleukin-1 beta (IL-1β, Tumor necrosis factor-alpha (TNF-α and Chemokine (C–C Motif Ligand 20 (CCL20 expression, was found in the control THP-1 cells, whereas the TLR10 knockdown cells exhibited a significant reduction in the expression of IL-8, IL-1β, and CCL20. TNF-α was the only cytokine for which the expression did not decrease in the TLR10 knockdown cells from that measured in the control cells. Analysis of putative binding sites for transcription factors using a binding-site-prediction program revealed that the TNF-α promoter does not have putative binding sites for AP-1 or c-Jun, comprising a major transcription factor along with NF-κB for TLR signaling. Our results suggest that TLR10 is involved in the recognition of FSL-1, LPS, and flagellin and TLR-ligand-induced expression of TNF-α does not depend on TLR10.

Stable Toll-Like Receptor 10 Knockdown in THP-1 Cells Reduces TLR-Ligand-Induced Proinflammatory Cytokine Expression.

Science.gov (United States)

Le, Hai Van; Kim, Jae Young

2016-06-01

Toll-like receptor 10 (TLR10) is the only orphan receptor whose natural ligand and function are unknown among the 10 human TLRs. In this study, to test whether TLR10 recognizes some known TLR ligands, we established a stable TLR10 knockdown human monocytic cell line THP-1 using TLR10 short hairpin RNA lentiviral particle and puromycin selection. Among 60 TLR10 knockdown clones that were derived from each single transduced cell, six clones were randomly selected, and then one of those clones, named E7, was chosen for the functional study. E7 exhibited approximately 50% inhibition of TLR10 mRNA and protein expression. Of all the TLRs, only the expression of TLR10 changed significantly in this cell line. Additionally, phorbol 12-myristate 13-acetate-induced macrophage differentiation of TLR10 knockdown cells was not affected in the knockdown cells. When exposed to TLR ligands, such as synthetic diacylated lipoprotein (FSL-1), lipopolysaccharide (LPS), and flagellin, significant induction of proinflammatory cytokine gene expression including Interleukin-8 (IL-8), Interleukin-1 beta (IL-1β), Tumor necrosis factor-alpha (TNF-α) and Chemokine (C-C Motif) Ligand 20 (CCL20) expression, was found in the control THP-1 cells, whereas the TLR10 knockdown cells exhibited a significant reduction in the expression of IL-8, IL-1β, and CCL20. TNF-α was the only cytokine for which the expression did not decrease in the TLR10 knockdown cells from that measured in the control cells. Analysis of putative binding sites for transcription factors using a binding-site-prediction program revealed that the TNF-α promoter does not have putative binding sites for AP-1 or c-Jun, comprising a major transcription factor along with NF-κB for TLR signaling. Our results suggest that TLR10 is involved in the recognition of FSL-1, LPS, and flagellin and TLR-ligand-induced expression of TNF-α does not depend on TLR10.

Cyclometalated Ruthenium(II) Anthraquinone Complexes Exhibit Strong Anticancer Activity in Hypoxic Tumor Cells.

Science.gov (United States)

Zeng, Leli; Chen, Yu; Huang, Huaiyi; Wang, Jinquan; Zhao, Donglei; Ji, Liangnian; Chao, Hui

2015-10-19

Hypoxia is the critical feature of the tumor microenvironment that is known to lead to resistance to many chemotherapeutic drugs. Six novel ruthenium(II) anthraquinone complexes were designed and synthesized; they exhibit similar or superior cytotoxicity compared to cisplatin in hypoxic HeLa, A549, and multidrug-resistant (A549R) tumor cell lines. Their anticancer activities are related to their lipophilicity and cellular uptake; therefore, these physicochemical properties of the complexes can be changed by modifying the ligands to obtain better anticancer candidates. Complex 1, the most potent member of the series, is highly active against hypoxic HeLa cancer cells (IC50 =0.53 μM). This complex likely has 46-fold better activity than cisplatin (IC50 =24.62 μM) in HeLa cells. This complex tends to accumulate in the mitochondria and the nucleus of hypoxic HeLa cells. Further mechanistic studies show that complex 1 induced cell apoptosis during hypoxia through multiple pathways, including those of DNA damage, mitochondrial dysfunction, and the inhibition of DNA replication and HIF-1α expression, making it an outstanding candidate for further in vivo studies. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Characterization of ligand binding to melanocortin 4 receptors using fluorescent peptides with improved kinetic properties.

Science.gov (United States)

Link, Reet; Veiksina, Santa; Rinken, Ago; Kopanchuk, Sergei

2017-03-15

Melanocortin 4 (MC 4 ) receptors are important drug targets as they regulate energy homeostasis, eating behaviour and sexual functions. The ligand binding process to these G protein-coupled receptors is subject to considerable complexity. Different steps in the complex dynamic regulation can be characterized by ligand binding kinetics. Optimization of these kinetic parameters in terms of on-rate and residence time can increase the rapid onset of drug action and reduce off-target effects. Fluorescence anisotropy (FA) is one of the homogeneous fluorescence-based assays that enable continuous online monitoring of ligand binding kinetics. FA has been implemented for the kinetic study of melanocortin MC 4 receptors expressed on budded baculoviruses. However, the slow dissociation of the fluorescently labelled peptide NDP-α-MSH does not enable reaching equilibrium nor enable more in-depth study of the binding mechanisms. To overcome this problem, two novel red-shifted fluorescent ligands were designed. These cyclized heptapeptide derivatives (UTBC101 and UTBC102) exhibited nanomolar affinity toward melanocortin MC 4 receptors but had relatively different kinetic properties. The dissociation half-lives of UTBC101 (τ 1/2 =160min) and UTBC102 (τ 1/2 =7min) were shorter compared to that what was previously reported for Cy3B-NDP-α-MSH (τ 1/2 =224min). The significantly shorter dissociation half-life of UTBC102 enables equilibrium in screening assays, whereas the higher affinity of UTBC101 helps to resolve a wider range of competitor potencies. These two ligands are suitable for further kinetic screening of novel melanocortin MC 4 receptor specific ligands and could complement each other in these studies. Copyright © 2017 Elsevier B.V. All rights reserved.

The chicken type III GnRH receptor homologue is predominantly expressed in the pituitary, and exhibits similar ligand selectivity to the type I receptor

Science.gov (United States)

Joseph, Nerine T; Morgan, Kevin; Sellar, Robin; McBride, Derek; Millar, Robert P; Dunn, Ian C

2009-01-01

Two GnRH isoforms (cGnRH-I and GnRH-II) and two GnRH receptor subtypes (cGnRH-R-I and cGnRH-R-III) occur in chickens. Differential roles for these molecules in regulating gonadotrophin secretion or other functions are unclear. To investigate this we cloned cGnRH-R-III from a broiler chicken and compared its structure, expression and pharmacological properties with cGnRH-R-I. The broiler cGnRH-R-III cDNA was 100% identical to the sequence reported in the red jungle fowl and white leghorn breed. Pituitary cGnRH-R-III mRNA was ∼1400-fold more abundant than cGnRH-R-I mRNA. Northern analysis indicated a single cGnRH-R-III transcript. A pronounced sex and age difference existed, with higher pituitary transcript levels in sexually mature females versus juvenile females. In contrast, higher expression levels occurred in juvenile males versus sexually mature males. Functional studies in COS-7 cells indicated that cGnRH-R-III has a higher binding affinity for GnRH-II than cGnRH-I (Kd: 0·57 vs 19·8 nM) with more potent stimulation of inositol phosphate production (ED50: 0·8 vs 4·38 nM). Similar results were found for cGnRH-R-I, (Kd: 0·51 vs 10·8 nM) and (ED50: 0·7 vs 2·8 nM). The initial rate of internalisation was faster for cGnRH-R-III than cGnRH-R-I (26 vs 15·8%/min). Effects of GnRH antagonists were compared at the two receptors. Antagonist #27 distinguished between cGnRH-R-I and cGnRH-R-III (IC50: 2·3 vs 351 nM). These results suggest that cGnRH-R-III is probably the major mediator of pituitary gonadotroph function, that antagonist #27 may allow delineation of receptor subtype function in vitro and in vivo and that tissue-specific recruitment of cGnRH-R isoforms has occurred during evolution. PMID:19380456

Synthesis and luminescence properties of europium and terbium complexes with pyridine- or bipyridine-linked oligothiophene ligand

International Nuclear Information System (INIS)

Liu Ping; Huang Mingsheng; Pan Wanzhang; Zhang Yamin; Hu Jianhua; Deng Wenji

2006-01-01

With an aim to develop novel luminescence materials, europium and terbium complexes of 2,5-(2-thiophene)-pyridine (TPY) and 5,5'-bis(5-(2,2'-bithiophene))-2,2'-bipyridine (B2TBPY) were synthesized, and their luminescence properties studied. The complexes exhibit ligand-sensitized emission, which is typical of Eu(III) and Tb(III) ions

Structural, spectral and biological studies of binuclear tetradentate metal complexes of N 3O Schiff base ligand synthesized from 4,6-diacetylresorcinol and diethylenetriamine

Science.gov (United States)

Emara, Adel A. A.

2010-09-01

The binuclear Schiff base, H 2L, ligand was synthesized by reaction of 4,6-diacetylresorcinol with diethylenetriamine in the molar ratio 1:2. The coordination behavior of the H 2L towards Cu(II), Ni(II), Co(II), Zn(II), Fe(III), Cr(III), VO(IV) and UO 2(VI) ions has been investigated. The elemental analyses, magnetic moments, thermal studies and IR, electronic, 1H NMR, ESR and mass spectra were used to characterize the isolated ligand and its metal complexes. The ligand acts as dibasic with two N 3O-tetradentate sites and can coordinate with two metal ions to form binuclear complexes. The bonding sites are the nitrogen atoms of the azomethine and amine groups and the oxygen atoms of the phenolic groups. The metal complexes exhibit either square planar, tetrahedral, square pyramid or octahedral structures. The Schiff base ligand and its metal complexes were tested against four pathogenic bacteria ( Staphylococcus aureus and Streptococcus pyogenes) as Gram-positive bacteria, and ( Pseudomonas fluorescens and Pseudomonas phaseolicola) as Gram-negative bacteria and two pathogenic fungi ( Fusarium oxysporum and Aspergillus fumigatus) to assess their antimicrobial properties. Most of the complexes exhibit mild antibacterial and antifungal activities against these organisms.

Reactivity of halide and pseudohalide ligands

International Nuclear Information System (INIS)

Kukushkin, Yu.N.

1987-01-01

Reactivity of halide and pseudohalide (cyanide, azide, thiocyanate, cyanate) ligands tending to form bridge bonds in transition metal (Re, Mo, W) complexes is considered. Complexes where transition metal salts are ligands of other, complex-forming ion, are described. Transformation of innerspheric pseudohalide ligands is an important way of directed synthesis of these metal coordination compounds

Synthesis, characterization and luminescent properties of lanthanide complexes with an unsymmetrical tripodal ligand

Energy Technology Data Exchange (ETDEWEB)

Yan Zhenzhong [State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000 (China); Tang Yu [State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000 (China)], E-mail: tangyu@lzu.edu.cn; Liu Weisheng; Tan Minyu [State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000 (China)

2008-09-15

Solid complexes of lanthanide nitrates with a new unsymmetrical tripodal ligand, bis[(2'-benzylaminoformyl)phenoxyl)ethyl](ethyl)amine (L) have been synthesized and characterized by elemental analysis, infrared spectra and molar conductivity measurements. At the same time, the luminescent properties of the Sm(III), Eu(III), Tb(III) and Dy(III) nitrate complexes in solid state were also investigated. Under the excitation of UV light, these complexes exhibited characteristic emission of central metal ions.

Metal-ligand cooperative activation of nitriles by a ruthenium complex with a de-aromatized PNN pincer ligand

NARCIS (Netherlands)

Eijsink, Linda E; Perdriau, Sébastien C P; de Vries, Johannes G; Otten, Edwin

2016-01-01

The pincer complex (PNN)RuH(CO), with a de-aromatized pyridine in the ligand backbone, is shown to react with nitriles in a metal-ligand cooperative manner. This leads to the formation of a series of complexes with new Ru-N(nitrile) and C(ligand)-C(nitrile) bonds. The initial nitrile cycloaddition

Improving binding mode and binding affinity predictions of docking by ligand-based search of protein conformations: evaluation in D3R grand challenge 2015

Science.gov (United States)

Xu, Xianjin; Yan, Chengfei; Zou, Xiaoqin

2017-08-01

The growing number of protein-ligand complex structures, particularly the structures of proteins co-bound with different ligands, in the Protein Data Bank helps us tackle two major challenges in molecular docking studies: the protein flexibility and the scoring function. Here, we introduced a systematic strategy by using the information embedded in the known protein-ligand complex structures to improve both binding mode and binding affinity predictions. Specifically, a ligand similarity calculation method was employed to search a receptor structure with a bound ligand sharing high similarity with the query ligand for the docking use. The strategy was applied to the two datasets (HSP90 and MAP4K4) in recent D3R Grand Challenge 2015. In addition, for the HSP90 dataset, a system-specific scoring function (ITScore2_hsp90) was generated by recalibrating our statistical potential-based scoring function (ITScore2) using the known protein-ligand complex structures and the statistical mechanics-based iterative method. For the HSP90 dataset, better performances were achieved for both binding mode and binding affinity predictions comparing with the original ITScore2 and with ensemble docking. For the MAP4K4 dataset, although there were only eight known protein-ligand complex structures, our docking strategy achieved a comparable performance with ensemble docking. Our method for receptor conformational selection and iterative method for the development of system-specific statistical potential-based scoring functions can be easily applied to other protein targets that have a number of protein-ligand complex structures available to improve predictions on binding.

Analysis of protein-protein docking decoys using interaction fingerprints: application to the reconstruction of CaM-ligand complexes

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Uchikoga Nobuyuki

2010-05-01

Full Text Available Abstract Background Protein-protein docking for proteins with large conformational changes was analyzed by using interaction fingerprints, one of the scales for measuring similarities among complex structures, utilized especially for searching near-native protein-ligand or protein-protein complex structures. Here, we have proposed a combined method for analyzing protein-protein docking by taking large conformational changes into consideration. This combined method consists of ensemble soft docking with multiple protein structures, refinement of complexes, and cluster analysis using interaction fingerprints and energy profiles. Results To test for the applicability of this combined method, various CaM-ligand complexes were reconstructed from the NMR structures of unbound CaM. For the purpose of reconstruction, we used three known CaM-ligands, namely, the CaM-binding peptides of cyclic nucleotide gateway (CNG, CaM kinase kinase (CaMKK and the plasma membrane Ca2+ ATPase pump (PMCA, and thirty-one structurally diverse CaM conformations. For each ligand, 62000 CaM-ligand complexes were generated in the docking step and the relationship between their energy profiles and structural similarities to the native complex were analyzed using interaction fingerprint and RMSD. Near-native clusters were obtained in the case of CNG and CaMKK. Conclusions The interaction fingerprint method discriminated near-native structures better than the RMSD method in cluster analysis. We showed that a combined method that includes the interaction fingerprint is very useful for protein-protein docking analysis of certain cases.

Synthesis, crystal structure, fluorescence and electrochemical studies of a new tridentate Schiff base ligand and its nickel(II) and palladium(II) complexes

Science.gov (United States)

Shafaatian, Bita; Soleymanpour, Ahmad; Kholghi Oskouei, Nasim; Notash, Behrouz; Rezvani, Seyyed Ahmad

2014-07-01

A new unsymmetrical tridentate Schiff base ligand was derived from the 1:1 M condensation of ortho-vanillin with 2-mercaptoethylamine. Nickel and palladium complexes were obtained by the reaction of the tridentate Schiff base ligand with nickel(II) acetate tetrahydrate and palladium(II) acetate in 2:1 M ratio. In nickel and palladium complexes the ligand was coordinated to metals via the imine N and enolic O atoms. The S groups of Schiff bases were not coordinated to the metals and S-S coupling was occured. The complexes have been found to possess 1:2 Metal:Ligand stoichiometry and the molar conductance data revealed that the metal complexes were non-electrolytes. The complexes exhibited octahedral coordination geometry. The emission spectra of the ligand and its complexes were studied in methanol. Electrochemical properties of the ligand and its metal complexes were investigated in the CH3CN solvent at the 100 mV s-1 scan rate. The ligand and metal complexes showed both reversible and quasi-reversible processes at this scan rate. The Schiff base and its complexes have been characterized by IR, 1H NMR, UV/Vis, elemental analyses and conductometry. The crystal structure of nickel complex has been determined by single crystal X-ray diffraction.

Towards ligand docking including explicit interface water molecules.

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Gordon Lemmon

Full Text Available Small molecule docking predicts the interaction of a small molecule ligand with a protein at atomic-detail accuracy including position and conformation the ligand but also conformational changes of the protein upon ligand binding. While successful in the majority of cases, docking algorithms including RosettaLigand fail in some cases to predict the correct protein/ligand complex structure. In this study we show that simultaneous docking of explicit interface water molecules greatly improves Rosetta's ability to distinguish correct from incorrect ligand poses. This result holds true for both protein-centric water docking wherein waters are located relative to the protein binding site and ligand-centric water docking wherein waters move with the ligand during docking. Protein-centric docking is used to model 99 HIV-1 protease/protease inhibitor structures. We find protease inhibitor placement improving at a ratio of 9:1 when one critical interface water molecule is included in the docking simulation. Ligand-centric docking is applied to 341 structures from the CSAR benchmark of diverse protein/ligand complexes [1]. Across this diverse dataset we see up to 56% recovery of failed docking studies, when waters are included in the docking simulation.

Syntheses, structures, and magnetic properties of cobalt(II) and nickel(II) coordination polymers based on a V-shaped ligand

Energy Technology Data Exchange (ETDEWEB)

Yao, Shuang [State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun 130022 (China); Yi, Fei-Yan [The School of Materials Science and Chemical Engineering, Ningbo University, Ningbo 315211 (China); Li, Guanghua [State Key Laboratory of Inorganic Synthesis & Preparative Chemistry, College of Chemistry, Jilin University, Changchun 130012 (China); Yu, Yang [State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun 130022 (China); Wang, Jing-yuan, E-mail: jywang@mail.ipc.ac.cn [Technical Institute of Physics and Chemistry of the Chinese Academy of Sciences, 29 Zhongguancun East Road, Haidian District, Beijing 100190 (China); Liu, Dan, E-mail: liudan2007@ciac.ac.cn [State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun 130022 (China); Song, Shu-Yan [State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun 130022 (China)

2017-06-15

Two coordination polymers [Co{sub 2}(TA)(4,4′-bipy){sub 2}(H{sub 2}O){sub 2}]·H{sub 2}O (1) and [Ni{sub 2}(TA)(4,4′-bipy){sub 2}(H{sub 2}O){sub 4}]·3H{sub 2}O (2) were prepared by hydrothermal reactions of MCl{sub 2}·6H{sub 2}O (M = Co, Ni) with a V-shaped ligand TDPA (3,3′,4,4′-thiodiphthalic anhydride) and a I-shaped N-donor co-ligand (4,4′-bipy). They were characterized by elemental analyses, thermogravinetric analyses, and magnetic behavior. As is expected, TDPA hydrolyzes into the corresponding tetra-carboxylate acid H{sub 4}TA (3,3′,4,4′-thiodiphthalic acid) during the reactions. Co{sub 2} dimer and Ni mononuclear center are connected into two-dimensional (2D) layers by H{sub 4}TA and 4,4′-bipy bridge in 1 and 2, respectively. The most amazing feature is that 1 and 2 exhibit interesting spin-canting metamagnetism and weak ferromagnetic behavior, respectively, with the critical Néel temperature of T{sub N} =4 K for 1 and T{sub N} =13 K for 2, based on variable temperature magnetic susceptibility measurements. In low mono- or dinuclear metal system, such magnetic behaviors have rare been observed. Furthermore, complex 1 will be a potential metamagnet material. - Graphical abstract: Two Co(II) and Ni(II) coordination polymers were synthesized by hydrothermal reactions from a V-shape ligand (3,3′,4,4′-thiodiphthalic anhydride) and a I-shape ligand (4,4′-bipy), which were characterized by single crystal X-ray diffraction, elemental analyses, thermogravinetric analyses, and magnetic behavior, and exhibit interesting spin-canting metamagnetism and weak ferromagnetic behavior, respectively. - Highlights: • Two Co(II) and Ni(II) coordination polymers were successfully synthesized. • Co(II) coordination polymer shows an interesting spin-canting metamagnetism. • Ni(II) coordination polymer exhibits a weak ferromagnetic behavior.

Ligand-specific conformational changes in the alpha1 glycine receptor ligand-binding domain

DEFF Research Database (Denmark)

Pless, Stephan Alexander; Lynch, Joseph W

2009-01-01

, and by the antagonist, strychnine. Voltage-clamp fluorometry involves labeling introduced cysteines with environmentally sensitive fluorophores and inferring structural rearrangements from ligand-induced fluorescence changes. In the inner beta-sheet, we labeled residues in loop 2 and in binding domain loops D and E....... At each position, strychnine and glycine induced distinct maximal fluorescence responses. The pre-M1 domain responded similarly; at each of four labeled positions glycine produced a strong fluorescence signal, whereas strychnine did not. This suggests that glycine induces conformational changes...... in the inner beta-sheet and pre-M1 domain that may be important for activation, desensitization, or both. In contrast, most labeled residues in loops C and F yielded fluorescence changes identical in magnitude for glycine and strychnine. A notable exception was H201C in loop C. This labeled residue responded...

Dispatched and Scube Mediate the Efficient Secretion of the Cholesterol-Modified Hedgehog Ligand

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Hanna Tukachinsky

2012-08-01

Full Text Available The Hedgehog (Hh signaling pathway plays critical roles in metazoan development and in cancer. How the Hh ligand is secreted and spreads to distant cells is unclear, given its covalent modification with a hydrophobic cholesterol molecule, which makes it stick to membranes. We demonstrate that Hh ligand secretion from vertebrate cells is accomplished via two distinct and synergistic cholesterol-dependent binding events, mediated by two proteins that are essential for vertebrate Hh signaling: the membrane protein Dispatched (Disp and a member of the Scube family of secreted proteins. Cholesterol modification is sufficient for a heterologous protein to interact with Scube and to be secreted in a Scube-dependent manner. Disp and Scube recognize different structural aspects of cholesterol similarly to how Niemann-Pick disease proteins 1 and 2 interact with cholesterol, suggesting a hand-off mechanism for transferring Hh from Disp to Scube. Thus, Disp and Scube cooperate to dramatically enhance the secretion and solubility of the cholesterol-modified Hh ligand.

Fringe proteins modulate Notch-ligand cis and trans interactions to specify signaling states.

Science.gov (United States)

LeBon, Lauren; Lee, Tom V; Sprinzak, David; Jafar-Nejad, Hamed; Elowitz, Michael B

2014-09-25

The Notch signaling pathway consists of multiple types of receptors and ligands, whose interactions can be tuned by Fringe glycosyltransferases. A major challenge is to determine how these components control the specificity and directionality of Notch signaling in developmental contexts. Here, we analyzed same-cell (cis) Notch-ligand interactions for Notch1, Dll1, and Jag1, and their dependence on Fringe protein expression in mammalian cells. We found that Dll1 and Jag1 can cis-inhibit Notch1, and Fringe proteins modulate these interactions in a way that parallels their effects on trans interactions. Fringe similarly modulated Notch-ligand cis interactions during Drosophila development. Based on these and previously identified interactions, we show how the design of the Notch signaling pathway leads to a restricted repertoire of signaling states that promote heterotypic signaling between distinct cell types, providing insight into the design principles of the Notch signaling system, and the specific developmental process of Drosophila dorsal-ventral boundary formation.

A 3D porous zinc MOF constructed from a flexible tripodal ligand: Synthesis, structure, and photoluminescence property

International Nuclear Information System (INIS)

Wen Lili; Wang Dong'e; Wang Chenggang; Wang Feng; Li Dongfeng; Deng Kejian

2009-01-01

A new metal-organic framework, [Zn 5 (trencba) 2 (OH) 2 Cl 2 .4H 2 O] (1) [H 3 trencba=N,N,N',N',N'',N''-tris[(4-carboxylate-2-yl)methyl]-tris (2-aminoethyl)amine], constructed from a flexible tripodal ligand based on C 3 symmetric tris(2-aminoethyl)amine, has been synthesized hydrothermally and characterized by elemental analysis, IR, TG, XRD and single-crystal X-ray diffraction analysis. Compound 1 contains an unprecedented linear penta-nuclear zinc cluster fragment. Each ligand links four penta-nuclear fragments, and every fragment links eight ligands to generate a three-dimensional non-interpenetrated porous framework. The uncoordinated water molecules were observed trapped in the void pores. Compound 1 represents the first example of (6,8)-connected 3D bi-nodal framework based on a single kind of organic ligand. The photoluminescence measurements showed that complex 1 exhibits relatively stronger blue emissions at room temperature than that of the ligand. - Graphical abstract: The MOF [Zn 5 (trencba) 2 (OH) 2 Cl 2 .4H 2 O] (H 3 trencba=N,N,N',N',N',N'-tris[(4-carboxylate-2-yl)methyl]-tris (2-aminoethyl)amine) reveals a (6,8)-connected bi-nodal three-dimensional porous framework with unprecedented penta-nuclear fragment, which appears to be a good candidate of hybrid inorganic-organic photoactive materials

Crystallization of bi-functional ligand protein complexes.

Science.gov (United States)

Antoni, Claudia; Vera, Laura; Devel, Laurent; Catalani, Maria Pia; Czarny, Bertrand; Cassar-Lajeunesse, Evelyn; Nuti, Elisa; Rossello, Armando; Dive, Vincent; Stura, Enrico Adriano

2013-06-01

Homodimerization is important in signal transduction and can play a crucial role in many other biological systems. To obtaining structural information for the design of molecules able to control the signalization pathways, the proteins involved will have to be crystallized in complex with ligands that induce dimerization. Bi-functional drugs have been generated by linking two ligands together chemically and the relative crystallizability of complexes with mono-functional and bi-functional ligands has been evaluated. There are problems associated with crystallization with such ligands, but overall, the advantages appear to be greater than the drawbacks. The study involves two matrix metalloproteinases, MMP-12 and MMP-9. Using flexible and rigid linkers we show that it is possible to control the crystal packing and that by changing the ligand-enzyme stoichiometric ratio, one can toggle between having one bi-functional ligand binding to two enzymes and having the same ligand bound to each enzyme. The nature of linker and its point of attachment on the ligand can be varied to aid crystallization, and such variations can also provide valuable structural information about the interactions made by the linker with the protein. We report here the crystallization and structure determination of seven ligand-dimerized complexes. These results suggest that the use of bi-functional drugs can be extended beyond the realm of protein dimerization to include all drug design projects. Copyright © 2013 Elsevier Inc. All rights reserved.

Oxygen Atom Exchange between H2O and Non-Heme Oxoiron(IV) Complexes: Ligand Dependence and Mechanism.

Science.gov (United States)

Puri, Mayank; Company, Anna; Sabenya, Gerard; Costas, Miquel; Que, Lawrence

2016-06-20

Detailed studies of oxygen atom exchange (OAE) between H2(18)O and synthetic non-heme oxoiron(IV) complexes supported by tetradentate and pentadentate ligands provide evidence that they proceed by a common mechanism but within two different kinetic regimes, with OAE rates that span 2 orders of magnitude. The first kinetic regime involves initial reversible water association to the Fe(IV) complex, which is evidenced by OAE rates that are linearly dependent on [H2(18)O] and H2O/D2O KIEs of 1.6, while the second kinetic regime involves a subsequent rate determining proton-transfer step between the bound aqua and oxo ligands that is associated with saturation behavior with [H2(18)O] and much larger H2O/D2O KIEs of 5-6. [Fe(IV)(O)(TMC)(MeCN)](2+) (1) and [Fe(IV)(O)(MePy2TACN)](2+) (9) are examples of complexes that exhibit kinetic behavior in the first regime, while [Fe(IV)(O)(N4Py)](2+) (3), [Fe(IV)(O)(BnTPEN)](2+) (4), [Fe(IV)(O)(1Py-BnTPEN)](2+) (5), [Fe(IV)(O)(3Py-BnTPEN)](2+) (6), and [Fe(IV)(O)(Me2Py2TACN)](2+) (8) represent complexes that fall in the second kinetic regime. Interestingly, [Fe(IV)(O)(PyTACN)(MeCN)](2+) (7) exhibits a linear [H2(18)O] dependence below 0.6 M and saturation above 0.6 M. Analysis of the temperature dependence of the OAE rates shows that most of these complexes exhibit large and negative activation entropies, consistent with the proposed mechanism. One exception is complex 9, which has a near-zero activation entropy and is proposed to undergo ligand-arm dissociation during the RDS to accommodate H2(18)O binding. These results show that the observed OAE kinetic behavior is highly dependent on the nature of the supporting ligand and are of relevance to studies of non-heme oxoiron(IV) complexes in water or acetonitrile/water mixtures for applications in photocatalysis and water oxidation chemistry.

Synthesis, characterization, DNA interaction and antimicrobial screening of isatin-based polypyridyl mixed-ligand Cu(II and Zn(II complexes

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NATARAJAN RAMAN

2010-06-01

Full Text Available Several mixed ligand Cu(II/Zn(II complexes using 3-(phenyl-imino-1,3-dihydro-2H-indol-2-one (obtained by the condensation of isatin and aniline as the primary ligand and 1,10-phenanthroline (phen/2,2’-bipyridine (bpy as an additional ligand were synthesized and characterized analytically and spectroscopically by elemental analyses, magnetic susceptibility and molar conductance measurements, as well as by UV–Vis, IR, NMR and FAB mass spectroscopy. The interaction of the complexes with calf thymus (CT DNA was studied using absorption spectra, cyclic voltammetric and viscosity measurements. They exhibit absorption hypochromicity, and the specific viscosity increased during the binding of the complexes to calf thymus DNA. The shifts in the oxidation–reduction potential and changes in peak current on addition of DNA were shown by CV measurements. The Cu(II/Zn(II complexes were found to promote cleavage of pUC19 DNA from the supercoiled form I to the open circular form II and linear form III. The complexes show enhanced antifungal and antibacterial activities compared with the free ligand.

New selective ligands for caesium. Application to Cs+/Na+ separation by nano-filtration-complexation in aqueous phase

International Nuclear Information System (INIS)

Pellet-Rostaing, S.; Chitry, F.; Lemaire, M.; Guy, A.; Foos, J.

2000-01-01

Separating traces of caesium from aqueous medium containing high sodium concentration is a harsh problem because caesium and sodium have a similar behaviour in aqueous medium. The aim of our study was to select a highly caesium-selective ligand in a nano-filtration-complexation process in order to achieve Cs + /Na + separation. This process involve a nano-filtration step combined with a preliminary complexation step. Caesium complexes are retained by the nano-filtration membrane whereas free sodium cations pass through it. We tried to find a relation between the ligands structure and their activity towards caesium-complexation. Among the synthesized receptors, Tetra-hydroxylated bis-crown-6 calix[4]arene was found to be the more caesium-selective ligand (S=β(Cs + )/β(Na+)=6600). Combined with a nano-filtration process, this ligand helped reaching 90% caesium retention in a highly concentrated aqueous medium ([NaNO 3 ] = 3 mol/L). (authors)

125I-BH-8-MeO-N-PAT, a new ligand for studying 5-HT1A receptors in the central nervous system

International Nuclear Information System (INIS)

Ponchant, M.; Beaucourt, J.P.; Vanhove, A.

1988-01-01

Specific radioactive ligands are needed for studying the pharmacological properties and the regional distribution of the different classes of 5-HT 1 receptors within the central nervous system. We describe here the synthesis and some characteristics of the first iodinated specific ligand of 5-HT 1A receptors. Like its parent compound, the agonist 8-hydroxy-2-(di-n-propylamino)tetralin or 8-OH-DPAT, [ 125 I]-BH-8-MeO-N-PAT, exhibits a high affinity and excellent selectivity for 5-HT 1A sites. Its high specific radioactivity makes this ligand a useful tool for studying 5-HT 1A receptors in membranes and sections of the rat brain [fr

G-LoSA for Prediction of Protein-Ligand Binding Sites and Structures.

Science.gov (United States)

Lee, Hui Sun; Im, Wonpil

2017-01-01

Recent advances in high-throughput structure determination and computational protein structure prediction have significantly enriched the universe of protein structure. However, there is still a large gap between the number of available protein structures and that of proteins with annotated function in high accuracy. Computational structure-based protein function prediction has emerged to reduce this knowledge gap. The identification of a ligand binding site and its structure is critical to the determination of a protein's molecular function. We present a computational methodology for predicting small molecule ligand binding site and ligand structure using G-LoSA, our protein local structure alignment and similarity measurement tool. All the computational procedures described here can be easily implemented using G-LoSA Toolkit, a package of standalone software programs and preprocessed PDB structure libraries. G-LoSA and G-LoSA Toolkit are freely available to academic users at http://compbio.lehigh.edu/GLoSA . We also illustrate a case study to show the potential of our template-based approach harnessing G-LoSA for protein function prediction.

Assessing the effect of dissolved organic ligands on mineral dissolution rates: An example from calcite dissolution

International Nuclear Information System (INIS)

DeMaio, T.; Grandstaff, D.E.

1997-01-01

Experiments suggest that dissolved organic ligands may primarily modify mineral dissolution rates by three mechanisms: (1) metal-ligand (M-L) complex formation in solution, which increases the degree of undersaturation, (2) formation of surface M-L complexes that attack the surface, and (3) formation of surface complexes which passivate or protect the surface. Mechanisms (1) and (2) increase the dissolution rate and the third decreases it compared with organic-free solutions. The types and importance of these mechanisms may be assessed from plots of dissolution rate versus degree of undersaturation. To illustrate this technique, calcite, a common repository cementing and vein-filling mineral, was dissolved at pH 7.8 and 22 C in Na-Ca-HCO 3 -Cl solutions with low concentrations of three organic ligands. Low citrate concentrations (50 microM) increased the dissolution rate consistent with mechanism (1). Oxalate decreased the rate, consistent with mechanism (3). Low phthalate concentration (<50 microM) decreased calcite dissolution rates; however, higher concentrations increased the dissolution rates, which became faster than in inorganic solutions. Thus, phthalate exhibits both mechanisms (2) and (3) at different concentrations. In such cases linear extrapolations of dissolution rates from high organic ligand concentrations may not be valid

Synthesis, spectroscopic studies and reactivity of triphenylphosphine ruthenium (II) complexes with N-heterocyclic ligands

International Nuclear Information System (INIS)

Rivera, A.B.

1989-01-01

Reported is the chemistry of triphenylphosphine ruthenium (II) complexes of general formula RuCl 2 (PPh 3 ) 2 L 2 and RuCl 2 (PPh 3 ) 2 A, obtained from the reaction of RuCl 2 (PPh 3 ) 3 with N-heterocyclic ligands L, or A (of ambidentate nature). The electronic spectra exhibit two strong metal-to-ligand charge-transfer bands, ascribed to the b 1 (dxz)->b 1 (pi) and a 2 (dxy)->a 2 (pi) transitions, and a third, weak band ascribed to the b 2 (dyz)->a 2 (pi) transition. The electronic states and the vibrational modes of the complexes were characterized by means of their resonance Raman and infrared absorption spectra. Thermogravimetric and thermodifferential analysis indicated that the melting process is succeeded by an exothermic reaction, and that the weigh loss starts to occur only after this step. The complexes dissociated in CHCl 3 solution, showing preferential labilization of the phosphine ligands, as in the case of the hydrogenation catalyst Ru(PPh 3 ) 3 Cl 2 . In the presence of CO, RuCl 2 (CO) 2 L 2 complexes were gennerated. Several derivatives were isolated and characterized. (author) [pt

Molecular Properties of Globin Channels and Pores: Role of Cholesterol in Ligand Binding and Movement

Directory of Open Access Journals (Sweden)

Gene A Morrill

2016-09-01

Full Text Available ABSTRACT: Globins contain one or more cavities that control or affect such functions as ligand movement and ligand binding. Here we report that the extended globin family [cytoglobin (Cygb; neuroglobin (Ngb; myoglobin (Mb; hemoglobin (Hb subunits Hba(α and Hbb(β] contain either a transmembrane (TM helix or pore-lining region as well as internal cavities. Protein motif/domain analyses indicate that Ngb and Hbb each contain 5 cholesterol-binding (CRAC/CARC domains and 1 caveolin binding motif, whereas the Cygb dimer has 6 cholesterol-binding domains but lacks caveolin-binding motifs. Mb and Hba each exhibit 2 cholesterol-binding domains and also lack caveolin-binding motifs. The Hb αβ-tetramer contains 14 cholesterol-binding domains. Computer algorithms indicate that Cygb and Ngb cavities display multiple partitions and C-terminal pore-lining regions, whereas Mb has three major cavities plus a C-terminal pore-lining region. The Hb tetramer exhibits a large internal cavity but the subunits differ in that they contain a C-terminal TM helix (Hba and pore-lining region (Hbb. The cavities include 43 of 190 Cygb residues, 38 of 151 of Ngb residues, 55 of 154 Mb residues and 137 of 688 residues in the Hb tetramer. Each cavity complex includes 6 to 8 residues of the TM helix or pore-lining region and CRAC/CARC domains exist within all cavities. Erythrocyte Hb αβ-tetramers are largely cytosolic but also bind to a membrane anion exchange protein, band 3, which contains a large internal cavity and 12 TM helices (5 being pore-lining regions. The Hba TM helix may be the erythrocyte membrane band 3 attachment site. Band 3 contributes 4 caveolin binding motifs and 10 CRAC/CARC domains. Cholesterol binding may create lipid-disordered phases that alter globin cavities and facilitate ligand movement, permitting ion channel formation and conformational changes that orchestrate anion and ligand (O2, CO2, NO movement within the large internal cavities and

A molecular dynamics investigation of CDK8/CycC and ligand binding: conformational flexibility and implication in drug discovery

Science.gov (United States)

Cholko, Timothy; Chen, Wei; Tang, Zhiye; Chang, Chia-en A.

2018-05-01

Abnormal activity of cyclin-dependent kinase 8 (CDK8) along with its partner protein cyclin C (CycC) is a common feature of many diseases including colorectal cancer. Using molecular dynamics (MD) simulations, this study determined the dynamics of the CDK8-CycC system and we obtained detailed breakdowns of binding energy contributions for four type-I and five type-II CDK8 inhibitors. We revealed system motions and conformational changes that will affect ligand binding, confirmed the essentialness of CycC for inclusion in future computational studies, and provide guidance in development of CDK8 binders. We employed unbiased all-atom MD simulations for 500 ns on twelve CDK8-CycC systems, including apoproteins and protein-ligand complexes, then performed principal component analysis (PCA) and measured the RMSF of key regions to identify protein dynamics. Binding pocket volume analysis identified conformational changes that accompany ligand binding. Next, H-bond analysis, residue-wise interaction calculations, and MM/PBSA were performed to characterize protein-ligand interactions and find the binding energy. We discovered that CycC is vital for maintaining a proper conformation of CDK8 to facilitate ligand binding and that the system exhibits motion that should be carefully considered in future computational work. Surprisingly, we found that motion of the activation loop did not affect ligand binding. Type-I and type-II ligand binding is driven by van der Waals interactions, but electrostatic energy and entropic penalties affect type-II binding as well. Binding of both ligand types affects protein flexibility. Based on this we provide suggestions for development of tighter-binding CDK8 inhibitors and offer insight that can aid future computational studies.

A highly sensitive quantitative cytosensor technique for the identification of receptor ligands in tissue extracts.

Science.gov (United States)

Lenkei, Z; Beaudet, A; Chartrel, N; De Mota, N; Irinopoulou, T; Braun, B; Vaudry, H; Llorens-Cortes, C

2000-11-01

Because G-protein-coupled receptors (GPCRs) constitute excellent putative therapeutic targets, functional characterization of orphan GPCRs through identification of their endogenous ligands has great potential for drug discovery. We propose here a novel single cell-based assay for identification of these ligands. This assay involves (a) fluorescent tagging of the GPCR, (b) expression of the tagged receptor in a heterologous expression system, (c) incubation of the transfected cells with fractions purified from tissue extracts, and (d) imaging of ligand-induced receptor internalization by confocal microscopy coupled to digital image quantification. We tested this approach in CHO cells stably expressing the NT1 neurotensin receptor fused to EGFP (enhanced green fluorescent protein), in which neurotensin promoted internalization of the NT1-EGFP receptor in a dose-dependent fashion (EC(50) = 0.98 nM). Similarly, four of 120 consecutive reversed-phase HPLC fractions of frog brain extracts promoted internalization of the NT1-EGFP receptor. The same four fractions selectively contained neurotensin, an endogenous ligand of the NT1 receptor, as detected by radioimmunoassay and inositol phosphate production. The present internalization assay provides a highly specific quantitative cytosensor technique with sensitivity in the nanomolar range that should prove useful for the identification of putative natural and synthetic ligands for GPCRs.

Molecular mechanism of ligand recognition by NR3 subtype glutamate receptors

Energy Technology Data Exchange (ETDEWEB)

Yao, Yongneng; Harrison, Chris B.; Freddolino, Peter L.; Schulten, Klaus; Mayer, Mark L. (UIUC); (NIH)

2008-10-27

NR3 subtype glutamate receptors have a unique developmental expression profile, but are the least well-characterized members of the NMDA receptor gene family, which have key roles in synaptic plasticity and brain development. Using ligand binding assays, crystallographic analysis, and all atom MD simulations, we investigate mechanisms underlying the binding by NR3A and NR3B of glycine and D-serine, which are candidate neurotransmitters for NMDA receptors containing NR3 subunits. The ligand binding domains of both NR3 subunits adopt a similar extent of domain closure as found in the corresponding NR1 complexes, but have a unique loop 1 structure distinct from that in all other glutamate receptor ion channels. Within their ligand binding pockets, NR3A and NR3B have strikingly different hydrogen bonding networks and solvent structures from those found in NR1, and fail to undergo a conformational rearrangement observed in NR1 upon binding the partial agonist ACPC. MD simulations revealed numerous interdomain contacts, which stabilize the agonist-bound closed-cleft conformation, and a novel twisting motion for the loop 1 helix that is unique in NR3 subunits.

Determination of ligand binding modes in weak protein–ligand complexes using sparse NMR data

Energy Technology Data Exchange (ETDEWEB)

Mohanty, Biswaranjan; Williams, Martin L.; Doak, Bradley C.; Vazirani, Mansha; Ilyichova, Olga [Monash University, Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences (Australia); Wang, Geqing [La Trobe University, La Trobe Institute for Molecular Bioscience (Australia); Bermel, Wolfgang [Bruker Biospin GmbH (Germany); Simpson, Jamie S.; Chalmers, David K. [Monash University, Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences (Australia); King, Glenn F. [The University of Queensland, Institute for Molecular Bioscience (Australia); Mobli, Mehdi, E-mail: m.mobli@uq.edu.au [The University of Queensland, Centre for Advanced Imaging (Australia); Scanlon, Martin J., E-mail: martin.scanlon@monash.edu [Monash University, Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences (Australia)

2016-11-15

We describe a general approach to determine the binding pose of small molecules in weakly bound protein–ligand complexes by deriving distance constraints between the ligand and methyl groups from all methyl-containing residues of the protein. We demonstrate that using a single sample, which can be prepared without the use of expensive precursors, it is possible to generate high-resolution data rapidly and obtain the resonance assignments of Ile, Leu, Val, Ala and Thr methyl groups using triple resonance scalar correlation data. The same sample may be used to obtain Met {sup ε}CH{sub 3} assignments using NOESY-based methods, although the superior sensitivity of NOESY using [U-{sup 13}C,{sup 15}N]-labeled protein makes the use of this second sample more efficient. We describe a structural model for a weakly binding ligand bound to its target protein, DsbA, derived from intermolecular methyl-to-ligand nuclear Overhauser enhancements, and demonstrate that the ability to assign all methyl resonances in the spectrum is essential to derive an accurate model of the structure. Once the methyl assignments have been obtained, this approach provides a rapid means to generate structural models for weakly bound protein–ligand complexes. Such weak complexes are often found at the beginning of programs of fragment based drug design and can be challenging to characterize using X-ray crystallography.

Ruthenium(II) carbonyl compounds with the 4'-chloro-2,2':6',2''-terpyridine ligand.

Science.gov (United States)

Tatikonda, Rajendhraprasad; Haukka, Matti

2017-04-01

Two ruthenium carbonyl complexes with the 4'-chloro-2,2':6',2''-terpyridine ligand (tpy-Cl, C 15 H 10 ClN 3 ), i.e. [RuCl(tpy-Cl)(CO) 2 ][RuCl 3 (CO) 3 ] (I) [systematic name: cis -di-carbonyl-chlorido(4'-chloro-2,2':6',2''-terpyridine-κ 3 N )ruthenium(II) fac -tricarbonyltri-chlorido-ruthenate(II)], and [RuCl 2 (tpy-Cl)(CO) 2 ] (II) [ cis -dicarbonyl- trans -di-chlorido(4'-chloro-2,2':6',2''-terpyridine-κ 2 N 1 , N 1' )ruthenium(II)], were synthesized and characterized by single-crystal X-ray diffraction. The Ru II atoms in both centrosymmetric structures (I) and (II) display similar, slightly distorted octa-hedral coordination spheres. The coordination sphere in the complex cation in compound (I) is defined by three N atoms of the tridentate tpy-Cl ligand, two carbonyl carbon atoms and one chlorido ligand; the charge is balanced by an octa-hedral [Ru(CO) 3 Cl 3 ] - counter-anion. In the neutral compound (II), the tpy-Cl ligand coordinates to the metal only through two of its N atoms. The coordination sphere of the Ru II atom is completed by two carbonyl and two chlorido ligands. In the crystal structures of both (I) and (II), weak C-H⋯Cl inter-actions are observed.

Radiation induced ligand loss from cobalt complexes

International Nuclear Information System (INIS)

Funston, A. M.; McFadyen, W.D.; Tregloan, P.A.

2000-01-01

Full text: Due to the rapid nature of ligand dissociation from cobalt(II) complexes the study of the rate of ligand dissociation necessitates the use of a technique such as pulse radiolysis. This allows the rapid reduction of the corresponding cobalt(III) complex by a reducing radical, such as the aquated electron, to form the cobalt(II) complex. However, to date, no systematic study of either the mechanism of reduction or the influence of the electronic structure on the rate of ligand dissociation has been carried out. In order to understand these processes more fully the mechanism of reduction of a range of related cobalt(III) complexes by the aquated electron and the subsequent rate of ligand dissociation from the resulting cobalt(II) complexes is being investigated. It has been found that a number of processes are observed following the initial rapid reaction of the cobalt(III) complex with the aquated electron. Ultimately ligand loss is observed. Depending upon the complex, the initial processes observed may include the formation of coordinated radicals and electron transfer within the complex. For complexes containing aromatic ligands such as 2,2'-bipyridine, 1,10-phenanthroline and dipyrido[3,2-a:2',3'-c]phenazine the formation of a coordinated radical is observed as the initial reduction step. The kinetics of ligand dissociation of these complexes has been determined. The loss of monodentate ligands is fast and has been indistinguishable from the reduction processes when aromatic ligands are also present in the complex. However, for diamine chelates and diimine chelates spectra of the transient species can be resolved

Ligand-Mediated Ring → Cube Transformation in a Catalytic Subnanocluster: Co4O4(MeCN)n with n = 1-6.

Science.gov (United States)

Luo, Sijie; Dibble, Collin J; Duncan, Michael A; Truhlar, Donald G

2014-08-07

We studied the Co4O4 subnanocluster and its MeCN-coated species using density functional theory, and we found that the Co4O4 core presents distinctive structures in bare and ligand-coated species. We propose a possible ligand-mediated ring → cube transformation mechanism during the ligand-coating process of the Co4O4 core due to the stronger binding energies of the MeCN ligands to the 3D distorted cube structure than to the 2D ring and ladder structures; theory indicates that three ligands are sufficient to stabilize the cube structure. Both ring and cube structures are ferromagnetic. Our finding is potentially useful for understanding the catalysis mechanism of Co4O4 species, which have important applications in solar energy conversion and water splitting; these catalysis reactions usually involve frequent addition and subtraction of various ligands and thus possibly involve core rearrangement processes similar to our findings.

Regulation mechanisms of the FLT3-ligand after irradiation; Mecanismes de regulation du FLT3-ligand apres irradiation

Energy Technology Data Exchange (ETDEWEB)

Prat-Lepesant, M

2005-06-15

The hematopoietic compartment is one of the most severely damaged after chemotherapy, radiotherapy or accidental irradiations. Whatever its origin, the resulting damage to the bone marrow remains difficult to evaluate. Thus, it would be of great interest to get a biological indicator of residual hematopoiesis in order to adapt the treatment to each clinical situation. Recent results indicated that the plasma Flt3 ligand concentration was increased in patients suffering from either acquired or induced aplasia, suggesting that Flt3 ligand might be useful as a biological indicator of bone marrow status. We thus followed in a mouse model as well as in several clinical situations the variations in plasma Flt3 ligand concentration, after either homogeneous or heterogeneous irradiations. These variations were correlated to the number of hematopoietic progenitors and to other parameters such as duration and depth of pancytopenia. The results indicated that the concentration of Flt3 ligand in the blood reflects the bone marrow status, and that the follow-up of plasma Flt3 ligand concentration could give predictive information about the bone marrow function and the duration and severity of pancytopenia and thrombocytopenia. Nevertheless, the clinical use of Flt3 ligand as a biological indicator of bone marrow damage require the knowledge of the mechanisms regulating the variations in plasma Flt3 ligand concentration. We thus developed a study in the mouse model. The results indicated that the variations in plasma Flt3 ligand variations were not solely due to a balance between its production by lymphoid cells and its consumption by hematopoietic cells. Moreover, we showed that T lymphocytes are not the main regulator of plasma Flt3 ligand concentration as previously suggested, and that other cell types, possibly including bone marrow stromal cells, might be strongly implicated. These results also suggest that the Flt3 ligand is a main systemic regulator of hematopoiesis

Synthesis and characterization of mixed ligand chiral nanoclusters

KAUST Repository

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

2016-01-01

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. © 2016 The Royal Society of Chemistry.

Synthesis and characterization of mixed ligand chiral nanoclusters

KAUST Repository

Guven, Zekiye P.

2016-06-22

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. © 2016 The Royal Society of Chemistry.

Identifying Marine Copper-Binding Ligands in Seawater

Science.gov (United States)

Whitby, H.; Hollibaugh, J. T.; Maldonado, M. T.; Ouchi, S.; van den Berg, S. M.

2016-02-01

Complexation reactions are important because they affect the bioavailability of trace metals such as copper and iron. For example, organic complexation can determine whether copper is a limiting or a toxic micronutrient at natural levels. Copper competes with iron for complexing ligands, and when iron is limiting, copper can also substitute for iron in some metabolic pathways. The speciation of copper can be measured using complexing capacity titrations, which provide the concentration of individual ligand classes (L1, L2 etc.) and the complex stabilities (log K). Using methods recently developed in our laboratory, we show that the ligands within these classes can be measured independently of titrations, thus confirming the titration method and simultaneously identifying the ligands within each class. Thiols were identified as the L1 ligand class and humic compounds as the weaker L2 class in samples from coastal Georgia, USA, collected monthly from April to December. Log K values of the ligand complexes were consistent with values expected for thiols and humic substances. Recent results from culture studies and from samples collected along Line P, a coastal - oceanic transect in the HNLC region of the NE subarctic Pacific, will be presented in comparison to the estuarine results. This comparison will help to broaden our perspective on copper complexation and the ligands responsible, furthering our understanding of ligand sources and life cycles.

Extraction complexes of Pu(IV) with carbamoylmethylphosphine oxide ligands. A relativistic density functional study

International Nuclear Information System (INIS)

Wang, Cong-Zhi; Lan, Jian-Hui; Feng, Yi-Xiao; Zhao, Yu-Liang; Chai, Zhi-Fang; Shi, Wei-Qun; Wei, Yue-Zhou

2014-01-01

The extraction complexes of Pu(IV) with n-octyl(phenyl)-N,N-diisobutyl-methylcarbamoyl phosphine oxide (CMPO) and diphenyl-N,N-diisobutyl carbamoyl phosphine oxide (Ph 2 CMPO) have been studied by using density functional theory (DFT) combined with relativistic small-core pseudopotentials. For most complexes, the CMPO and Ph 2 CMPO molecules are coordinated as bidentate chelating ligands through the carbonyl oxygen and phosphoric oxygen atoms. The metal-ligand bonding is mainly ionic for all of these complexes. The neutral PuL(NO 3 ) 4 and PuL 2 (NO 3 ) 4 complexes are predicted to be the most thermodynamically stable molecules according to the metal-ligand complexation reactions. In addition, hydration energies may also play a significant role in the extractability of CMPO and Ph 2 CMPO for the plutonium cations. In most cases, the complexes with CMPO possess qualitatively similar geometries and electron structures to those with Ph 2 CMPO, and they also have comparable metal-ligand binding energies. Thus, replacement of alkyl groups by phenyl groups at the phosphorus atom of CMPO seems to have no obvious influence on the extraction of Pu(IV). (orig.)

Alkyl group dependence on structure and magnetic properties in layered cobalt coordination polymers containing substituted glutarate ligands and 4,4'-bipyridine

International Nuclear Information System (INIS)

Nettleman, Joseph H.; Supkowski, Ronald M.; LaDuca, Robert L.

2010-01-01

Five two-dimensional divalent cobalt coordination polymers containing 4,4'-bipyridine (bpy) and substituted or unsubstituted glutarate ligands have been prepared hydrothermally and structurally characterized by single-crystal X-ray diffraction. [Co(mg)(bpy)] n (1, mg=3-methylglutarate) forms a (4,4) rhomboid grid structure based on the connection of {Co 2 (CO 2 ) 2 } dimeric units. Using the more sterically encumbered ligands 3,3-dimethylglutarate (dmg) and 3-ethyl, 3-methylglutarate (emg) generated {[Co(dmg)(bpy)(H 2 O)].2H 2 O} n (2) and {[Co(emg)(bpy)(H 2 O)].H 2 O} n (3), respectively. These complexes manifest {Co(CO 2 )} n chains linked into 2-D by aliphatic dicarboxylate and bpy ligands. The 'tied-back' substituted glutarate ligand 1,1-cyclopentanediacetate (cda) afforded [Co(cda)(bpy)] n (4), and the unsubstituted glutarate (glu) generated [Co(glu)(bpy)] n (5), both of which exhibit a topology similar to that of 1. The magnetic properties of complexes 1-4 were analyzed successfully with a recently developed phenomenological chain model accounting for both magnetic coupling (J) and zero-field splitting effects (D), even though 1 and 4 contain isolated, discrete {Co 2 (CO 2 ) 2 } dimers. The D parameter in this series varied between 21.8(8) and 48.0(9) cm -1 . However weak antiferromagnetic coupling was observed in 1 (J=-2.43(4) cm -1 ) and 4 (J=-0.89(2) cm -1 ), while weak ferromagnetic coupling appears to be operative in both 2 (J=0.324(5) cm -1 ) and 3 (J=0.24(1) cm -1 ). - Five two-dimensional divalent cobalt coordination polymers containing 4,4'-bipyridine (bpy) and substituted or unsubstituted glutarate ligands have been prepared and structurally characterized by single-crystal X-ray diffraction. Three contain dimeric {Co 2 (CO 2 ) 2 } units, while two manifest {Co(CO 2 )} n chains, depending on the steric bulk of the substituent. The magnetic properties of the complexes were analyzed successfully with a recently developed phenomenological chain model

Substrate coated with receptor and labelled ligand for assays

International Nuclear Information System (INIS)

1980-01-01

Improvements in the procedures for assaying ligands are described. The assay consists of a polystyrene tube on which receptors are present for both the ligand to be assayed and a radioactively labelled form of the ligand. The receptors on the bottom portion of the tube are also coated with labelled ligands, thus eliminating the necessity for separate addition of the labelled ligand and sample during an assay. Examples of ligands to which this method is applicable include polypeptides, nucleotides, nucleosides and proteins. Specific examples are given in which the ligand to be assayed is digoxin, the labelled form of the ligand is 3-0-succinyl digoxyigenin tyrosine ( 125 I) and the receptor is digoxin antibody. (U.K.)

Multitarget-directed tricyclic pyridazinones as G protein-coupled receptor ligands and cholinesterase inhibitors.

Science.gov (United States)

Pau, Amedeo; Catto, Marco; Pinna, Giovanni; Frau, Simona; Murineddu, Gabriele; Asproni, Battistina; Curzu, Maria M; Pisani, Leonardo; Leonetti, Francesco; Loza, Maria Isabel; Brea, José; Pinna, Gérard A; Carotti, Angelo

2015-06-01

By following a multitarget ligand design approach, a library of 47 compounds was prepared, and they were tested as binders of selected G protein-coupled receptors (GPCRs) and inhibitors of acetyl and/or butyryl cholinesterase. The newly designed ligands feature pyridazinone-based tricyclic scaffolds connected through alkyl chains of variable length to proper amine moieties (e.g., substituted piperazines or piperidines) for GPCR and cholinesterase (ChE) molecular recognition. The compounds were tested at three different GPCRs, namely serotoninergic 5-HT1A, adrenergic α1A, and dopaminergic D2 receptors. Our main goal was the discovery of compounds that exhibit, in addition to ChE inhibition, antagonist activity at 5-HT1A because of its involvement in neuronal deficits typical of Alzheimer's and other neurodegenerative diseases. Ligands with nanomolar affinity for the tested GPCRs were discovered, but most of them behaved as dual antagonists of α1A and 5-HT1A receptors. Nevertheless, several compounds displaying this GPCR affinity profile also showed moderate to good inhibition of AChE and BChE, thus deserving further investigations to exploit the therapeutic potential of such unusual biological profiles. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Improved Oxygen Reduction Activity and Durability of Dealloyed PtCox Catalysts for Proton Exchange Membrane Fuel Cells: Strain, Ligand, and Particle Size Effects

Science.gov (United States)

Jia, Qingying; Caldwell, Keegan; Strickland, Kara; Ziegelbauer, Joseph M.; Liu, Zhongyi; Yu, Zhiqiang; Ramaker, David E.; Mukerjee, Sanjeev

2015-01-01

The development of active and durable catalysts with reduced platinum content is essential for fuel cell commercialization. Herein we report that the dealloyed PtCo/HSC and PtCo3/HSC nanoparticle (NP) catalysts exhibit the same levels of enhancement in oxygen reduction activity (~4-fold) and durability over pure Pt/C NPs. Surprisingly, ex situ high-angle annular dark field scanning transmission electron microscopy (HAADF STEM) shows that the bulk morphologies of the two catalysts are distinctly different: D-PtCo/HSC catalyst is dominated by NPs with solid Pt shells surrounding a single ordered PtCo core; however, the D-PtCo3/HSC catalyst is dominated by NPs with porous Pt shells surrounding multiple disordered PtCo cores with local concentration of Co. In situ X-ray absorption spectroscopy (XAS) reveals that these two catalysts possess similar Pt–Pt and Pt–Co bond distances and Pt coordination numbers (CNs), despite their dissimilar morphologies. The similar activity of the two catalysts is thus ascribed to their comparable strain, ligand, and particle size effects. Ex situ XAS performed on D-PtCo3/HSC under different voltage cycling stage shows that the continuous dissolution of Co leaves behind the NPs with a Pt-like structure after 30k cycles. The attenuated strain and/or ligand effects caused by Co dissolution are presumably counterbalanced by the particle size effects with particle growth, which likely accounts for the constant specific activity of the catalysts along with voltage cycling. PMID:26413384

Synthesis, Characterization, DNA Interaction, and Antitumor Activities of La (III) Complex with Schiff Base Ligand Derived from Kaempferol and Diethylenetriamine.

Science.gov (United States)

Wang, Qin; Huang, Yu; Zhang, Jin-Sheng; Yang, Xin-Bin

2014-01-01

A novel La (III) complex, [LaL(H2O)3]NO3 ·3H2O, with Schiff base ligand L derived from kaempferol and diethylenetriamine, has been synthesized and characterized by elemental analysis, IR, UV-visible, (1)H NMR, thermogravimetric analysis, and molar conductance measurements. The fluorescence spectra, circular dichroism spectra, and viscosity measurements and gel electrophoresis experiments indicated that the ligand L and La (III) complex could bind to CT-DNA presumably via intercalative mode and the La (III) complex showed a stronger ability to bind and cleave DNA than the ligand L alone. The binding constants (K b ) were evaluated from fluorescence data and the values ranged from 0.454 to 0.659 × 10(5) L mol(-1) and 1.71 to 17.3 × 10(5) L mol(-1) for the ligand L and La (III) complex, respectively, in the temperature range of 298-310 K. It was also found that the fluorescence quenching mechanism of EB-DNA by ligand L and La (III) complex was a static quenching process. In comparison to free ligand L, La (III) complex exhibited enhanced cytotoxic activities against tested tumor cell lines HL-60 and HepG-2, which may correlate with the enhanced DNA binding and cleaving abilities of the La (III) complex.

Correcting binding parameters for interacting ligand-lattice systems

Science.gov (United States)

Hervy, Jordan; Bicout, Dominique J.

2017-07-01

Binding of ligands to macromolecules is central to many functional and regulatory biological processes. Key parameters characterizing ligand-macromolecule interactions are the stoichiometry, inducing the number of ligands per macromolecule binding site, and the dissociation constant, quantifying the ligand-binding site affinity. Both these parameters can be obtained from analyses of classical saturation experiments using the standard binding equation that offers the great advantage of mathematical simplicity but becomes an approximation for situations of interest when a ligand binds and covers more than one single binding site on the macromolecule. Using the framework of car-parking problem with latticelike macromolecules where each ligand can cover simultaneously several consecutive binding sites, we showed that employing the standard analysis leads to underestimation of binding parameters, i.e., ligands appear larger than they actually are and their affinity is also greater than it is. Therefore, we have derived expressions allowing to determine the ligand size and true binding parameters (stoichiometry and dissociation constant) as a function of apparent binding parameters retrieved from standard saturation experiments.

THERMODYNAMICS OF PROTEIN-LIGAND INTERACTIONS AND THEIR ANALYSIS

Directory of Open Access Journals (Sweden)

Rummi Devi Saini

2017-11-01

Full Text Available Physiological processes are controlled mainly by intermolecular recognition mechanisms which involve protein–protein and protein–ligand interactions with a high specificity and affinity to form a specific complex. Proteins being an important class of macromolecules in biological systems, it is important to understand their actions through binding to other molecules of proteins or ligands. In fact, the binding of low molecular weight ligands to proteins plays a significant role in regulating biological processes such as cellular metabolism and signal transmission. Therefore knowledge of the protein–ligand interactions and the knowledge of the mechanisms involved in the protein-ligand recognition and binding are key in understanding biology at molecular level which will facilitate the discovery, design, and development of drugs. In this review, the mechanisms involved in protein–ligand binding, the binding kinetics, thermodynamic concepts and binding driving forces are discussed. Thermodynamic mechanisms involved in a few important protein-ligand binding are described. Various spectroscopic, non-spectroscopic and computational method for analysis of protein–ligand binding are also discussed.

Development of immobilized ligands for actinide separations

International Nuclear Information System (INIS)

Paine, R.T.

1994-01-01

Primary goals during this grant period were to (1) synthesize new bifunctional chelating ligands, (2) characterize the structural features of the Ln and An coordination complexes formed by these ligands, (3) use structural data to iteratively design new classes of multifunctional ligands, and (4) explore additional routes for attachment of key ligands to solid supports that could be useful for chromatographic separations. Some highlights of recently published work as well as a summary of submitted, unpublished and/or still in progress research are outlined

Crystallographic analysis of murine constitutive androstane receptor ligand-binding domain complexed with 5α-androst-16-en-3α-ol

International Nuclear Information System (INIS)

Vincent, Jeremy; Shan, Li; Fan, Ming; Brunzelle, Joseph S.; Forman, Barry M.; Fernandez, Elias J.

2004-01-01

The purification and structure determination of the murine constitutive androstane receptor bound to its inverse agonist/antagonist androstenol is described. The constitutive androstane receptor (CAR) is a member of the nuclear receptor superfamily. In contrast to classical nuclear receptors, which possess small-molecule ligand-inducible activity, CAR exhibits constitutive transcriptional activity in the apparent absence of ligand. CAR is among the most important transcription factors; it coordinately regulates the expression of microsomal cytochrome P450 genes and other drug-metabolizing enzymes. The murine CAR ligand-binding domain (LBD) was coexpressed with the steroid receptor coactivator protein (SRC-1) receptor-interacting domain (RID) in Escherichia coli. The mCAR LBD subunit was purified away from SRC-1 by affinity, anion-exchange and size-exclusion chromatography, crystallized with androstenol and the structure of the complex determined by molecular replacement

Preparation and characterisation of mixed ligand complexes of Co(III), Fe(III) and Cr(III) containing phthalimide and phenols

International Nuclear Information System (INIS)

Miah, M.A.J.; Islam, M.S.; Pal, S.C.; Barma, T.K.

1996-01-01

Some novel mixed ligand complexes of Co(III), Fe(III) and Cr(III) containing phthalimide as primary and 2-aminophenol and 3-aminophenol as secondary ligands have been synthesized and characterised on the basis of elemental analyses, conductivity and magnetic measurements and infrared and electronic spectral studies. Complexes containing 2-aminophenol are 1:1 electrolyte in N,N dimethylformamide. Spectral studies indicate that all the complexes exhibit octahedral geometry. The complexes have the general composition; K[M(pim)/sub 2/(L)/sub 2/]; where m=Co(III), Fe(III) and Cr(III), pim-anion of phthalimamide and L=anion of 2-aminophenol and 3-aminophenol. (author)

Exploiting structure similarity in refinement: automated NCS and target-structure restraints in BUSTER

Energy Technology Data Exchange (ETDEWEB)

Smart, Oliver S., E-mail: osmart@globalphasing.com; Womack, Thomas O.; Flensburg, Claus; Keller, Peter; Paciorek, Włodek; Sharff, Andrew; Vonrhein, Clemens; Bricogne, Gérard [Global Phasing Ltd, Sheraton House, Castle Park, Cambridge CB3 0AX (United Kingdom)

2012-04-01

Local structural similarity restraints (LSSR) provide a novel method for exploiting NCS or structural similarity to an external target structure. Two examples are given where BUSTER re-refinement of PDB entries with LSSR produces marked improvements, enabling further structural features to be modelled. Maximum-likelihood X-ray macromolecular structure refinement in BUSTER has been extended with restraints facilitating the exploitation of structural similarity. The similarity can be between two or more chains within the structure being refined, thus favouring NCS, or to a distinct ‘target’ structure that remains fixed during refinement. The local structural similarity restraints (LSSR) approach considers all distances less than 5.5 Å between pairs of atoms in the chain to be restrained. For each, the difference from the distance between the corresponding atoms in the related chain is found. LSSR applies a restraint penalty on each difference. A functional form that reaches a plateau for large differences is used to avoid the restraints distorting parts of the structure that are not similar. Because LSSR are local, there is no need to separate out domains. Some restraint pruning is still necessary, but this has been automated. LSSR have been available to academic users of BUSTER since 2009 with the easy-to-use -autoncs and @@target target.pdb options. The use of LSSR is illustrated in the re-refinement of PDB entries http://scripts.iucr.org/cgi-bin/cr.cgi?rm, where -target enables the correct ligand-binding structure to be found, and http://scripts.iucr.org/cgi-bin/cr.cgi?rm, where -autoncs contributes to the location of an additional copy of the cyclic peptide ligand.

Synthesis, spectral, thermal and biological studies of mixed ligand complexes with newly prepared Schiff base and 1,10-phenanthroline ligands

Science.gov (United States)

Abd El-Halim, Hanan F.; Mohamed, Gehad G.; Khalil, Eman A. M.

2017-10-01

A series of mixed ligand complexes were prepared from the Schiff base (L1) as a primary ligand, prepared by condensation of oxamide and furan-2-carbaldehyde, and 1,10-phenanthroline (1,10-phen) as a secondary ligand. The Schiff base ligand and its mixed ligand chelates were characterized based on elemental analysis, IR, 1H NMR, thermal analysis, UV-Visible, mass, molar conductance, magnetic moment. X-ray diffraction, solid reflectance and ESR also have been studied. The mixed ligand complexes were found to have the formulae of [M(L1) (1,10-phen)]Clm.nH2O (M = Cr(III) and Fe(III) (m = 3) (n = 0); M = Mn(II), Cu(II) and Cd(II) (m = 2) (n = 0); and M = Co(II) (m = 2) (n = 1), Ni(II) (m = 2) (n = 2) and Zn(II) (m = 2) (n = 3)) and that the geometrical structure of the complexes were octahedral. The parameters of thermodynamic using Coats-Redfern and Horowitz-Metzger equations were calculated. The synthesized Schiff base ligand, 1,10-phenanthroline ligand and Their mixed ligand complexes were also investigated for their antibacterial and antifungal activity against bacterial species (Gram-Ve bacteria: Pseudomonas aeruginosa and Escherichia coli) and (Gram + Ve bacteria: Bacillus subtilis and Streptococcus pneumonia) and fungi (Aspergillus fumigates and Candida albicans). The anticancer activity of the new compounds had been tested against breast (MFC7) and colon (HCT-116) cell lines. The results showed high activity for the synthesized compounds.

Dockomatic - automated ligand creation and docking.

Science.gov (United States)

Bullock, Casey W; Jacob, Reed B; McDougal, Owen M; Hampikian, Greg; Andersen, Tim

2010-11-08

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. 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. DockoMatic significantly reduces the complexity of managing multiple AutoDock jobs by facilitating ligand and AutoDock job creation and management.

Dockomatic - automated ligand creation and docking

Directory of Open Access Journals (Sweden)

Hampikian Greg

2010-11-01

Full Text Available Abstract 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.

Assessing potential peptide targeting ligands by quantification of cellular adhesion of model nanoparticles under flow conditions.

Science.gov (United States)

Broda, Ellen; Mickler, Frauke Martina; Lächelt, Ulrich; Morys, Stephan; Wagner, Ernst; Bräuchle, Christoph

2015-09-10

Sophisticated drug delivery systems are coated with targeting ligands to improve the specific adhesion to surface receptors on diseased cells. In our study, we developed a method with which we assessed the potential of peptide ligands to specifically bind to receptor overexpressing target cells. Therefore, a microfluidic setup was used where the cellular adhesion of nanoparticles with ligand and of control nanoparticles was observed in parallel under the same experimental conditions. The effect of the ligand on cellular binding was quantified by counting the number of adhered nanoparticles with ligand and differently labeled control nanoparticles on single cells after incubation under flow conditions. To provide easy-to-synthesize, stable and reproducible nanoparticles which mimic the surface characteristics of drug delivery systems and meet the requirements for quantitative analysis, latex beads based on amine-modified polystyrene were used as model nanoparticles. Two short peptides were tested to serve as targeting ligand on the beads by increasing the specific binding to HuH7 cells. The c-Met binding peptide cMBP2 was used for hepatocyte growth factor receptor (c-Met) targeting and the peptide B6 for transferrin receptor (TfR) targeting. The impact of the targeting peptide on binding was investigated by comparing the beads with ligand to different internal control beads: 1) without ligand and tailored surface charge (electrostatic control) and 2) with scrambled peptide and similar surface charge, but a different amino acid sequence (specificity control). Our results demonstrate that the method is very useful to select suitable targeting ligands for specific nanoparticle binding to receptor overexpressing tumor cells. We show that the cMBP2 ligand specifically enhances nanoparticle adhesion to target cells, whereas the B6 peptide mediates binding to tumor cells mainly by nonspecific interactions. All together, we suggest that cMBP2 is a suitable choice for

Context-Dependent Functional Divergence of the Notch Ligands DLL1 and DLL4 In Vivo.

Directory of Open Access Journals (Sweden)

Kristina Preuße

2015-06-01

Full Text Available Notch signalling is a fundamental pathway that shapes the developing embryo and sustains adult tissues by direct communication between ligand and receptor molecules on adjacent cells. Among the ligands are two Delta paralogues, DLL1 and DLL4, that are conserved in mammals and share a similar structure and sequence. They activate the Notch receptor partly in overlapping expression domains where they fulfil redundant functions in some processes (e.g. maintenance of the crypt cell progenitor pool. In other processes, however, they appear to act differently (e.g. maintenance of foetal arterial identity raising the questions of how similar DLL1 and DLL4 really are and which mechanism causes the apparent context-dependent divergence. By analysing mice that conditionally overexpress DLL1 or DLL4 from the same genomic locus (Hprt and mice that express DLL4 instead of DLL1 from the endogenous Dll1 locus (Dll1Dll4ki, we found functional differences that are tissue-specific: while DLL1 and DLL4 act redundantly during the maintenance of retinal progenitors, their function varies in the presomitic mesoderm (PSM where somites form in a Notch-dependent process. In the anterior PSM, every cell expresses both Notch receptors and ligands, and DLL1 is the only activator of Notch while DLL4 is not endogenously expressed. Transgenic DLL4 cannot replace DLL1 during somitogenesis and in heterozygous Dll1Dll4ki/+ mice, the Dll1Dll4ki allele causes a dominant segmentation phenotype. Testing several aspects of the complex Notch signalling system in vitro, we found that both ligands have a similar trans-activation potential but that only DLL4 is an efficient cis-inhibitor of Notch signalling, causing a reduced net activation of Notch. These differential cis-inhibitory properties are likely to contribute to the functional divergence of DLL1 and DLL4.

Polymer complexes.. XXXX. Supramolecular assembly on coordination models of mixed-valence-ligand poly[1-acrylamido-2-(2-pyridyl)ethane] complexes

Science.gov (United States)

El-Sonbati, A. Z.; El-Bindary, A. A.; Diab, M. A.

2003-02-01

The build-up of polymer metallic supramolecules based on homopolymer (1-acrylamido-2-(2-pyridyl)ethane (AEPH)) and ruthenium, rhodium, palladium as well as platinum complexes has been pursued with great interest. The homopolymer shows three types of coordination behaviour. In the mixed valence paramagnetic trinuclear polymer complexes [( 11)+( 12)] in the paper and in mononuclear polymer complexes ( 1)-( 5) it acts as a neutral bidentate ligand coordinating through the N-pyridine and NH-imino atoms, while in the mixed ligand diamagnetic poly-chelates, which are obtained from the reaction of AEPH with PdX 2 and KPtCl 4 in the presence of N-heterocyclic base consisting of polymer complexes ( 9)+( 10), and in monouclear compounds ( 6)-( 8), it behaves as a monobasic bidentate ligand coordinating through the same donor atoms. In mononuclear compounds ( 13)+( 14) it acts as a monobasic and neutral bidentate ligand coordinating only through the same donor atoms. Monomeric distorted octahedral or trimeric chlorine-bridged, approximately octahedral structures are proposed for these polymer complexes. The poly-chelates are of 1:1, 1:2 and 3:2 (metal-homopolymer) stoichiometry and exhibit six coordination. The values of ligand field parameters were calculated. The homopolymer and their polymer complexes have been characterized physicochemically.

Synthesis and photoluminescence properties of silver(I) complexes based on N-benzoyl-L-glutamic acid and N-donor ligands with different flexibility

Science.gov (United States)

Yan, Ming-Jie; Feng, Qi; Song, Hui-Hua

2016-05-01

By changing the N-donor ancillary ligand, three novel silver (I) complexes {[Ag(HbzgluO) (4,4‧-bipy)]·H2O}n (1), {[Ag2(HbzgluO)2 (bpe)2]·2H2O}n (2) and {[Ag(HbzgluO)(bpp)]·2H2O}n (3) (H2bzgluO = N-benzoyl-L-glutamic acid, 4,4‧-bipy = 4,4ˊ-bipyridine, bpe = 1,2-di(4-pyridyl)ethane, bpp = 1,3-di(4-pyridyl)propane) were synthesized. Their structures have been determined by single-crystal X-ray diffraction analyses and further characterized by elemental analyses, IR spectra, powder X-ray diffraction (PXRD), and thermogravimetric analyses (TGA). In this study, the N-donor ligands are changed from rigidity (4,4‧-bipy), quasi-flexibility (bpe) to flexibility (bpp), the structures of complexes also change. Complex 1 features a 1D chain structure which is further linked together to construct a 2D supramolecular structure through hydrogen bonds. Complex 2 is a 1D double-chains configuration which eventually forms a 3D supramolecular network via hydrogen bonding interactions. Whereas, complex 3 exhibits a 2D pleated grid structure which is linked by hydrogen bonding interactions into a 3D supramolecular network. The present observations demonstrate that the modulation of coordination polymers with different structures can accomplish by changing the spacer length of N-donor ligands. In addition, the solid-state circular dichroism (CD) spectra indicated that compound 2 exhibited negative cotton effect which originated from the chiral ligands H2bzgluO and the solid-state fluorescence spectra of the three complexes demonstrated the auxiliary ligands have influence on the photoluminescence properties of the complexes.

Evolution of Recognition of Ligands from Gram-Positive Bacteria: Similarities and Differences in the TLR2-Mediated Response between Mammalian Vertebrates and Teleost Fish

NARCIS (Netherlands)

Ribeiro, Carla M. S.; Hermsen, Trudi; Taverne-Thiele, Anja J.; Savelkoul, Huub F. J.; Wiegertjes, Geert F.

2010-01-01

We investigated the role of the TLR2 receptor in the recognition of ligands from Gram-positive bacteria in fish. Comparative sequence analysis showed a highly conserved Toll/IL-1 receptor domain. Although the leucine-rich repeat domain was less conserved, the position of the critical peptidoglycan

Ruthenium(II) bipyridine complexes bearing new keto-enol azoimine ligands: synthesis, structure, electrochemistry and DFT calculations.

Science.gov (United States)

Al-Noaimi, Mousa; Awwadi, Firas F; Mansi, Ahmad; Abdel-Rahman, Obadah S; Hammoudeh, Ayman; Warad, Ismail

2015-01-25

The novel azoimine ligand, Ph-NH-N=C(COCH3)-NHPh(C≡CH) (H2L), was synthesized and its molecular structure was determined by X-ray crystallography. Catalytic hydration of the terminal acetylene of H2L in the presence of RuCl3·3H2O in ethanol at reflux temperature yielded a ketone (L1=Ph-N=N-C(COCH3)=N-Ph(COCH3) and an enol (L2=Ph-N=N-C(COCH3)=N-PhC(OH)=CH2) by Markovnikov addition of water. Two mixed-ligand ruthenium complexes having general formula, trans-[Ru(bpy)(Y)Cl2] (1-2) (where Y=L1 (1) and Y=L2 (2), bpy is 2.2'-bipyrdine) were achieved by the stepwise addition of equimolar amounts of (H2L) and bpy ligands to RuCl3·3H2O in absolute ethanol. Theses complexes were characterized by elemental analyses and spectroscopic (IR, UV-Vis, and NMR (1D (1)H NMR, (13)C NMR, (DEPT-135), (DEPT-90), 2D (1)H-(1)H and (13)C-(1)H correlation (HMQC) spectroscopy)). The two complexes exhibit a quasi-reversible one electron Ru(II)/Ru(III) oxidation couple at 604 mV vs. ferrocene/ferrocenium (Cp2Fe(0/+)) couple along with one electron ligand reduction at -1010 mV. The crystal structure of complex 1 showed that the bidentate ligand L1 coordinates to Ru(II) by the azo- and imine-nitrogen donor atoms. The complex adopts a distorted trans octahedral coordination geometry of chloride ligands. The electronic spectra of 1 and 1+ in dichloromethane have been modeled by time-dependent density functional theory (TD-DFT). Copyright © 2014 Elsevier B.V. All rights reserved.

Dispatched and scube mediate the efficient secretion of the cholesterol-modified hedgehog ligand.

Science.gov (United States)

Tukachinsky, Hanna; Kuzmickas, Ryan P; Jao, Cindy Y; Liu, Jing; Salic, Adrian

2012-08-30

The Hedgehog (Hh) signaling pathway plays critical roles in metazoan development and in cancer. How the Hh ligand is secreted and spreads to distant cells is unclear, given its covalent modification with a hydrophobic cholesterol molecule, which makes it stick to membranes. We demonstrate that Hh ligand secretion from vertebrate cells is accomplished via two distinct and synergistic cholesterol-dependent binding events, mediated by two proteins that are essential for vertebrate Hh signaling: the membrane protein Dispatched (Disp) and a member of the Scube family of secreted proteins. Cholesterol modification is sufficient for a heterologous protein to interact with Scube and to be secreted in a Scube-dependent manner. Disp and Scube recognize different structural aspects of cholesterol similarly to how Niemann-Pick disease proteins 1 and 2 interact with cholesterol, suggesting a hand-off mechanism for transferring Hh from Disp to Scube. Thus, Disp and Scube cooperate to dramatically enhance the secretion and solubility of the cholesterol-modified Hh ligand. Copyright © 2012 The Authors. Published by Elsevier Inc. All rights reserved.

Labeled receptor ligands for spect

International Nuclear Information System (INIS)

Kung, H.F.

1989-01-01

Receptor specific imaging agents for single photon emission computed tomography (SPECT) can potentially be useful in the understanding of basic biochemistry and pharmacology of receptors. SPECT images may also provide tools for evaluation of density and binding kinetics of a specific receptor, information important for diagnosis and patient management. Basic requirements for receptor imaging agents are: (a) they are labeled with short-lived isotopes, (b) they show high selectivity and specific uptake, (c) they exhibit high target/background ratio, and (d) they can be modeled to obtain quantitative information. Several good examples of CNS receptor specific ligands labeled with I-123 have been developed, including iodoQNB, iodoestrogen iodobenzadiazepine, iodobenazepine, iodobenzamides for muscarinic, estrogen benzadiazepine, D-1 and D-2 dopamine receptors. With the advent of newer and faster SPECT imaging devices, it may be feasible to quantitate the receptor density by in vivo imaging techniques. These new brain imaging agents can provide unique diagnostic information, which may not be available through other imaging modalities, such as CT and MRI

Adaptor proteins intersectin 1 and 2 bind similar proline-rich ligands but are differentially recognized by SH2 domain-containing proteins.

Directory of Open Access Journals (Sweden)

Olga Novokhatska

Full Text Available BACKGROUND: Scaffolding proteins of the intersectin (ITSN family, ITSN1 and ITSN2, are crucial for the initiation stage of clathrin-mediated endocytosis. These proteins are closely related but have implications in distinct pathologies. To determine how these proteins could be separated in certain cell pathways we performed a comparative study of ITSNs. METHODOLOGY/PRINCIPAL FINDINGS: We have shown that endogenous ITSN1 and ITSN2 colocalize and form a complex in cells. A structural comparison of five SH3 domains, which mediated most ITSNs protein-protein interactions, demonstrated a similarity of their ligand-binding sites. We showed that the SH3 domains of ITSN2 bound well-established interactors of ITSN1 as well as newly identified ITSNs protein partners. A search for a novel interacting interface revealed multiple tyrosines that could be phosphorylated in ITSN2. Phosphorylation of ITSN2 isoforms but not ITSN1 short isoform was observed in various cell lines. EGF stimulation of HeLa cells enhanced tyrosine phosphorylation of ITSN2 isoforms and enabled their recognition by the SH2 domains of the Fyn, Fgr and Abl1 kinases, the regulatory subunit of PI3K, the adaptor proteins Grb2 and Crk, and phospholipase C gamma. The SH2 domains mentioned were unable to bind ITSN1 short isoform. CONCLUSIONS/SIGNIFICANCE: Our results indicate that during evolution of vertebrates ITSN2 acquired a novel protein-interaction interface that allows its specific recognition by the SH2 domains of signaling proteins. We propose that these data could be important to understand the functional diversity of paralogous ITSN proteins.

Synthesis of novel '4+1' Tc(III)/Re(III) mixed-ligand complexes with dendritically modified ligands

International Nuclear Information System (INIS)

Gniazdowska, E.; Kuenstler, J.U.; Stephan, H.; Pietzsch, H.J.

2006-01-01

Coordination chemistry of technetium and rhenium attracts a considerable interest due to the nuclear medicine applications of their radionuclides. Inert, so-called '3+1' or '4+1' technetium/rhenium mixed-ligand complexes open a new way to application of 99 mTc/ 188 Re labeled compounds in tumor diagnosis and therapy. In the presented paper, authors describe the synthesis and study of novel 99 mTc/ 188 Re complexes with dendritically functionalized tetradentate (tripodal chelator 2,2',2''-nitrilotris(ethanethiol), NS 3 and carboxyl group-bearing ligand, NS 3 (COOH) 3 ) and monodentate (dendritically modified isocyanide, CN-R(COOMe) 3 and isocyanide-modified peptide, CN-GGY) ligands. To verify the identity of the prepared n.c.a. complexes, non-radioactive analogous '4+1' Re compounds were synthesized. The experimental data show that a dendritic modification of the tetradentate/monodentate ligands changes the complex lipophilicity and does not influence its stability

Synthesis, characterization and biological activity of symmetric dinuclear complexes derived from a novel macrocyclic compartmental ligand

Energy Technology Data Exchange (ETDEWEB)

Mruthyunjayaswamy, B.H.M.; Ijare, Omkar B.; Jadegoud, Y. [Gulbarga University (India). Dept. of Chemistry]. E-mail: bhmmswamy53@rediffmail.com

2005-07-15

A phenol based novel macrocyclic binucleating compartmental ligand N,N-bis(2,6-diiminomethyl-4-methyl-1-hydroxyphenyl)malonoyldicarboxamide was prepared. The complexes were prepared by template method by reacting 2,6-diformyl-4-methylphenol, malonoyl dihydrazide and the metal chlorides of Cu(II), Ni(II), Co(II), Cd(II), Zn(II) and Hg(II) in methanol to get a series of dinuclear complexes. The complexes were characterized by elemental analyses, conductivity measurements, magnetic susceptibility data, IR, UV-Vis, ESR, NMR and FAB mass spectral data. The dinuclear nature of the complexes was confirmed on the basis of elemental analyses, magnetic susceptibility, ESR and FAB mass spectral data. The ligand as well as Cu(II), Ni(II), Co(II) and Zn(II) complexes were tested for their antibacterial and antifungal properties against Escherichia coli, Staphyloccocus aureus, Aspergillus niger and Fusarium oxysporum. Magnetic susceptibility measurements of Cu(II), Ni(II) and Co(II) complexes reveal that these complexes exhibit antiferromagnetic coupling behavior due to the presence of two metal ions in close proximity. FAB mass spectrum of the Cu(II) complex gave a clear evidence for the dinuclear nature. The ligand and the complexes were found to be less active against the tested bacteria, but the ligand alone was found active against the fungus Fusarium oxysporum. (author)

Synthesis, characterization and biological activity of symmetric dinuclear complexes derived from a novel macrocyclic compartmental ligand

International Nuclear Information System (INIS)

Mruthyunjayaswamy, B.H.M.; Ijare, Omkar B.; Jadegoud, Y.

2005-01-01

A phenol based novel macrocyclic binucleating compartmental ligand N,N-bis(2,6-diiminomethyl-4-methyl-1-hydroxyphenyl)malonoyldicarboxamide was prepared. The complexes were prepared by template method by reacting 2,6-diformyl-4-methylphenol, malonoyl dihydrazide and the metal chlorides of Cu(II), Ni(II), Co(II), Cd(II), Zn(II) and Hg(II) in methanol to get a series of dinuclear complexes. The complexes were characterized by elemental analyses, conductivity measurements, magnetic susceptibility data, IR, UV-Vis, ESR, NMR and FAB mass spectral data. The dinuclear nature of the complexes was confirmed on the basis of elemental analyses, magnetic susceptibility, ESR and FAB mass spectral data. The ligand as well as Cu(II), Ni(II), Co(II) and Zn(II) complexes were tested for their antibacterial and antifungal properties against Escherichia coli, Staphyloccocus aureus, Aspergillus niger and Fusarium oxysporum. Magnetic susceptibility measurements of Cu(II), Ni(II) and Co(II) complexes reveal that these complexes exhibit antiferromagnetic coupling behavior due to the presence of two metal ions in close proximity. FAB mass spectrum of the Cu(II) complex gave a clear evidence for the dinuclear nature. The ligand and the complexes were found to be less active against the tested bacteria, but the ligand alone was found active against the fungus Fusarium oxysporum. (author)

Evaluation of tricine and EDDA as Co-ligands for 99mTc-labeled HYNIC-MSH analogs for melanoma imaging.

Science.gov (United States)

Garcia, Maria Fernanda; Zhang, Xiuli; Gallazzi, Fabio; Fernandez, Marcelo; Moreno, Maria; Gambini, Juan Pablo; Porcal, Williams; Cabral, Pablo; Quinn, Thomas P

2015-01-01

Several radiolabeled alpha-melanocyte stimulating hormone (α-MSH) analogs have been studied for their abilities to target melanoma tumor cells through specific recognition and binding to the melanocortin receptor 1 (MCR1). In this work, a lactam bridgecyclized α-MSH analog was labeled with (99m) via the hydrazinonicotinamide (HYNIC) chelator and characterized for its melanoma tumor targeting properties. The bifunctional chelating agent HYNIC-Boc was attached to the N-terminus of the MSH peptide followed by the lactam cyclization, resulting in the HYNIC-cyc-MSH analog. The lactam cyclized peptide displayed high affinity and specificity for MC1-receptors present on B16/F1 melanoma tumor cells, exhibiting an IC50 of 6.48 nM. HYNIC-cyc-MSH was radiolabeled with (99m)Tc using two common co-ligands, tricine and EDDA. In vitro, the radiochemical stability, cell binding and efflux properties were similar between the peptides radiolabeled with tricine and EDDA as co-ligands. In vivo, biodistribution studies (n=4) demonstrated that (99m)Tc- HYNIC-cyc-MSH/tricine had superior tumor to muscle and tumor to blood ratios than (99m)Tc-HYNIC-cyc-MSH/EDDA at early time points. Planar gamma imaging of melanoma bearing mice showed that 99mTc-HYNIC-cyc-MSH/tricine was able to clearly visualize tumors, underscoring the potential utility of (99m)Tc labeled lactam cyclized MSH molecules as melanoma imaging agents.

Synthesis of Copper Nanoparticles Coated with Nitrogen Ligands

Directory of Open Access Journals (Sweden)

Rubén Sierra-Ávila

2014-01-01

Full Text Available The synthesis of copper nanoparticles was studied by wet chemical methods using copper sulfate pentahydrate (CuSO4·5H2O and nitrogen ligands allylamine (AAm and polyallylamine (PAAm as stabilizers. The results suggest that the use of these ligands leads to the exclusive formation of metallic copper nanoparticles (Cu-NPs. The use of partially crosslinked polyallylamine (PAAmc leads to nanoparticles (NPs with low yields and high coating content, while linear PAAm leads to NPs with high yields and low coating content. The chemical composition of the particles was determined by XRD and average particle diameters were determined by the Debye-Scherrer equation. TGA analysis provided evidence of the content and thermal stability of the coating on the nanoparticles and PAAm. The morphology, particle size distribution, and presence of PAAm coating were observed through TEM. The use of AAm in the synthesis of NPs could be a good alternative to reduce costs. By using TGA, TEM, and DSC techniques, it was determined that synthesized NPs with AAm presented a coating with similar characteristics to NPs with PAAm, suggesting that AAm underwent polymerization during the synthesis.

On the analysis and comparison of conformer-specific essential dynamics upon ligand binding to a protein

International Nuclear Information System (INIS)

Grosso, Marcos; Kalstein, Adrian; Parisi, Gustavo; Fernandez-Alberti, Sebastian; Roitberg, Adrian E.

2015-01-01

The native state of a protein consists of an equilibrium of conformational states on an energy landscape rather than existing as a single static state. The co-existence of conformers with different ligand-affinities in a dynamical equilibrium is the basis for the conformational selection model for ligand binding. In this context, the development of theoretical methods that allow us to analyze not only the structural changes but also changes in the fluctuation patterns between conformers will contribute to elucidate the differential properties acquired upon ligand binding. Molecular dynamics simulations can provide the required information to explore these features. Its use in combination with subsequent essential dynamics analysis allows separating large concerted conformational rearrangements from irrelevant fluctuations. We present a novel procedure to define the size and composition of essential dynamics subspaces associated with ligand-bound and ligand-free conformations. These definitions allow us to compare essential dynamics subspaces between different conformers. Our procedure attempts to emphasize the main similarities and differences between the different essential dynamics in an unbiased way. Essential dynamics subspaces associated to conformational transitions can also be analyzed. As a test case, we study the glutaminase interacting protein (GIP), composed of a single PDZ domain. Both GIP ligand-free state and glutaminase L peptide-bound states are analyzed. Our findings concerning the relative changes in the flexibility pattern upon binding are in good agreement with experimental Nuclear Magnetic Resonance data

On the analysis and comparison of conformer-specific essential dynamics upon ligand binding to a protein

Energy Technology Data Exchange (ETDEWEB)

Grosso, Marcos; Kalstein, Adrian; Parisi, Gustavo; Fernandez-Alberti, Sebastian, E-mail: sfalberti@gmail.com [Universidad Nacional de Quilmes, Roque Saenz Peña 352, B1876BXD Bernal (Argentina); Roitberg, Adrian E. [Departments of Physics and Chemistry, University of Florida, Gainesville, Florida 32611 (United States)

2015-06-28

The native state of a protein consists of an equilibrium of conformational states on an energy landscape rather than existing as a single static state. The co-existence of conformers with different ligand-affinities in a dynamical equilibrium is the basis for the conformational selection model for ligand binding. In this context, the development of theoretical methods that allow us to analyze not only the structural changes but also changes in the fluctuation patterns between conformers will contribute to elucidate the differential properties acquired upon ligand binding. Molecular dynamics simulations can provide the required information to explore these features. Its use in combination with subsequent essential dynamics analysis allows separating large concerted conformational rearrangements from irrelevant fluctuations. We present a novel procedure to define the size and composition of essential dynamics subspaces associated with ligand-bound and ligand-free conformations. These definitions allow us to compare essential dynamics subspaces between different conformers. Our procedure attempts to emphasize the main similarities and differences between the different essential dynamics in an unbiased way. Essential dynamics subspaces associated to conformational transitions can also be analyzed. As a test case, we study the glutaminase interacting protein (GIP), composed of a single PDZ domain. Both GIP ligand-free state and glutaminase L peptide-bound states are analyzed. Our findings concerning the relative changes in the flexibility pattern upon binding are in good agreement with experimental Nuclear Magnetic Resonance data.

Structural basis for the ligand-binding specificity of fatty acid-binding proteins (pFABP4 and pFABP5) in gentoo penguin.

Science.gov (United States)

Lee, Chang Woo; Kim, Jung Eun; Do, Hackwon; Kim, Ryeo-Ok; Lee, Sung Gu; Park, Hyun Ho; Chang, Jeong Ho; Yim, Joung Han; Park, Hyun; Kim, Il-Chan; Lee, Jun Hyuck

2015-09-11

Fatty acid-binding proteins (FABPs) are involved in transporting hydrophobic fatty acids between various aqueous compartments of the cell by directly binding ligands inside their β-barrel cavities. Here, we report the crystal structures of ligand-unbound pFABP4, linoleate-bound pFABP4, and palmitate-bound pFABP5, obtained from gentoo penguin (Pygoscelis papua), at a resolution of 2.1 Å, 2.2 Å, and 2.3 Å, respectively. The pFABP4 and pFABP5 proteins have a canonical β-barrel structure with two short α-helices that form a cap region and fatty acid ligand binding sites in the hydrophobic cavity within the β-barrel structure. Linoleate-bound pFABP4 and palmitate-bound pFABP5 possess different ligand-binding modes and a unique ligand-binding pocket due to several sequence dissimilarities (A76/L78, T30/M32, underlining indicates pFABP4 residues) between the two proteins. Structural comparison revealed significantly different conformational changes in the β3-β4 loop region (residues 57-62) as well as the flipped Phe60 residue of pFABP5 than that in pFABP4 (the corresponding residue is Phe58). A ligand-binding study using fluorophore displacement assays shows that pFABP4 has a relatively strong affinity for linoleate as compared to pFABP5. In contrast, pFABP5 exhibits higher affinity for palmitate than that for pFABP4. In conclusion, our high-resolution structures and ligand-binding studies provide useful insights into the ligand-binding preferences of pFABPs based on key protein-ligand interactions. Copyright © 2015 Elsevier Inc. All rights reserved.

Bexarotene ligand pharmaceuticals.

Science.gov (United States)

Hurst, R E

2000-12-01

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

An unbiased method to build benchmarking sets for ligand-based virtual screening and its application to GPCRs.

Science.gov (United States)

Xia, Jie; Jin, Hongwei; Liu, Zhenming; Zhang, Liangren; Wang, Xiang Simon

2014-05-27

Benchmarking data sets have become common in recent years for the purpose of virtual screening, though the main focus had been placed on the structure-based virtual screening (SBVS) approaches. Due to the lack of crystal structures, there is great need for unbiased benchmarking sets to evaluate various ligand-based virtual screening (LBVS) methods for important drug targets such as G protein-coupled receptors (GPCRs). To date these ready-to-apply data sets for LBVS are fairly limited, and the direct usage of benchmarking sets designed for SBVS could bring the biases to the evaluation of LBVS. Herein, we propose an unbiased method to build benchmarking sets for LBVS and validate it on a multitude of GPCRs targets. To be more specific, our methods can (1) ensure chemical diversity of ligands, (2) maintain the physicochemical similarity between ligands and decoys, (3) make the decoys dissimilar in chemical topology to all ligands to avoid false negatives, and (4) maximize spatial random distribution of ligands and decoys. We evaluated the quality of our Unbiased Ligand Set (ULS) and Unbiased Decoy Set (UDS) using three common LBVS approaches, with Leave-One-Out (LOO) Cross-Validation (CV) and a metric of average AUC of the ROC curves. Our method has greatly reduced the "artificial enrichment" and "analogue bias" of a published GPCRs benchmarking set, i.e., GPCR Ligand Library (GLL)/GPCR Decoy Database (GDD). In addition, we addressed an important issue about the ratio of decoys per ligand and found that for a range of 30 to 100 it does not affect the quality of the benchmarking set, so we kept the original ratio of 39 from the GLL/GDD.

Photodegradation of luminescence in organic-ligand-capped Eu3+:LaF3 nano-particles

International Nuclear Information System (INIS)

King, Gavin G. G.; Taylor, Luke R.; Longdell, Jevon J.; Clarke, David J.; Quilty, J. W.

2014-01-01

The luminescence from europium doped lanthanum trifluoride (Eu 3+ :LaF 3 ) nano-crystals can be greatly enhanced by capping with β-diketonate organic ligands. Here, we report on photo-stability measurements for the case of nano-crystals capped with thenoyltrifluroacetone (TTA) and compared with those capped with an inactive ligand, oleic acid. With exposure to UV pump light, we observed significant decrease in fluorescence and change in emission spectrum of the TTA-capped nano-particles whilst the fluorescence lifetime remained approximately constant. After a dose of order 70 kJ cm −2 , the luminescence level was similar to that of oleic acid capped nano-crystals. We discuss possible mechanisms

Synthesis and characterization β-ketoamine ligands

Science.gov (United States)

Zaid, Nurzati Amani Mohamed; Hassan, Nur Hasyareeda; Karim, Nurul Huda Abd

2018-04-01

β-ketoamine ligands are important members of heterodonor ligand because of their ease of preparation and modification of both steric and/or electronic effects. Complexes with β-ketoamine has received much less attention and there has been no study about this complex with β-ketoamine in ionic liquid reported. Two type of β-ketoamine ligands which are 4-amino-3-pentene-2-onato (A) and 3-amino-2-butenoic acid methyl ester (B) have been synthesized in this work. The resulting compound formed was characterized using standard spectroscopic and structural techniques which includes 1H and 13C, NMR spectroscopy and FTIR spectroscopy. The 1H and 13C NMR spectrum displayed all the expected signals with correct integration and multiplicity. And it is proved that there are some differences between two ligands as observed in NMR and FTIR spectrum.

Synthesis, characterization, single crystal X-ray determination, fluorescence and electrochemical studies of new dinuclear nickel(II) and oxovanadium(IV) complexes containing double Schiff base ligands

Science.gov (United States)

Shafaatian, Bita; Ozbakzaei, Zahra; Notash, Behrouz; Rezvani, S. Ahmad

2015-04-01

A series of new bimetallic complexes of nickel(II) and vanadium(IV) have been synthesized by the reaction of the new double bidentate Schiff base ligands with nickel acetate and vanadyl acetylacetonate in 1:1 M ratio. In nickel and also vanadyl complexes the ligands were coordinated to the metals via the imine N and enolic O atoms. The complexes have been found to possess 1:1 metals to ligands stoichiometry and the molar conductance data revealed that the metal complexes were non-electrolytes. The nickel and vanadyl complexes exhibited distorted square planar and square pyramidal coordination geometries, respectively. The emission spectra of the ligands and their complexes were studied in methanol. Electrochemical properties of the ligands and their metal complexes were also investigated in DMSO solvent at 150 mV s-1 scan rate. The ligands and metal complexes showed both quasi-reversible and irreversible processes at this scan rate. The Schiff bases and their complexes have been characterized by FT-IR, 1H NMR, UV/Vis spectroscopies, elemental analysis and conductometry. The crystal structure of the nickel complex has been determined by single crystal X-ray diffraction.

Luminescent hybrid materials functionalized with lanthanide ethylenodiaminotetraacetate complexes containing β-diketonate as antenna ligands

Energy Technology Data Exchange (ETDEWEB)

Aguiar, Franklin P.; Costa, Israel F.; Espínola, José Geraldo P.; Faustino, Wagner M.; Moura, Jandeilson L. [Departamento de Química-Universidade Federal da Paraíba, 58051-970 João Pessoa, PB (Brazil); Brito, Hermi F.; Paolini, Tiago B. [Departamento de Química Fundamental-Instituto de Química da Universidade de São Paulo, 05508-900 São Paulo, SP (Brazil); Felinto, Maria Cláudia F.C. [Instituto de Pesquisas energéticas e Nucleares-IPEN, 05508-900 São Paulo, SP (Brazil); Teotonio, Ercules E.S., E-mail: teotonioees@quimica.ufpb.br [Departamento de Química-Universidade Federal da Paraíba, 58051-970 João Pessoa, PB (Brazil)

2016-02-15

Three organic–inorganic hybrid materials based on silica gel functionalized with (3-aminopropyl)trimethoxysilane (APTS), [3-(2-aminoetilamino)-propil]-trimetoxissilano (DAPTS) and 3-[2-(2-aminoetilamino)etilamino] propiltrimetoxysilane (TAPTS) and subsequently modified with EDTA derivative were prepared by nonhomogeneous route and were then characterized. The resulting materials named SilXN-EDTA (X=1 for APTS, 2 for DAPTS and 3 for TAPTS) were used to obtain new lanthanide Ln{sup 3+}-β-diketonate (Ln{sup 3+}=Eu{sup 3+}, Gd{sup 3+} and Tb{sup 3+}) complexes covalently linked to the functionalized silica gel surfaces (named SilXN-EDTALn-dik, dik=tta, dbm, bzac and acac). The photophysical properties of the new luminescent materials were investigated and compared with those with similar system presenting water molecules coordinated to the lanthanide ions, SilXN-EDTALn-H{sub 2}O. The SilXN-EDTAEu-dik and SilXN-EDTATb-dik systems displayed characteristic red and green luminescence when excited by UV radiation. Furthermore, the quantitative results showed that the emission quantum efficiency (η), experimental intensity parameters Ω{sub 2} and Ω{sub 4}, and Einstein's emission coefficient (A{sub 0J}) of the SilXN-EDTAEu-dik materials were largely dependent on the ligands. Based on the luminescence data, the most efficient intramolecular energy transfer processes were found to the SilXN-EDTAEu-dik (dik: tta and dbm) and SilXN-EDTATb-acac materials, which exhibited more pure emission colors. These materials are promising red and green phosphors, respectively. - Highlights: • New highly luminescent hybrid materials containing lanthanide-EDTA complexes. • The effect of three silylanting agent on the adsorption and luminescent properties has been studied. • The luminescence sensitizing by different β-diketonate ligands have been investigated.

New pinene-derived pyridines as bidentate chiral ligands

Czech Academy of Sciences Publication Activity Database

Malkov, A. V.; Stewart-Liddon, A.; Teplý, Filip; Kobr, L.; Muir, K. W.; Haigh, D.; Kočovský, P.

2008-01-01

Roč. 64, č. 18 (2008), s. 4011-4025 ISSN 0040-4020 Institutional research plan: CEZ:AV0Z40550506 Keywords : chiral ligands * transition metal catalysis * asymmetric catalysis * pyridine ligands * oxazoline ligands Subject RIV: CC - Organic Chemistry Impact factor: 2.897, year: 2008

Ligand-specific regulation of the extracellular surface of a G-protein-coupled receptor

Energy Technology Data Exchange (ETDEWEB)

Bokoch, Michael P.; Zou, Yaozhong; Rasmussen, Søren G.F.; Liu, Corey W.; Nygaard, Rie; Rosenbaum, Daniel M.; Fung, Juan José; Choi, Hee-Jung; Thian, Foon Sun; Kobilka, Tong Sun; Puglisi, Joseph D.; Weis, William I.; Pardo, Leonardo; Prosser, R. Scott; Mueller, Luciano; Kobilka, Brian K. (Stanford-MED); (Toronto); (BMS); (UAB, Spain)

2010-01-14

G-protein-coupled receptors (GPCRs) are seven-transmembrane proteins that mediate most cellular responses to hormones and neurotransmitters. They are the largest group of therapeutic targets for a broad spectrum of diseases. Recent crystal structures of GPCRs have revealed structural conservation extending from the orthosteric ligand-binding site in the transmembrane core to the cytoplasmic G-protein-coupling domains. In contrast, the extracellular surface (ECS) of GPCRs is remarkably diverse and is therefore an ideal target for the discovery of subtype-selective drugs. However, little is known about the functional role of the ECS in receptor activation, or about conformational coupling of this surface to the native ligand-binding pocket. Here we use NMR spectroscopy to investigate ligand-specific conformational changes around a central structural feature in the ECS of the {beta}{sub 2} adrenergic receptor: a salt bridge linking extracellular loops 2 and 3. Small-molecule drugs that bind within the transmembrane core and exhibit different efficacies towards G-protein activation (agonist, neutral antagonist and inverse agonist) also stabilize distinct conformations of the ECS. We thereby demonstrate conformational coupling between the ECS and the orthosteric binding site, showing that drugs targeting this diverse surface could function as allosteric modulators with high subtype selectivity. Moreover, these studies provide a new insight into the dynamic behaviour of GPCRs not addressable by static, inactive-state crystal structures.

Immersive Exhibitions

DEFF Research Database (Denmark)

Achiam, Marianne

2015-01-01

The immersive exhibition is a specialized exhibition genre in museums, which creates the illusion of time and place by representing key characteristics of a reference world and by integrating the visitor in this three-dimensionally reconstructed world (Mortensen 2010). A successful representation...... of the reference world depends on three criteria: whether the exhibition is staged as a coherent whole with all the displayed objects supporting the representation, whether the visitor is integrated as a component of the exhibition, and whether the content and message of the exhibition become dramatized...

"Precipitation on Nanoparticles": Attractive Intermolecular Interactions Stabilize Specific Ligand Ratios on the Surfaces of Nanoparticles.

Science.gov (United States)

Chu, Zonglin; Han, Yanxiao; Kral, Petr; Klajn, Rafal

2018-04-19

Confining organic molecules to the surfaces of inorganic nanoparticles can induce intermolecular interactions between them, which can affect the composition of the mixed self-assembled monolayers obtained by co-adsorption from solution of two different molecules. Here, we study co-adsorption of two thiolated ligands-a dialkylviologen and a zwitterionic sulfobetaine-that can interact with each other electrostatically, onto gold nanoparticles. Consequently, the nanoparticles favor a narrow range of ratios of these two molecules that is largely independent of the molar ratio in solution. We show that changing the solution molar ratio of two ligands by a factor of ~5,000 affects the on-nanoparticle ratio of these ligands by only 3 times. This behavior is reminiscent of the formation of insoluble inorganic salts (e.g., AgCl), which similarly compensate positive and negative charges upon crystallizing. Our results pave the way towards developing well-defined hybrid organic-inorganic nanostructures. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Luminescence properties of copper(I), zinc(II) and cadmium(II) coordination compounds with picoline ligands

Energy Technology Data Exchange (ETDEWEB)

Małecki, Jan Grzegorz, E-mail: gmalecki@us.edu.pl; Maroń, Anna

2017-06-15

Mononuclear coordination compounds of copper(I) – [Cu(PPh{sub 3}){sub 2}(picoline)(NO{sub 3})], zinc(II) – [ZnCl{sub 2}(picoline){sub 2}] (picoline=3– and 4–methylpyridine) and polymeric cadmium(II) – [CdCl{sub 2}(β-picoline){sub 2}]{sub n} were prepared and their luminescence properties in solid state and acetonitrile solutions were determined. Single crystal X-ray crystallography revealed distorted tetrahedral geometry around the central ions of the compounds. The compounds exhibit green photoluminescence in solid state and in acetonitrile solutions. The emission of copper(I) compounds originated from metal-to-ligand charge transfer state combined with nitrato-to-picoline charge transfer state i.e. ({sup 1}(M+X)LCT). The presence of nitrato ligand in the coordination sphere of copper(I) compounds quenches the emission. Luminescence of zinc(II) and cadmium(II) compounds results from chloride-to-picoline charge transfer state and the quantum efficiency in the case of the polymeric Cd(II) compound reaches 39%. The photoluminescence quantum yields of the mononuclear zinc(II) compounds vary from 10 to 16% depending on the conditions (solid state, solution). - Graphical abstract: Coordination compounds of copper(I), zinc(II) and polymeric cadmium(II) with picoline ligands were prepared and their luminescence properties in solid state and acetonitrile solutions were determined. The compounds exhibit green photoluminescence in solid state and in acetonitrile solutions. Emission of copper(I) compounds originated from {sup 1}(M+X)LCT state. Luminescence of zinc(II) and cadmium(II) compounds results from chloride-to-picoline charge transfer state and the quantum efficiency in the case of the polymeric Cd(II) compound reaches 39%. The photoluminescence quantum yields of the mononuclear zinc(II) compounds vary from 10 to 16% depending on the conditions (solid state, solution).

A ligand's view of target similarity

DEFF Research Database (Denmark)

Garland, Stephen L; Gloriam, David E

2011-01-01

GPCR binding site-directed techniques are rapidly evolving into powerful tools for modern drug discovery. Many of these approaches bridge chemistry and biology, which are inseparable concepts in nature but are often treated as separate worlds in drug discovery and science in general. This review ...

Glucagon-like peptide-1 receptor ligand interactions: structural cross talk between ligands and the extracellular domain.

Directory of Open Access Journals (Sweden)

Graham M West

Full Text Available 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.

Catalposide is a natural agonistic ligand of peroxisome proliferator-activated receptor-α

International Nuclear Information System (INIS)

Lee, Ji Hae; Jun, Hee-jin; Hoang, Minh-Hien; Jia, Yaoyao; Han, Xiang Hua; Lee, Dong-Ho; Lee, Hak-Ju; Hwang, Bang Yeon; Lee, Sung-Joon

2012-01-01

Highlights: ► Catalposide is a novel ligand for PPARα. ► Cell stimulated with catalposide improved fatty acid uptake, regulated target genes in fatty acid β-oxidation and synthesis. ► Catalposdie reduces hepatic triacylglycerides. ► Theses demonstrate catalposide could ameliorate hyperlipidemia and hepatic steatosis. -- Abstract: Peroxisome proliferator-activated receptor-alpha (PPARα) is a nuclear receptor that regulates the expression of genes related to cellular lipid uptake and oxidation. Thus, PPARα agonists may be important in the treatment of hypertriglyceridemia and hepatic steatosis. In this study, we demonstrated that catalposide is a novel natural PPARα agonist, identified from reporter gene assay-based activity screening with approximately 900 natural plant and seaweed extracts. Results of time-resolved fluorescence resonance energy transfer analyses suggested that the compound interacted directly with the ligand-binding domain of PPARα. Cultured hepatocytes stimulated with catalposide exhibited significantly reduced cellular triglyceride concentrations, by 21%, while cellular uptake of fatty acids was increased, by 70% (P < 0.05). Quantitative PCR analysis revealed that the increase in cellular fatty acid uptake was due to upregulation of fatty acid transporter protein-4 (+19% vs. the control) in cells stimulated with catalposide. Additionally, expression of genes related to fatty acid oxidation and high-density lipoprotein metabolism were upregulated, while that of genes related to fatty acid synthesis were suppressed. In conclusion, catalposide is hypolipidemic by activation of PPARα via a ligand-mediated mechanism that modulates the expression of in lipid metabolism genes in hepatocytes.

Ligand-assisted fabrication, structure, and luminescence properties of Fe:ZnSe quantum dots

International Nuclear Information System (INIS)

Xie, Ruishi; Zhang, Xingquan; Liu, Haifeng

2014-01-01

Highlights: • A green route is developed for synthesis of water-soluble and fluorescent Fe:ZnSe quantum dots. • Tunable luminescence intensity can be realized with different ligand-to-Zn molar ratios. • The obtained quantum dots are in the so-called “quantum confinement regime”. -- Abstract: Here, we report a synthetic route for highly emissive Fe:ZnSe quantum dots in aqueous media using the mercaptoacetic acid ligand as stabilizing agent. The structural, morphological, componential, and optical properties of the resulting quantum dots were explored by the X-ray diffraction, transmission electron microscopy, energy-dispersive X-ray spectroscopy, inductively coupled plasma mass spectrometry, X-ray photoelectron spectroscopy, Fourier transform infrared spectroscopy, photoluminescence and UV–visible absorption spectroscopies. The average crystallite size was calculated to be about ca., 4.0 nm using the Scherrer equation, which correlates well with the value obtained from the transmission electron microscopy analysis. The obtained water-soluble Fe:ZnSe quantum dots in the so-called “quantum confinement regime” are spherical shaped, possess the cubic sphalerite crystal structure, and exhibit tunable luminescence properties. The presence of mercaptoacetic acid on the surface of Fe:ZnSe quantum dots was confirmed by the Fourier transform infrared spectroscopy measurements. As the ligand/Zn molar ratio increases from 1.3 to 2.8, there is little shift in the absorption peak of the Fe:ZnSe sample, indicating that the particle size of the obtained quantum dots is not changed during the synthetic process. The photoluminescence quantum yield of the as-prepared water-soluble Fe:ZnSe quantum dots can be up to 39%. The molar ratio of ligand-to-Zn plays a crucial role in determining the final luminescence properties of the resulting quantum dots, and the maximum PL intensity appears as the ligand-to-Zn molar ratio is 2.2. In addition, the underlying mechanism for

Ligand-assisted fabrication, structure, and luminescence properties of Fe:ZnSe quantum dots

Energy Technology Data Exchange (ETDEWEB)

Xie, Ruishi, E-mail: rxie@foxmail.com; Zhang, Xingquan; Liu, Haifeng

2014-03-15

Highlights: • A green route is developed for synthesis of water-soluble and fluorescent Fe:ZnSe quantum dots. • Tunable luminescence intensity can be realized with different ligand-to-Zn molar ratios. • The obtained quantum dots are in the so-called “quantum confinement regime”. -- Abstract: Here, we report a synthetic route for highly emissive Fe:ZnSe quantum dots in aqueous media using the mercaptoacetic acid ligand as stabilizing agent. The structural, morphological, componential, and optical properties of the resulting quantum dots were explored by the X-ray diffraction, transmission electron microscopy, energy-dispersive X-ray spectroscopy, inductively coupled plasma mass spectrometry, X-ray photoelectron spectroscopy, Fourier transform infrared spectroscopy, photoluminescence and UV–visible absorption spectroscopies. The average crystallite size was calculated to be about ca., 4.0 nm using the Scherrer equation, which correlates well with the value obtained from the transmission electron microscopy analysis. The obtained water-soluble Fe:ZnSe quantum dots in the so-called “quantum confinement regime” are spherical shaped, possess the cubic sphalerite crystal structure, and exhibit tunable luminescence properties. The presence of mercaptoacetic acid on the surface of Fe:ZnSe quantum dots was confirmed by the Fourier transform infrared spectroscopy measurements. As the ligand/Zn molar ratio increases from 1.3 to 2.8, there is little shift in the absorption peak of the Fe:ZnSe sample, indicating that the particle size of the obtained quantum dots is not changed during the synthetic process. The photoluminescence quantum yield of the as-prepared water-soluble Fe:ZnSe quantum dots can be up to 39%. The molar ratio of ligand-to-Zn plays a crucial role in determining the final luminescence properties of the resulting quantum dots, and the maximum PL intensity appears as the ligand-to-Zn molar ratio is 2.2. In addition, the underlying mechanism for

Interactions between alkaline earth cations and oxo ligands. DFT study of the affinity of the Mg²+ cation for phosphoryl ligands.

Science.gov (United States)

da Costa, Leonardo Moreira; de Mesquita Carneiro, José Walkimar; Paes, Lilian Weitzel Coelho

2011-08-01

DFT (B3LYP/6-31+G(d)) calculations of Mg(2+) affinities for a set of phosphoryl ligands were performed. Two types of ligands were studied: a set of trivalent [O = P(R)] and a set of pentavalent phosphoryl ligands [O = P(R)(3)] (R = H, F, Cl, Br, OH, OCH(3), CH(3), CN, NH(2) and NO(2)), with R either bound directly to the phosphorus atom or to the para position of a phenyl ring. The affinity of the Mg(2+) cation for the ligands was quantified by means of the enthalpy for the substitution of one water molecule in the [Mg(H(2)O)(6)](2+) complex for a ligand. The enthalpy of substitution was correlated with electronic and geometric parameters. Electron-donor groups increase the interaction between the cation and the ligand, while electron-acceptor groups decrease the interaction enthalpy.

Mixed-ligand Al complex—a new approach for more high efficient OLEDs

International Nuclear Information System (INIS)

Petrova, Petia K.; Tomova, Reni L.; Stoycheva-Topalova, Rumiana T.; Kaloyanova, Stefka S.; Deligeorgiev, Todor G.

2012-01-01

The mixed-ligand Aluminum bis(8-hydroxyquinoline) acetylacetonate (Alq 2 Acac) complex was presented and its performance as electroluminescent and electron transporting layer for OLED was studied. The photophysical properties of the novel complex were investigated and compared with the properties of the parent Alq 3 . Highly efficient OLED based on the mixed-ligand Al complex was developed with two times higher luminescence and efficiency compared to the identical OLED based on the conventional Alq 3 The better performance of the devices make the novel Al complex a very promising material for OLEDs. - Highlights: ► A novel electroluminescent Alq 2 Acac complex is presented as material for OLED. ► Electroluminescent emission of Alq 2 Acac is very similar to that of commercial Alq 3 . ► Devices with Alq 2 Acac show better characteristics compared to those with Alq 3 .

Characterization of chicken thrombocyte responses to Toll-like receptor ligands.

Directory of Open Access Journals (Sweden)

Michael St Paul

Full Text Available Thrombocytes are the avian equivalent to mammalian platelets. In addition to their hemostatic effects, mammalian platelets rely in part on pattern recognition receptors, such as the Toll-like receptors (TLR, to detect the presence of pathogens and signal the release of certain cytokines. Ligands for TLRs include lipopolysaccharide (LPS, which is bound by TLR4, as well as unmethylated CpG DNA motifs, which are bound by TLR9 in mammals and TLR21 in chickens. Similar to mammalian platelets, avian thrombocytes have been shown to express TLR4 and secrete some pro-inflammatory cytokines in response to LPS treatment. However, the full extent of the contributions made by thrombocytes to host immunity has yet to be elucidated. Importantly, the mechanisms by which TLR stimulation may modulate thrombocyte effector functions have not been well characterized. As such, the objective of the present study was to gain further insight into the immunological role of thrombocytes by analyzing their responses to treatment with ligands for TLR4 and TLR21. To this end, we quantified the relative expression of several immune system genes at 1, 3, 8 and 18 hours post-treatment using real-time RT-PCR. Furthermore, production of nitric oxide and phagocytic activity of thrombocytes was measured after their activation with TLR ligands. We found that thrombocytes constitutively express transcripts for both pro- and anti-inflammatory cytokines, in addition to those associated with anti-viral responses and antigen presentation. Moreover, we found that both LPS and CpG oligodeoxynucleotides (ODN induced robust pro-inflammatory responses in thrombocytes, as characterized by more than 100 fold increase in interleukin (IL-1β, IL-6 and IL-8 transcripts, while only LPS enhanced nitric oxide production and phagocytic capabilities. Future studies may be aimed at examining the responses of thrombocytes to other TLR ligands.

Semiconductor Quantum Dots with Photoresponsive Ligands.

Science.gov (United States)

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

2016-10-01

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

The role of ligands on the equilibria between functional states of a G protein-coupled receptor.

Science.gov (United States)

Kim, Tae Hun; Chung, Ka Young; Manglik, Aashish; Hansen, Alexandar L; Dror, Ron O; Mildorf, Thomas J; Shaw, David E; Kobilka, Brian K; Prosser, R Scott

2013-06-26

G protein-coupled receptors exhibit a wide variety of signaling behaviors in response to different ligands. When a small label was incorporated on the cytosolic interface of transmembrane helix 6 (Cys-265), (19)F NMR spectra of the β2 adrenergic receptor (β2AR) reconstituted in maltose/neopentyl glycol detergent micelles revealed two distinct inactive states, an activation intermediate state en route to activation, and, in the presence of a G protein mimic, a predominant active state. Analysis of the spectra as a function of temperature revealed that for all ligands, the activation intermediate is entropically favored and enthalpically disfavored. β2AR enthalpy changes toward activation are notably lower than those observed with rhodopsin, a likely consequence of basal activity and the fact that the ionic lock and other interactions stabilizing the inactive state of β2AR are weaker. Positive entropy changes toward activation likely reflect greater mobility (configurational entropy) in the cytoplasmic domain, as confirmed through an order parameter analysis. Ligands greatly influence the overall changes in enthalpy and entropy of the system and the corresponding changes in population and amplitude of motion of given states, suggesting a complex landscape of states and substates.

Copper (II) complexes of bidentate ligands exhibit potent anti-cancer activity regardless of platinum sensitivity status.

Science.gov (United States)

Wehbe, Mohamed; Lo, Cody; Leung, Ada W Y; Dragowska, Wieslawa H; Ryan, Gemma M; Bally, Marcel B

2017-12-01

Insensitivity to platinum, either through inherent or acquired resistance, is a major clinical problem in the treatment of many solid tumors. Here, we explored the therapeutic potential of diethyldithiocarbamate (DDC), pyrithione (Pyr), plumbagin (Plum), 8-hydroxyquinoline (8-HQ), clioquinol (CQ) copper complexes in a panel of cancer cell lines that differ in their sensitivity to platins (cisplatin/carboplatin) using a high-content imaging system. Our data suggest that the copper complexes were effective against both platinum sensitive (IC 50  ~ 1 μM platinum) and insensitive (IC 50  > 5 μM platinum) cell lines. Furthermore, copper complexes of DDC, Pyr and 8-HQ had greater therapeutic activity compared to the copper-free ligands in all cell lines; whereas the copper-dependent activities of Plum and CQ were cell-line specific. Four of the copper complexes (Cu(DDC) 2 , Cu(Pyr) 2 , Cu(Plum) 2 and Cu(8-HQ) 2 ) showed IC 50 values less than that of cisplatin in all tested cell lines. The complex copper DDC (Cu(DDC) 2 ) was selected for in vivo evaluation due to its low nano-molar range activity in vitro and the availability of an injectable liposomal formulation. Liposomal (Cu(DDC) 2 ) was tested in a fast-growing platinum-resistant A2780-CP ovarian xenograft model and was found to achieve a statistically significant reduction (50%; p < 0.05) in tumour size. This work supports the potential use of copper-based therapeutics to treat cancers that are insensitive to platinum drugs.

Machine Learning Based Dimensionality Reduction Facilitates Ligand Diffusion Paths Assessment: A Case of Cytochrome P450cam.

Science.gov (United States)

Rydzewski, J; Nowak, W

2016-04-12

In this work we propose an application of a nonlinear dimensionality reduction method to represent the high-dimensional configuration space of the ligand-protein dissociation process in a manner facilitating interpretation. Rugged ligand expulsion paths are mapped into 2-dimensional space. The mapping retains the main structural changes occurring during the dissociation. The topological similarity of the reduced paths may be easily studied using the Fréchet distances, and we show that this measure facilitates machine learning classification of the diffusion pathways. Further, low-dimensional configuration space allows for identification of residues active in transport during the ligand diffusion from a protein. The utility of this approach is illustrated by examination of the configuration space of cytochrome P450cam involved in expulsing camphor by means of enhanced all-atom molecular dynamics simulations. The expulsion trajectories are sampled and constructed on-the-fly during molecular dynamics simulations using the recently developed memetic algorithms [ Rydzewski, J.; Nowak, W. J. Chem. Phys. 2015 , 143 ( 12 ), 124101 ]. We show that the memetic algorithms are effective for enforcing the ligand diffusion and cavity exploration in the P450cam-camphor complex. Furthermore, we demonstrate that machine learning techniques are helpful in inspecting ligand diffusion landscapes and provide useful tools to examine structural changes accompanying rare events.

Hydrothermal syntheses, crystal structures, and photophysical properties of two coordination polymers with mixed ligands

Science.gov (United States)

Yan, Li; Liu, Chun-Ling

2017-10-01

Two novel metal-organic coordination polymers [Cd(ipdt)(m-BDC)·3H2O]n (1) and [Pb(mip)2(NTC) ·2H2O]n (2) [ipdt = 2,6-Dimethoxy-4-(1H-1,3,7,8-tetraaza-cyclopenta[l]phenanthren-2-yl)-phenol, mip = 2-(3-methoxyphenyl)-1H-imidazo[4,5-f][1,10]phenanthroline, m-BDC = isophthalic acid, NTC = nicotinic acid] have been synthesized by hydrothermal reactions and characterized by elemental analysis, thermogravimetric (TG) analysis, infrared spectrum (IR) and single-crystal X-ray diffraction. Single-crystal X-ray diffraction reveals that 1 exhibits two-dimensional (2D) layer architecture, and 2 shows 1D chain architecture. TG analysis shows clear courses of weight loss, which corresponds to the decomposition of different ligands. The luminescent properties for the ligand ipdt, mip and complexes 1-2 are also discussed in detail, which should be acted as potential luminescent material.

Metal coordination by sterically hindered heterocyclic ligands, including 2-vinylpyridine, assessed by investigation of cobaloximes.

Science.gov (United States)

Siega, Patrizia; Randaccio, Lucio; Marzilli, Patricia A; Marzilli, Luigi G

2006-04-17

Structural and 1H NMR data have been obtained for cobaloximes with the bulkiest substituted pyridines reported so far. We have isolated in noncoordinating solvents the complexes CH3Co(DH)2L (methylcobaloxime, where DH = the monoanion of dimethylglyoxime) with L = sterically hindered N-donor ligands: quinoline, 4-CH3quinoline, 2,4-(CH3)2pyridine, and 2-R-pyridine (R = CH3, OCH3, CH2CH3, CH=CH2). We have found that the Co-N(ax) bond is very long in the structurally characterized complexes. In particular, CH3Co(DH)2(4-CH3quinoline) has a longer Co-N(ax) bond (2.193(3) A) than any reported for methylcobaloximes. The main cause of the long bonds is unambiguously identified as the steric bulk of L by the fairly linear relationship found for Co-N(ax) distance vs CCA (calculated cone angle, CCA, a computed measure of bulk) over an extensive series of methylcobaloximes. The linear relationship improves if L basicity (quantified by pKa) is taken into account. In anhydrous CDCl3 at 25 degrees C, all complexes except the 2-aminopyridine adduct exhibit 1H NMR spectra consistent with partial dissociation of L to form the methylcobaloxime dimer. 1H NMR experiments at -20 degrees C allowed us to assess qualitatively the relative binding ability of L as follows: 2,4-(CH3)2pyridine > 4-CH3quinoline approximately = quinoline approximately = 2-CH3pyridine > 2-CH3Opyridine > 2-CH3CH2pyridine > 2-CH2=CHpyridine. The broadness of the 1H NMR signals at 25 degrees C suggests a similar order for the ligand exchange rate. The lack of dissociation by 2-aminopyridine is attributed to an intramolecular hydrogen bond between the NH2 group and an oxime O atom. The weaker than expected binding of 2-vinylpyridine relative to the Co-N(ax) bond length is attributed to rotation of the 2-vinyl group required for this bulky ligand to bind to the metal center, a conclusion supported by pronounced changes in 2-vinylpyridine signals upon coordination.

Ruthenium(II) arene complexes with chelating chloroquine analogue ligands: Synthesis, characterization and in vitro antimalarial activity†

Science.gov (United States)

Glans, Lotta; Ehnbom, Andreas; de Kock, Carmen; Martínez, Alberto; Estrada, Jesús; Smith, Peter J.; Haukka, Matti; Sánchez-Delgado, Roberto A.; Nordlander, Ebbe

2012-01-01

Three new ruthenium complexes with bidentate chloroquine analogue ligands, [Ru(η6-cym)(L1)Cl]Cl (1, cym = p-cymene, L1 = N-(2-((pyridin-2-yl)methylamino)ethyl)-7-chloroquinolin-4-amine), [Ru(η6-cym)(L2)Cl]Cl (2, L2 = N-(2-((1-methyl-1H-imidazol-2-yl)methylamino)ethyl)-7-chloroquinolin-4-amine) and [Ru(η6-cym)(L3)Cl] (3, L3 = N-(2-((2-hydroxyphenyl)methylimino)ethyl)-7-chloroquinolin-4-amine) have been synthesized and characterized. In addition, the X-ray crystal structure of 2 is reported. The antimalarial activity of complexes 1–3 and ligands L1, L2 and L3, as well as the compound N-(2-(bis((pyridin-2-yl)methyl)amino)ethyl)-7-chloroquinolin-4-amine (L4), against chloroquine sensitive and chloroquine resistant Plasmodium falciparum malaria strains was evaluated. While 1 and 2 are less active than the corresponding ligands, 3 exhibits high antimalarial activity. The chloroquine analogue L2 also shows good activity against both the choloroquine sensitive and the chloroquine resistant strains. Heme aggregation inhibition activity (HAIA) at an aqueous buffer/n-octanol interface (HAIR50) and lipophilicity (D, as measured by water/n-octanol distribution coefficients) have been measured for all ligands and metal complexes. A direct correlation between the D and HAIR50 properties cannot be made because of the relative structural diversity of the complexes, but it may be noted that these properties are enhanced upon complexation of the inactive ligand L3 to ruthenium, to give a metal complex (3) with promising antimalarial activity. PMID:22249579

C-H functionalization: thoroughly tuning ligands at a metal ion, a chemist can greatly enhance catalyst's activity and selectivity.

Science.gov (United States)

Shul'pin, Georgiy B

2013-09-28

This brief essay consists of a few "exciting stories" devoted to relations within a metal-complex catalyst between a metal ion and a coordinated ligand. When, as in the case of a human couple, the rapport of the partners is cordial and a love cements these relations, a chemist finds an ideal married couple, in other words he obtains a catalyst of choice which allows him to functionalize C-H bonds very efficiently and selectively. Examples of such lucky marriages in the catalytic world of ions and ligands are discussed here. Activity of the catalyst is characterized by turnover number (TON) or turnover frequency (TOF) as well as by yield of a target product. Introducing a chelating N,N- or N,O-ligand to the catalyst molecule (this can be an iron or manganese derivative) sharply enhances its activity. However, the activity of vanadium derivatives (with additionally added to the solution pyrazinecarboxylic acid, PCA) as well as of various osmium complexes does not dramatically depend on the nature of ligands surrounding metal ions. Complexes of these metals are very efficient catalysts in oxidations with H2O2. Osmium derivatives are record-holders exhibiting extremely high TONs whereas vanadium complexes are on the second position. Finally, elegant examples of alkane functionalization on the ions of non-transition metals (aluminium, gallium etc.) are described when one ligand within the metal complex (namely, hydroperoxyl ligand HOO(-)) helps other ligand of this complex (H2O2 molecule coordinated to the metal) to disintegrate into two species, generating very reactive hydroxyl radical. Hydrogen peroxide molecule, even ligated to the metal ion, is perfectly stable without the assistance of the neighboring HOO(-) ligand. This ligand can be easily oxidized donating an electron to its partner ligand (H2O2). In an analogous case, when the central ion in the catalyst is a transition metal, this ion changing its oxidation state can donate an electron to the coordinated H2O2

Metal-Ligand Cooperative Reactivity in the (pseudo)-Dearomatized PNX(P) Systems: the Influence of the Zwitterionic Form in Dearomatized Pincer Complexes

KAUST Repository

Goncalves, Theo

2017-09-01

The concept of aromaticity in pincer ligands and complexes was discussed in order to provide insights into their metal-ligand cooperative activities. The aromatic PNx(P) and dearomatized PNx(P)* pincer ligands and the corresponding transition metal complexes were studied with the nucleus-independent chemical shift (NICSzz), anisotropy of the current (induced) density (ACID), isochemical shielding surfaces (ICSSzz), harmonic oscillator model of aromaticity (HOMA), MCBO, Shannon aromaticity, and natural bond order (NBO) analyses. The study on the model systems showed that for the dearomatized species the decrease of the NICS(1)zz value comes with the larger contribution of the aromatic zwitterionic mesomeric form. In all examples, the incorporation of the metal center into the pincer ligand decreases the NICS(1)zz values. The DFT calculations support the dearomatized pyridine ring in PNP* or PNN* ligand indeed being nonaromatic, in contrast to the PN3(P)* ligand which has partial aromatic character due to the larger contribution of the zwitterionic resonance structure. The difference in aromaticity between the rings contributes to the thermodynamic balance of the metal ligand cooperative reactions, changing the energetics of the process when different dearomatized pincer ligands are used. This was further exemplified by aromaticity analysis of the heterolytic hydrogen cleavage reaction of ruthenium PNN complexes of Milstein and the PN3 of Huang, with similar geometries but distinctive thermodynamic preference.

Metal-Ligand Cooperative Reactivity in the (pseudo)-Dearomatized PNX(P) Systems: the Influence of the Zwitterionic Form in Dearomatized Pincer Complexes

KAUST Repository

Goncalves, Theo; Huang, Kuo-Wei

2017-01-01

The concept of aromaticity in pincer ligands and complexes was discussed in order to provide insights into their metal-ligand cooperative activities. The aromatic PNx(P) and dearomatized PNx(P)* pincer ligands and the corresponding transition metal complexes were studied with the nucleus-independent chemical shift (NICSzz), anisotropy of the current (induced) density (ACID), isochemical shielding surfaces (ICSSzz), harmonic oscillator model of aromaticity (HOMA), MCBO, Shannon aromaticity, and natural bond order (NBO) analyses. The study on the model systems showed that for the dearomatized species the decrease of the NICS(1)zz value comes with the larger contribution of the aromatic zwitterionic mesomeric form. In all examples, the incorporation of the metal center into the pincer ligand decreases the NICS(1)zz values. The DFT calculations support the dearomatized pyridine ring in PNP* or PNN* ligand indeed being nonaromatic, in contrast to the PN3(P)* ligand which has partial aromatic character due to the larger contribution of the zwitterionic resonance structure. The difference in aromaticity between the rings contributes to the thermodynamic balance of the metal ligand cooperative reactions, changing the energetics of the process when different dearomatized pincer ligands are used. This was further exemplified by aromaticity analysis of the heterolytic hydrogen cleavage reaction of ruthenium PNN complexes of Milstein and the PN3 of Huang, with similar geometries but distinctive thermodynamic preference.

Preparation of Different Substitued Polypyridine Ligands, Ruthenium(II)-Bridged Complexes and Spectoscopıc Studies.

Science.gov (United States)

Obali, Aslihan Yilmaz; Ucan, Halil Ismet

2016-09-01

Novel different substitued polypyridine ligands 4-((4-(1H-imidazo[4,5-f][1,10]phenanthroline-2-yl)phenoxy)methyl)benzaldehyde (BA-PPY), (E)-N-(4-((4-(1H-imidazo[4,5-f][1,10]phenanthroline-2-yl)phenoxy)methyl)benzylidene)-pyrene-4-amine (PR-PPY), (E)-N-(4-((4-(1H-imidazo[4,5-f][1,10] phenanthroline-2-yl)phenoxy)methyl)benzylidene)-1,10-phenanthroline-5amine (FN-PPY), 2-(4-(bromomethyl)phenyl)-1H-imidazo[4,5-f][1,10] phenanthroline (BR-PPY), 2-(4-(azidomethyl)phenyl)-1H-imidazo[4,5-f][1,10]phenanthroline (N3-PPY) and triazole containing polypyridine ligand 3,4-bis[(4-(metoxy)-1,2,3-triazole)1-methylphenyl)-1H-imidazo[4,5-f][1,10]phenanthroline)] benzaldehyde (BA-DIPPY) and Ruthenium(II) complexes were synthesized and characterized. Their photopysical properties were investigated. The complexes RuP(PR-PPY), RuB(PR-PPY, RuP(FN-PPY) and RuB(FN-PPY) exhibited a broad absorption bands at 485, 475, 476, and 453 nm, respectively, assignable to the spin-allowed MLCT (dπ-π*) transition. The emission maxima of the pyrene-appended polypyridine ligand PR-PPY was observed at λems = 616 nm and the phenanthroline-appended polypyridine ligand FN-PPY was observed at λems = 668 nm. And the emission maxima of the complexes RuP(PR-PPY), RuB(PR-PPY), RuP(FN-PPY) and RuB(FN-PPY) were observed at λems = 646, 646, 685 and 685 nm, respectively. As seen in fluorescence spectra, the fluorescence intensities of the ligands are higher than their metal complexes. This is because of quenching effect of Ruthenium(II) metal on chromophore groups.

Discovering protein-ligand chalcogen bonding in the protein data bank using endocyclic sulfur-containing heterocycles as ligand search subsets.

Science.gov (United States)

Mitchell, Miguel O

2017-09-24

The chalcogen bond, the noncovalent, electrostatic attraction between covalently bonded atoms in group 16 and Lewis bases, is present in protein-ligand interactions based on X-ray structures deposited in the Protein Data Bank (PDB). Discovering protein-ligand chalcogen bonding in the PDB employed a strategy that focused on searching the database for protein complexes of five-membered, heterocyclic ligands containing endocyclic sulfur with endo electron-withdrawing groups (isothiazoles; thiazoles; 1,2,3-, 1,2.4-, 1,2,5-, 1,3,4-thiadiazoles) and thiophenes with exo electron-withdrawing groups, e.g., 2-chloro, 2-bromo, 2-amino, 2-alkylthio. Out of 930 ligands investigated, 33 or 3.5% have protein-ligand S---O interactions of which 31 are chalcogen bonds and two appear to be S---HO hydrogen bonds. The bond angles for some of the chalcogen bonds found in the PDB are less than 90°, and an electrostatic model is proposed to explain this phenomenon.

Synthesis, physicochemical studies and biological evaluation of unimetallic and heterobimetallic complexes of hexadentate dihydrazone ligands

Directory of Open Access Journals (Sweden)

Fathy A. El Saied

2017-03-01

Full Text Available A new coordination unimetallic and heterobimetallic complexes of hexadentate N2O4 donor dihydrazone ligands were prepared by the condensation of 4-formyl antipyrine with adipic dihydrazide and succinic dihydrazide. The ligands (1 and (11 and their complexes thoroughly characterized using various analytical, physical and spectroscopic techniques, which indicate a distorted octahedral geometry around the metal ions. The ESR spectra of solid copper(II complexes (2–4 and (12–14 showed axial symmetry with g||>g⊥ > ge, indicating distorted octahedral structure and the presence of the unpaired electron in a d(x2−y2 orbital with significant covalent bond character. The antimicrobial activity results of the metal compounds (2–5, (7, (10, (12–15 and (17 show that, all these complexes exhibit inhibitory moderate to mild effects towards Bacillus subtilis, Escherichia coli and Aspergillus niger.

Novel bispidine ligands with a possible application in nuclear medicine; Neue Bispidin-Liganden mit potenzieller Anwendung in der Nuklearmedizin

Energy Technology Data Exchange (ETDEWEB)

Rudolf, Henning

2013-10-24

Due to our current way of life and the environmental influences we are exposed in the industrial nations, cancer diseases turn out to be a more and more serious threat to our civilization. The ongoing research during the last decades leads to a better insight in cancer diseases and enables an earlier recognition of developing carcinoma. The detection of pathological tissue changes at an early stage increases the patients' chances of cure. Magnetic resonance tomography (MRT) and computed tomography (CT) as well as radiopharmaceutically assisted imaging techniques, like positron emission tomography (PET) and scintigraphy are an indispensable clinical tool in the oncological early diagnosis. By the development of multimodality imaging agents that combine the benefits of several imaging techniques, the early recognition of tumors can be more efficient and in consequence a matching therapy can be applied. This thesis deals with the synthesis of novel bispidine based ligands and their transition metal complexes as potential mono- and bimodal imaging agents for a {sup 64}Cu-assisted radiopharmaceutical application in positron emission tomography (PET) and optical imaging (OI). The synthesized ligands L and L{sup OH} are offering the opportunity to build up a ruthenium(II) polypyridine complex by one of the ligand's donor sets, to act as a fluorescence dye for optical imaging (OI), and to coordinate {sup 64}Cu{sup II} by the ligand's vacant cavity for positron emission tomography (PET). The Ru{sup II} complex exhibits two different fluorescence activities with two different lifetimes and only one of the two fluorescences is quenched by subsequent complexation of Cu{sup II}. The calculated Cu{sup II} stability constant of L and L{sup OH} is similar to that of the isomeric ligand N{sub 2}py{sub 2} which has been already evaluated as a {sup 64}Cu-radiotracer. Further transition metal complexes of Fe{sup II}, Fe{sup III} and Mn{sup II} are dealing with

Chimeric RXFP1 and RXFP2 receptors highlight the similar mechanism of activation utilizing their N-terminal low density lipoprotein class A modules

Directory of Open Access Journals (Sweden)

Shoni eBruell

2013-11-01

Full Text Available Relaxin family peptide (RXFP receptors 1 and 2 are unique G-protein coupled receptors in that they contain an N-terminal low density lipoprotein type A (LDLa module which is necessary for receptor activation. The current hypothesis suggests that upon ligand binding the LDLa module interacts with the transmembrane (TM domain of a homodimer partner receptor to induce the active receptor conformations. We recently demonstrated that three residues in the N-terminus of the RXFP1 LDLa module are potentially involved in hydrophobic interactions with the receptor to drive activation. RXFP2 shares two out of three of the residues implicated, suggesting that the two LDLa modules could be interchanged without adversely affecting activity. However, in 2007 it was shown that a chimera consisting of the RXFP1 receptor with its LDLa swapped for that of RXFP2 did not signal. We noticed this construct also contained the RXFP2 region linking the LDLa to the leucine-rich repeats. We therefore constructed chimeric RXFP1 and RXFP2 receptors with their LDLa modules swapped immediately C-terminally to the final cysteine residue of the module, retaining the native linker. In addition, we exchanged the TM domains of the chimeras to explore if matching the LDLa module with the TM domain of its native receptor altered activity. All of the chimeras were expressed at the surface of HEK293T cells with ligand binding profiles similar to the wild-type receptors. Importantly, as predicted, ligand binding was able to induce cAMP based signalling. Chimeras of RXFP1 with the LDLa of RXFP2 demonstrated reduced H2 relaxin potency with the pairing of the RXFP2 TM with the RXFP2 LDLa necessary for full ligand efficacy. In contrast the ligand mediated potencies and efficacies on the RXFP2 chimeras were similar suggesting the RXFP1 LDLa module has similar efficacy on the RXFP2 TM domain. Our studies demonstrate the LDLa modules of RXFP1 and RXFP2 modulate receptor activation via a

An Unusual Ligand Coordination Gives Rise to a New Family of Rhodium Metalloinsertors with Improved Selectivity and Potency

Science.gov (United States)

2015-01-01

Rhodium metalloinsertors are octahedral complexes that bind DNA mismatches with high affinity and specificity and exhibit unique cell-selective cytotoxicity, targeting mismatch repair (MMR)-deficient cells over MMR-proficient cells. Here we describe a new generation of metalloinsertors with enhanced biological potency and selectivity, in which the complexes show Rh–O coordination. In particular, it has been found that both Δ- and Λ-[Rh(chrysi)(phen)(DPE)]2+ (where chrysi =5,6 chrysenequinone diimmine, phen =1,10-phenanthroline, and DPE = 1,1-di(pyridine-2-yl)ethan-1-ol) bind to DNA containing a single CC mismatch with similar affinities and without racemization. This is in direct contrast with previous metalloinsertors and suggests a possible different binding disposition for these complexes in the mismatch site. We ascribe this difference to the higher pKa of the coordinated immine of the chrysi ligand in these complexes, so that the complexes must insert into the DNA helix with the inserting ligand in a buckled orientation; spectroscopic studies in the presence and absence of DNA along with the crystal structure of the complex without DNA support this assignment. Remarkably, all members of this new family of compounds have significantly increased potency in a range of cellular assays; indeed, all are more potent than cisplatin and N-methyl-N′-nitro-nitrosoguanidine (MNNG, a common DNA-alkylating chemotherapeutic agent). Moreover, the activities of the new metalloinsertors are coupled with high levels of selective cytotoxicity for MMR-deficient versus proficient colorectal cancer cells. PMID:25254630

Similar or different? The role of the ventrolateral prefrontal cortex in similarity detection.

Directory of Open Access Journals (Sweden)

Béatrice Garcin

Full Text Available Patients with frontal lobe syndrome can exhibit two types of abnormal behaviour when asked to place a banana and an orange in a single category: some patients categorize them at a concrete level (e.g., "both have peel", while others continue to look for differences between these objects (e.g., "one is yellow, the other is orange". These observations raise the question of whether abstraction and similarity detection are distinct processes involved in abstract categorization, and that depend on separate areas of the prefrontal cortex (PFC. We designed an original experimental paradigm for a functional magnetic resonance imaging (fMRI study involving healthy subjects, confirming the existence of two distinct processes relying on different prefrontal areas, and thus explaining the behavioural dissociation in frontal lesion patients. We showed that: 1 Similarity detection involves the anterior ventrolateral PFC bilaterally with a right-left asymmetry: the right anterior ventrolateral PFC is only engaged in detecting physical similarities; 2 Abstraction per se activates the left dorsolateral PFC.

L-Asp is a useful tool in the purification of the ionotropic glutamate receptor A2 ligand-binding domain

DEFF Research Database (Denmark)

Krintel, Christian; Frydenvang, Karla; Ceravalls de Rabassa, Anna

2014-01-01

In purification of the ionotropic glutamate receptor A2 (GluA2) ligand-binding domain (LBD), L-Glu supplemented buffers have previously been used for protein stabilization during the procedure. This sometimes hampers structural studies of low affinity ligands because L-Glu is difficult to displace...... crystallized as a mixed dimer with L-Glu present in one subunit while neither L-Asp nor L-Glu were found in the other subunit. Thus, residual L-Glu is still present from the expression. On the other hand, only L-Asp was found at the binding site when using 50 mM or 250 mM L-Asp for crystallization. The binding...... mode observed for L-Asp at the GluA2 LBD is very similar to that described for L-Glu. Taken together, we have shown that L-Asp can be used instead of L-Glu for ligand-dependent stabilization of the GluA2 LBD during purification. This will enable structural studies of low affinity ligands for lead...

Complexation of trivalent cationic lanthanides by N.O donor ligands: physico-chemical studies of the association and selectivity in solution

International Nuclear Information System (INIS)

Bravard, F.

2004-01-01

The aim of this work is to study the complexation of f-elements in solution by ligands incorporating N-heterocyclic donors. These ligands display interesting properties for the selective separation of An(III)/Ln(III) have been studied to obtain a better understanding of the coordination properties with f-elements and to develop more selective extractants. The hepta-dentate ligand tpaam shows an affinity for Ln(III) similar to the tetradentate ligand tpa in water even when the three additional amide groups are bonded to the metal. Even though the complexation with tpa is exothermic, that with tpaam is endothermic with a more positive entropy. The dehydration of the cation disfavours the formation of Ln(III) complexes with ligands containing weak donors. The analysis of the solution paramagnetic relaxation times of the tpaam complexes is in agreement with data in the solid-state. There is little difference between the formation constants of the Ln 3+ complexes with different ligands (tpaam, tpzen, tpa and tpza) as determined by UV-vis spectrophotometry in anhydrous acetonitrile. The limitations encountered during this study are intrinsic to the ligands studied. The preliminary study of two tetrapodal ligands containing acid and pyridine groups (L py )or pyrazine (L pz ) show the formation of 1:1 complexes in water. Analysis of the formation constants of the corresponding Gd(III) complexes shows that replacement of a pyridine group by pyrazine result in a loss of stability of 1.6 logarithmic units. (author) [fr

eMatchSite: sequence order-independent structure alignments of ligand binding pockets in protein models.

Directory of Open Access Journals (Sweden)

Michal Brylinski

2014-09-01

Full Text Available Detecting similarities between ligand binding sites in the absence of global homology between target proteins has been recognized as one of the critical components of modern drug discovery. Local binding site alignments can be constructed using sequence order-independent techniques, however, to achieve a high accuracy, many current algorithms for binding site comparison require high-quality experimental protein structures, preferably in the bound conformational state. This, in turn, complicates proteome scale applications, where only various quality structure models are available for the majority of gene products. To improve the state-of-the-art, we developed eMatchSite, a new method for constructing sequence order-independent alignments of ligand binding sites in protein models. Large-scale benchmarking calculations using adenine-binding pockets in crystal structures demonstrate that eMatchSite generates accurate alignments for almost three times more protein pairs than SOIPPA. More importantly, eMatchSite offers a high tolerance to structural distortions in ligand binding regions in protein models. For example, the percentage of correctly aligned pairs of adenine-binding sites in weakly homologous protein models is only 4-9% lower than those aligned using crystal structures. This represents a significant improvement over other algorithms, e.g. the performance of eMatchSite in recognizing similar binding sites is 6% and 13% higher than that of SiteEngine using high- and moderate-quality protein models, respectively. Constructing biologically correct alignments using predicted ligand binding sites in protein models opens up the possibility to investigate drug-protein interaction networks for complete proteomes with prospective systems-level applications in polypharmacology and rational drug repositioning. eMatchSite is freely available to the academic community as a web-server and a stand-alone software distribution at http://www.brylinski.org/ematchsite.

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

Science.gov (United States)

Lin, Ying-Ting

2013-04-30

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. 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. 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.

Mutual control of axial and equatorial ligands: model studies with [Ni]-bacteriochlorophyll-a.

Science.gov (United States)

Yerushalmi, Roie; Noy, Dror; Baldridge, Kim K; Scherz, Avigdor

2002-07-17

Modification of the metal's electronic environment by ligand association and dissociation in metalloenzymes is considered cardinal to their catalytic activity. We have recently presented a novel system that utilizes the bacteriochlorophyll (BChl) macrocycle as a ligand and reporter. This system allows for charge mobilization in the equatorial plane and experimental estimate of changes in the electronic charge density around the metal with no modification of the metal's chemical environment. The unique spectroscopy, electrochemistry and coordination chemistry of [Ni]-bacteriochlorophyll ([Ni]-BChl) enable us to follow directly fine details and steps involved in the function of the metal redox center. This approach is utilized here whereby electro-chemical reduction of [Ni]-BChl to the monoanion [Ni]-BChl(-) results in reversible dissociation of biologically relevant axial ligands. Similar ligand dissociation was previously detected upon photoexcitation of [Ni]-BChl (Musewald, C.; Hartwich, G.; Lossau, H.; Gilch, P.; Pollinger-Dammer, F.; Scheer, H.; Michel-Beyerle, M. E. J. Phys. Chem. B 1999, 103, 7055-7060 and Noy, D.; Yerushalmi, R.; Brumfeld, V.; Ashur, I.; Baldridge, K. K.; Scheer, H.; Scherz, A. J. Am. Chem. Soc. 2000, 122, 3937-3944). The electrochemical measurements and quantum mechanical (QM) calculations performed here for the neutral, singly reduced, monoligated, and singly reduced, monoligated [Ni]-BChl suggest the following: (a) Electroreduction, although resulting in a pi anion [Ni]-BChl(-) radical, causes electron density migration to the [Ni]-BChl core. (b) Reduction of nonligated [Ni]-BChl does not change the macrocycle conformation, whereas axial ligation results in a dramatic expansion of the metal core and a flattening of the highly ruffled macrocycle conformation. (c) In both the monoanion and singly excited [Ni]-BChl ([Ni]-BChl*), the frontier singly occupied molecular orbital (SOMO) has a small but nonnegligible metal character. Finally, (d

A ligand predication tool based on modeling and reasoning with imprecise probabilistic knowledge.

Science.gov (United States)

Liu, Weiru; Yue, Anbu; Timson, David J

2010-04-01

Ligand prediction has been driven by a fundamental desire to understand more about how biomolecules recognize their ligands and by the commercial imperative to develop new drugs. Most of the current available software systems are very complex and time-consuming to use. Therefore, developing simple and efficient tools to perform initial screening of interesting compounds is an appealing idea. In this paper, we introduce our tool for very rapid screening for likely ligands (either substrates or inhibitors) based on reasoning with imprecise probabilistic knowledge elicited from past experiments. Probabilistic knowledge is input to the system via a user-friendly interface showing a base compound structure. A prediction of whether a particular compound is a substrate is queried against the acquired probabilistic knowledge base and a probability is returned as an indication of the prediction. This tool will be particularly useful in situations where a number of similar compounds have been screened experimentally, but information is not available for all possible members of that group of compounds. We use two case studies to demonstrate how to use the tool. 2009 Elsevier Ireland Ltd. All rights reserved.

-Pincer Ligand Family through Ligand Post-Modification

KAUST Repository

Huang, Mei-Hui; Hu, Jinsong; Huang, Kuo-Wei

2017-01-01

A series of air-stable nickel complexes containing triazine-based PN3P-pincer ligands were synthesized and fully characterized. Complex 3 contains a de-aromatized central triazine ring from the deprotonation of one of the N–H arms. With a post-modification strategy, the Me-PN3P*NiCl complex (3) could be converted into a new class of diimine–traizine PN3P-pincer nickel complexes.

-Pincer Ligand Family through Ligand Post-Modification

KAUST Repository

Huang, Mei-Hui

2017-10-02

A series of air-stable nickel complexes containing triazine-based PN3P-pincer ligands were synthesized and fully characterized. Complex 3 contains a de-aromatized central triazine ring from the deprotonation of one of the N–H arms. With a post-modification strategy, the Me-PN3P*NiCl complex (3) could be converted into a new class of diimine–traizine PN3P-pincer nickel complexes.

Rational assembly of Pb(II)/Cd(II)/Mn(II) coordination polymers based on flexible V-shaped dicarboxylate ligand: Syntheses, helical structures and properties

Energy Technology Data Exchange (ETDEWEB)

Yang, Gao-Shan [School of Environment and Chemical Engineering, Nanchang Hangkong University, Nanchang 330063 (China); Liu, Chong-Bo, E-mail: cbliu@nchu.edu.cn [School of Environment and Chemical Engineering, Nanchang Hangkong University, Nanchang 330063 (China); School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332 (United States); Liu, Hong [School of Environment and Chemical Engineering, Nanchang Hangkong University, Nanchang 330063 (China); Robbins, Julianne; Zhang, Z. John [School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332 (United States); Yin, Hong-Shan [School of Environment and Chemical Engineering, Nanchang Hangkong University, Nanchang 330063 (China); Wen, Hui-Liang [State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang 330047 (China); Wang, Yu-Hua [School of Environment and Chemical Engineering, Nanchang Hangkong University, Nanchang 330063 (China)

2015-05-15

Six new coordination polymers, namely, [Pb(L)(H{sub 2}O)] (1), [Pb(L)(phen)] (2), [Pb{sub 2}(L){sub 2}(4,4′-bipy){sub 0.5}] (3), [Cd(L)(phen)] (4), [Cd(L)(4,4′-bipy)]·H{sub 2}O (5) and [Mn(L)(4,4′-bipy)]·H{sub 2}O (6) have been synthesized by the hydrothermal reaction of 2,2′-[hexafluoroisopropylidenebis(p-phenyleneoxy)]diacetic acid (H{sub 2}L) with Pb(II)/Cd(II)/Mn(II) in the presence of ancillary ligands 4,4′-bipyridine (4,4′-bipy) or 1,10-phenanthroline (phen). Complexes 1 and 4–6 exhibit 2-D structures, and complexes 2–3 display 3-D frameworks, of which L{sup 2−} ligands join metal ions to single-stranded helical chains of 1, 3–6 and double-stranded helical chains of 2. Complexes 2 and 3 also contain double-stranded Metal–O helices. Topology analysis reveals that complexes 1 and 4 both represent 4-connected sql net, 2 represents 6-connected pcu net, 3 exhibits a novel (3,12)-connected net, while 5 and 6 display (3,5)-connected gek1 net. The six complexes exhibit two kinds of inorganic–organic connectivities: I{sup 0}O{sup 2} for 1, 4–6, and I{sup 1}O{sup 2} for 2–3. The photoluminescent properties of 4–5 and the magnetic properties of 6 have been investigated. - Graphical abstract: Six new Pb(II)/Cd(II)/Mn(II) coordination polymers with helical structures based on flexible V-shaped dicarboxylate ligand have been synthesized and structurally characterized. Photoluminescent and magnetic properties have been investigated. - Highlights: • Six novel M(II) coordination polymers with 2,2′-[hexafluoroisopropylidenebis(p-phenyleneoxy)]diacetic acid and N-donor ligands. • Complexes 1–6 show diverse intriguing helical characters. • The luminescent properties of complexes 1–5 were investigated. • Complex 6 shows antiferromagnetic coupling.

Diversity of coordination modes in the polymers based on 3,3',4,4'-biphenylcarboxylate ligand

International Nuclear Information System (INIS)

Du Xiaodi; Xiao Hongping; Zhou Xinhui; Wu Tao; You Xiaozeng

2010-01-01

Four new compounds [Ni 2 (4,4'-bpy)(3,4-bptc)(H 2 O) 4 ] n (1), [Ni(4,4'-bpy)(3,4-H 2 bptc)(H 2 O) 3 ] n (2), [Mn 2 (2,2'-bpy) 4 (3,4-H 2 bptc) 2 ] (3) and {[Mn(1,10-phen) 2 (3,4-H 2 bptc)].4H 2 O} n (4) (3,4-H 4 bptc=3,3',4,4'-biphenyltetracarboxylic acid, 4,4'-bpy=4,4'-bipyridine, 2,2'-bpy=2,2'-bipyridine, 1, 10-phen=1, 10-phenanthroline), have been prepared and structurally characterized. In all compounds, the derivative ligands of 3,4-H 4 bptc (3,4-bptc 4- and 3,4-H 2 bptc 2- ) exhibit different coordination modes and lead to the formation of various architectures. Compounds 1 and 2 display the three-dimensional (3D) framework: 1 shows a 3,4-connected topological network with (8 3 )(8 5 .10) topology symbol based on the coordination bonds while in 2, the hydrogen-bonding interactions are observed to connect the 1D linear chain generating a final 3D framework. 3 exhibits the 2D layer constructed from the hydrogen-bonding interactions between the dinuclear manganese units. Complex 4 shows the double layers motif through connecting the 1D zigzag chains with hydrogen-bonded rings. The thermal stability of 1-4 and magnetic property of 1 were also reported. - Graphical abstract: Four coordination compounds exhibiting four coordination modes of the 3,3',4,4'-biphenylcarboxylate ligand, with three of new in this system, are obtained showing diversified architectures.

High Throughput, Label-free Screening Small Molecule Compound Libraries for Protein-Ligands using Combination of Small Molecule Microarrays and a Special Ellipsometry-based Optical Scanner.

Science.gov (United States)

Landry, James P; Fei, Yiyan; Zhu, X D

2011-12-01

Small-molecule compounds remain the major source of therapeutic and preventative drugs. Developing new drugs against a protein target often requires screening large collections of compounds with diverse structures for ligands or ligand fragments that exhibit sufficiently affinity and desirable inhibition effect on the target before further optimization and development. Since the number of small molecule compounds is large, high-throughput screening (HTS) methods are needed. Small-molecule microarrays (SMM) on a solid support in combination with a suitable binding assay form a viable HTS platform. We demonstrate that by combining an oblique-incidence reflectivity difference optical scanner with SMM we can screen 10,000 small-molecule compounds on a single glass slide for protein ligands without fluorescence labeling. Furthermore using such a label-free assay platform we can simultaneously acquire binding curves of a solution-phase protein to over 10,000 immobilized compounds, thus enabling full characterization of protein-ligand interactions over a wide range of affinity constants.

Biomolecular ligands screening using radiation damping difference WaterLOGSY spectroscopy

International Nuclear Information System (INIS)

Sun Peng; Jiang Xianwang; Jiang Bin; Zhang Xu; Liu Maili

2013-01-01

Water-ligand observed via gradient spectroscopy (WaterLOGSY) is a widely used nuclear magnetic resonance method for ligand screening. The crucial procedure for the effectiveness of WaterLOGSY is selective excitation of the water resonance. The selective excitation is conventionally achieved by using long selective pulse, which causes partial saturation of the water magnetization leading to reduction of sensitivity, in addition to time consuming and error prone. Therefore, many improvements have been made to enhance the sensitivity and robustness of the method. Here we propose an alternative selective excitation scheme for WaterLOGSY by utilizing radiation damping effect. The pulse scheme starts simply with a hard inversion pulse, instead of selective pulse or pulse train, followed by a pulse field gradient to control the radiation damping effect. The rest parts of the pulse scheme are similar to conventional WaterLOGSY. When the gradient pulse is applied immediately after the inversion pulse, the radiation damping effect is suppressed, and all of the magnetization is inversed. When the gradient pulse and the inversion pulse are about 10–20 ms apart, the radiation damping effect remains active and drives the water magnetization toward +z-axis, resulting in selective non-inversion of the water magnetization. By taking the differences of the spectra obtained under these two conditions, one should get the result of WaterLOGSY. The method is demonstrated to be simple, robust and sensitive for ligand screening

Receptor-ligand binding sites and virtual screening.

Science.gov (United States)

Hattotuwagama, Channa K; Davies, Matthew N; Flower, Darren R

2006-01-01

Within the pharmaceutical industry, the ultimate source of continuing profitability is the unremitting process of drug discovery. To be profitable, drugs must be marketable: legally novel, safe and relatively free of side effects, efficacious, and ideally inexpensive to produce. While drug discovery was once typified by a haphazard and empirical process, it is now increasingly driven by both knowledge of the receptor-mediated basis of disease and how drug molecules interact with receptors and the wider physiome. Medicinal chemistry postulates that to understand a congeneric ligand series, or set thereof, is to understand the nature and requirements of a ligand binding site. Likewise, structural molecular biology posits that to understand a binding site is to understand the nature of ligands bound therein. Reality sits somewhere between these extremes, yet subsumes them both. Complementary to rules of ligand design, arising through decades of medicinal chemistry, structural biology and computational chemistry are able to elucidate the nature of binding site-ligand interactions, facilitating, at both pragmatic and conceptual levels, the drug discovery process.

The affinity plutonium(IV) for nitrogen donor ligands

International Nuclear Information System (INIS)

Jarvis, N.V.; Hancock, R.D.

1994-01-01

Established ligand design principles are used to predict the solution chemistry of Pu(IV) with nitrogen donor ligands which do not contain carboxylate donors. pK a 's of the nitrogen donors are lowered by addition of hydroxyalkyl groups causing Pu(IV) to have a greater affinity for these ligands than for hydroxide. Potentiometric studies using the ligands N,N,N'N',N''-pentakis(2-hydroxypropyl)-1,4,7-triazaheptane; N,N,N',N',N''-pentakis(2-hydroxyethyl)-1,4,7-triazaheptane; N,N,N',N',N'-tetrakis(2-hydroxyethyl)-1,2-diaminoethane; N,N,N',N'-tetrakis(2-hydroxyethyl)-trans-1,2-diaminocyclohexane; 1,4,8,11-tetrakis(2-hydroxyethyl)-1,4,8,11-tetraazacyclotetradecane and N,N-bis(2-hydroxyethyl)glycine with Pu(IV) showed that Pu(IV) has a considerable aqueous solution chemistry with these ligands. Data were processed by the ESTA library of programs and stability constants for all the systems are reported. Implications for selective ligand design for Pu(IV) are discussed. (orig.)

Protonation of Ferrous Dinitrogen Complexes Containing a Diphosphine Ligand with a Pendant Amine

Energy Technology Data Exchange (ETDEWEB)

Heiden, Zachariah M.; Chen, Shentan; Mock, Michael T.; Dougherty, William G.; Kassel, W. S.; Rousseau, Roger J.; Bullock, R. Morris

2013-04-01

The addition of protons to pendant amine containing ferrous dinitrogen complexes, of the type [FeX(N2)(PEtNMePEt)(dmpm)]+ (X = H, Cl, or Br; PEtNMePEt = Et2PCH2N(Me)CH2PEt2 and dmpm = Me2PCH2PMe2), was found to protonate at the pendant amine as opposed to the dinitrogen ligand. This protonation increased the νN2 of the complex by about 25 cm-1, shifting the Fe(II/I) couple 330 mV to a more positive potential. A similar shift was observed in the case of [FeX(CO)(PEtNMePEt)(dmpm)]+ (X = H, Cl, or Br). Computational analysis verified these experimental results and showed the coordination of N2 to Fe(II) centers increases the basicity of N2 (vs. free N2) by 13 and 20 pKa units for the trans halides and hydrides, respectively. Although the iron center was found to increase the basicity of the bound N2 ligand, coordinated N2 is not sufficiently basic to be protonated. In the case of ferrous dinitrogen complexes containing a basic pendant methylamine, the amine site was determined to be the most basic site by 30 pKa units compared to protonation at the N2 ligand. To increase the basicity of the N2 ligand in order to promote proton transfer from the pendant amine to the N2 ligand, chemical reduction of these ferrous dinitrogen complexes was performed and found to result in oxidative addition of the methylene C-H bond of the PEtNMePEt ligand to Fe, preventing isolation of a reduced Fe(0) N2 complex. This work was supported as part of the Center for Molecular Electrocatalysis, an Energy Frontier Research Center funded by the U.S. Department of Energy Office of Science, Office of Basic Energy Sciences.

Predicting Nanocrystal Shape through Consideration of Surface-Ligand Interactions

KAUST Repository

Bealing, Clive R.

2012-03-27

Density functional calculations for the binding energy of oleic acid-based ligands on Pb-rich {100} and {111} facets of PbSe nanocrystals determine the surface energies as a function of ligand coverage. Oleic acid is expected to bind to the nanocrystal surface in the form of lead oleate. The Wulff construction predicts the thermodynamic equilibrium shape of the PbSe nanocrystals. The equilibrium shape is a function of the ligand surface coverage, which can be controlled by changing the concentration of oleic acid during synthesis. The different binding energy of the ligand on the {100} and {111} facets results in different equilibrium ligand coverages on the facets, and a transition in the equilibrium shape from octahedral to cubic is predicted when increasing the ligand concentration during synthesis. © 2012 American Chemical Society.

Mixed ligand chelates of rare earths in aqueous solution

International Nuclear Information System (INIS)

Lakhani, S.U.; Thakur, G.S.; Sangal, S.P.

1981-01-01

Mixed ligand chelates of the 1:1 trivalent lanthanoids-EDTA, HEDTA and NTA chelates-1, 2-Dihydroxybenzene (Pyrocatechol) have been investigated at 35degC and 0.2 M ionic strength maintained by NaC10 4 . The formation of mixed ligand chelates has been found in all cases. The formation of mixed ligand chelates with EDTA shows the coordination number of lanthanoids to be eight, while the mixed ligand chelates with HEDTA and NTA shows the coordination number to be seven and six respectively. The stability constants of mixed ligand chelates are smaller than the binary complexes. The order of stability constants with respect to primary ligands follows the order NTA>HEDTA>EDTA. With respect to metal ions the stability constants increases with the decrease in ionic radii such as Gd< Er< Yb. (author)

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

Science.gov (United States)

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.

Ligand Binding Site Detection by Local Structure Alignment and Its Performance Complementarity

Science.gov (United States)

Lee, Hui Sun; Im, Wonpil

2013-01-01

Accurate determination of potential ligand binding sites (BS) is a key step for protein function characterization and structure-based drug design. Despite promising results of template-based BS prediction methods using global structure alignment (GSA), there is a room to improve the performance by properly incorporating local structure alignment (LSA) because BS are local structures and often similar for proteins with dissimilar global folds. We present a template-based ligand BS prediction method using G-LoSA, our LSA tool. A large benchmark set validation shows that G-LoSA predicts drug-like ligands’ positions in single-chain protein targets more precisely than TM-align, a GSA-based method, while the overall success rate of TM-align is better. G-LoSA is particularly efficient for accurate detection of local structures conserved across proteins with diverse global topologies. Recognizing the performance complementarity of G-LoSA to TM-align and a non-template geometry-based method, fpocket, a robust consensus scoring method, CMCS-BSP (Complementary Methods and Consensus Scoring for ligand Binding Site Prediction), is developed and shows improvement on prediction accuracy. The G-LoSA source code is freely available at http://im.bioinformatics.ku.edu/GLoSA. PMID:23957286

Exhibit Engineering

DEFF Research Database (Denmark)

Mortensen, Marianne Foss

Science museums define the objectives of their exhibitions in terms of visitor learning outcomes. Yet, exhibit designers lack theoretical and empirical research findings on which to base the creation of such educational environments. Here, this shortcoming is addressed through the development...... of tools and processes to guide the design of educational science exhibits. The guiding paradigm for this development is design-based research, which is characterised by an iterative cycle of design, enactment, and analysis. In the design phase, an educational intervention is planned and carried out based...... on the generation of theoretical ideas for exhibit design is offered in a fourth and parallel research undertaking, namely the application of the notion of cultural border-crossing to a hypothetical case of exhibit design....

Importance of the pharmacological profile of the bound ligand in enrichment on nuclear receptors: toward the use of experimentally validated decoy ligands.

Science.gov (United States)

Lagarde, Nathalie; Zagury, Jean-François; Montes, Matthieu

2014-10-27

The evaluation of virtual ligand screening methods is of major importance to ensure their reliability. Taking into account the agonist/antagonist pharmacological profile should improve the quality of the benchmarking data sets since ligand binding can induce conformational changes in the nuclear receptor structure and such changes may vary according to the agonist/antagonist ligand profile. We indeed found that splitting the agonist and antagonist ligands into two separate data sets for a given nuclear receptor target significantly enhances the quality of the evaluation. The pharmacological profile of the ligand bound in the binding site of the target structure was also found to be an additional critical parameter. We also illustrate that active compound data sets for a given pharmacological activity can be used as a set of experimentally validated decoy ligands for another pharmacological activity to ensure a reliable and challenging evaluation of virtual screening methods.

Natural HLA-B*2705 Protein Ligands with Glutamine as Anchor Motif

Science.gov (United States)

Infantes, Susana; Lorente, Elena; Barnea, Eilon; Beer, Ilan; Barriga, Alejandro; Lasala, Fátima; Jiménez, Mercedes; Admon, Arie; López, Daniel

2013-01-01

The presentation of short viral peptide antigens by human leukocyte antigen (HLA) class I molecules on cell surfaces is a key step in the activation of cytotoxic T lymphocytes, which mediate the killing of pathogen-infected cells or initiate autoimmune tissue damage. HLA-B27 is a well known class I molecule that is used to study both facets of the cellular immune response. Using mass spectrometry analysis of complex HLA-bound peptide pools isolated from large amounts of HLA-B*2705+ cells, we identified 200 naturally processed HLA-B*2705 ligands. Our analyses revealed that a change in the position (P) 2 anchor motif was detected in the 3% of HLA-B*2705 ligands identified. B*2705 class I molecules were able to bind these six GlnP2 peptides, which showed significant homology to pathogenic bacterial sequences, with a broad range of affinities. One of these ligands was able to bind with distinct conformations to HLA-B27 subtypes differentially associated with ankylosing spondylitis. These conformational differences could be sufficient to initiate autoimmune damage in patients with ankylosing spondylitis-associated subtypes. Therefore, these kinds of peptides (short, with GlnP2, and similar low affinity to all HLA-B27 subtypes tested but with unlike conformations in differentially ankylosing spondylitis-associated subtypes) must not be excluded from future researches involving potential arthritogenic peptides. PMID:23430249

Expression of nociceptive ligands in canine osteosarcoma.

Science.gov (United States)

Shor, S; Fadl-Alla, B A; Pondenis, H C; Zhang, X; Wycislo, K L; Lezmi, S; Fan, T M

2015-01-01

Canine osteosarcoma (OS) is associated with localized pain as a result of tissue injury from tumor infiltration and peritumoral inflammation. Malignant bone pain is caused by stimulation of peripheral pain receptors, termed nociceptors, which reside in the localized tumor microenvironment, including the periosteal and intramedullary bone cavities. Several nociceptive ligands have been determined to participate directly or indirectly in generating bone pain associated with diverse skeletal abnormalities. Canine OS cells actively produce nociceptive ligands with the capacity to directly or indirectly activate peripheral pain receptors residing in the bone tumor microenvironment. Ten dogs with appendicular OS. Expression of nerve growth factor, endothelin-1, and microsomal prostaglandin E synthase-1 was characterized in OS cell lines and naturally occurring OS samples. In 10 dogs with OS, circulating concentrations of nociceptive ligands were quantified and correlated with subjective pain scores and tumor volume in patients treated with standardized palliative therapies. Canine OS cells express and secrete nerve growth factor, endothelin-1, and prostaglandin E2. Naturally occurring OS samples uniformly express nociceptive ligands. In a subset of OS-bearing dogs, circulating nociceptive ligand concentrations were detectable but failed to correlate with pain status. Localized foci of nerve terminal proliferation were identified in a minority of primary bone tumor samples. Canine OS cells express nociceptive ligands, potentially permitting active participation of OS cells in the generation of malignant bone pain. Specific inhibitors of nociceptive ligand signaling pathways might improve pain control in dogs with OS. Copyright © 2015 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of American College of Veterinary Internal Medicine.

5f state interaction with inner coordination sphere ligands: einsteinium 3+ ion fluorescence in aqueous and organic phases

International Nuclear Information System (INIS)

Beitz, J.V.; Wester, D.W.; Williams, C.W.

1983-01-01

The interaction between 5f electron states of einsteinium 3+ ion and coordinated ligands in solution has been probed using laser-induced fluorescence. Aquo einsteinium 3+ ion was observed to fluoresce from its first excited J = 5 state in a broad-band peaking at 9260 wavenumbers. The observed fluorescence lifetimes were 1.05 microseconds and 2.78 microseconds in H 2 O and D 2 O (99+ % D atom), respectively. The non-radiative decay rates derived from the lifetime data are compared with previously reported data for Cm, Sm, Eu, Tb, and Dy aquo 3+ ions. The 5f actinide states exhibit substantially greater non-radiative decay rates than do lanthanide 4f states of similar energy gap. This provides evidence that actinide 5f electrons interact more strongly with their inner coordination sphere than do lanthanide ion 4f electrons. The fluorescence lifetime of einsteinium 3+ ion complexed with 1 formal di(2-ethylhexyl)orthophosphoric acid in h-heptane was 2.34 microseconds. 3 figures, 1 table

Sub-20 nm Stable Micelles Based on a Mixture of Coiled-Coils: A Platform for Controlled Ligand Presentation.

Science.gov (United States)

Ang, JooChuan; Ma, Dan; Jung, Benson T; Keten, Sinan; Xu, Ting

2017-11-13

Ligand-functionalized, multivalent nanoparticles have been extensively studied for biomedical applications from imaging agents to drug delivery vehicles. However, the ligand cluster size is usually heterogeneous and the local valency is ill-defined. Here, we present a mixed micelle platform hierarchically self-assembled from a mixture of two amphiphilic 3-helix and 4-helix peptide-polyethylene glycol (PEG)-lipid hybrid conjugates. We demonstrate that the local multivalent ligand cluster size on the micelle surface can be controlled based on the coiled-coil oligomeric state. The oligomeric states of mixed peptide bundles were found to be in their individual native states. Similarly, mixed micelles indicate the orthogonal self-association of coiled-coil amphiphiles. Using differential scanning calorimetry, fluorescence recovery spectroscopy, and coarse-grained molecular dynamics simulation, we studied the distribution of coiled-coil bundles within the mixed micelles and observed migration of coiled-coils into nanodomains within the sub-20 nm mixed micelle. This report provides important insights into the assembly and formation of nanophase-separated micelles with precise control over the local multivalent state of ligands on the micelle surface.

A Versatile Dinucleating Ligand Containing Sulfonamide Groups

DEFF Research Database (Denmark)

Sundberg, Jonas; Witt, Hannes; Cameron, Lisa

2014-01-01

ligand can be prepared in aqueous solutions using only divalent metal ions. Two of the copper(II) complexes, [Cu2(psmp)(OH)] and [Cu2(psmp)(OAc)2]-, demonstrate the anticipated 1:2 ligand/metal stoichiometry and show that the dimetallic binding site created for exogenous ligands possesses high inherent...... of antiferromagnetic coupling. This is corroborated computationally by broken-symmetry density functional theory, which for isotropic modeling of the coupling predicts an antiferromagnetic coupling strength of J = 70.5 cm-1....

Implicit ligand theory for relative binding free energies

Science.gov (United States)

Nguyen, Trung Hai; Minh, David D. L.

2018-03-01

Implicit ligand theory enables noncovalent binding free energies to be calculated based on an exponential average of the binding potential of mean force (BPMF)—the binding free energy between a flexible ligand and rigid receptor—over a precomputed ensemble of receptor configurations. In the original formalism, receptor configurations were drawn from or reweighted to the apo ensemble. Here we show that BPMFs averaged over a holo ensemble yield binding free energies relative to the reference ligand that specifies the ensemble. When using receptor snapshots from an alchemical simulation with a single ligand, the new statistical estimator outperforms the original.

Quantitative chemogenomics: machine-learning models of protein-ligand interaction.

Science.gov (United States)

Andersson, Claes R; Gustafsson, Mats G; Strömbergsson, Helena

2011-01-01

Chemogenomics is an emerging interdisciplinary field that lies in the interface of biology, chemistry, and informatics. Most of the currently used drugs are small molecules that interact with proteins. Understanding protein-ligand interaction is therefore central to drug discovery and design. In the subfield of chemogenomics known as proteochemometrics, protein-ligand-interaction models are induced from data matrices that consist of both protein and ligand information along with some experimentally measured variable. The two general aims of this quantitative multi-structure-property-relationship modeling (QMSPR) approach are to exploit sparse/incomplete information sources and to obtain more general models covering larger parts of the protein-ligand space, than traditional approaches that focuses mainly on specific targets or ligands. The data matrices, usually obtained from multiple sparse/incomplete sources, typically contain series of proteins and ligands together with quantitative information about their interactions. A useful model should ideally be easy to interpret and generalize well to new unseen protein-ligand combinations. Resolving this requires sophisticated machine-learning methods for model induction, combined with adequate validation. This review is intended to provide a guide to methods and data sources suitable for this kind of protein-ligand-interaction modeling. An overview of the modeling process is presented including data collection, protein and ligand descriptor computation, data preprocessing, machine-learning-model induction and validation. Concerns and issues specific for each step in this kind of data-driven modeling will be discussed. © 2011 Bentham Science Publishers

DISTINCT ROLES OF β1 MIDAS, ADMIDAS AND LIMBS CATION-BINDING SITES IN LIGAND RECOGNITION BY INTEGRIN α2β1*

Science.gov (United States)

Valdramidou, Dimitra; Humphries, Martin J.; Mould, A. Paul

2012-01-01

Integrin-ligand interactions are regulated in a complex manner by divalent cations, and previous studies have identified ligand-competent, stimulatory, and inhibitory cation-binding sites. In collagen-binding integrins, such as α2β1, ligand recognition takes place exclusively at the α subunit I domain. However, activation of the αI domain depends on its interaction with a structurally similar domain in the β subunit known as the I-like or βI domain. The top face of the βI domain contains three cation-binding sites: the metal-ion dependent adhesion site (MIDAS), the ADMIDAS (adjacent to MIDAS) and LIMBS (ligand-associated metal binding site). The role of these sites in controlling ligand binding to the αI domain has yet to be elucidated. Mutation of the MIDAS or LIMBS completely blocked collagen binding to α2β1; in contrast mutation of the ADMIDAS reduced ligand recognition but this effect could be overcome by the activating mAb TS2/16. Hence, the MIDAS and LIMBS appear to be essential for the interaction between αI and βI whereas occupancy of the ADMIDAS has an allosteric effect on the conformation of βI. An activating mutation in the α2 I domain partially restored ligand binding to the MIDAS and LIMBS mutants. Analysis of the effects of Ca2+, Mg2+ and Mn2+ on ligand binding to these mutants showed that the MIDAS is a ligand-competent site through which Mn2+ stimulates ligand binding, whereas the LIMBS is a stimulatory Ca2+-binding site, occupancy of which increases the affinity of Mg2+ for the MIDAS. PMID:18820259

[Supercomputer investigation of the protein-ligand system low-energy minima].

Science.gov (United States)

Oferkin, I V; Sulimov, A V; Katkova, E V; Kutov, D K; Grigoriev, F V; Kondakova, O A; Sulimov, V B

2015-01-01

The accuracy of the protein-ligand binding energy calculations and ligand positioning is strongly influenced by the choice of the docking target function. This work demonstrates the evaluation of the five different target functions used in docking: functions based on MMFF94 force field and functions based on PM7 quantum-chemical method accounting or without accounting the implicit solvent model (PCM, COSMO or SGB). For these purposes the ligand positions corresponding to the minima of the target function and the experimentally known ligand positions in the protein active site (crystal ligand positions) were compared. Each function was examined on the same test-set of 16 protein-ligand complexes. The new parallelized docking program FLM based on Monte Carlo search algorithm was developed to perform the comprehensive low-energy minima search and to calculate the protein-ligand binding energy. This study demonstrates that the docking target function based on the MMFF94 force field can be used to detect the crystal or near crystal positions of the ligand by the finding the low-energy local minima spectrum of the target function. The importance of solvent accounting in the docking process for the accurate ligand positioning is also shown. The accuracy of the ligand positioning as well as the correlation between the calculated and experimentally determined protein-ligand binding energies are improved when the MMFF94 force field is substituted by the new PM7 method with implicit solvent accounting.

Statistical Estimation of the Protein-Ligand Binding Free Energy Based On Direct Protein-Ligand Interaction Obtained by Molecular Dynamics Simulation

Directory of Open Access Journals (Sweden)

Haruki Nakamura

2012-09-01

Full Text Available We have developed a method for estimating protein-ligand binding free energy (DG based on the direct protein-ligand interaction obtained by a molecular dynamics simulation. Using this method, we estimated the DG value statistically by the average values of the van der Waals and electrostatic interactions between each amino acid of the target protein and the ligand molecule. In addition, we introduced fluctuations in the accessible surface area (ASA and dihedral angles of the protein-ligand complex system as the entropy terms of the DG estimation. The present method included the fluctuation term of structural change of the protein and the effective dielectric constant. We applied this method to 34 protein-ligand complex structures. As a result, the correlation coefficient between the experimental and calculated DG values was 0.81, and the average error of DG was 1.2 kcal/mol with the use of the fixed parameters. These results were obtained from a 2 nsec molecular dynamics simulation.

D3R Grand Challenge 2: blind prediction of protein-ligand poses, affinity rankings, and relative binding free energies

Science.gov (United States)

Gaieb, Zied; Liu, Shuai; Gathiaka, Symon; Chiu, Michael; Yang, Huanwang; Shao, Chenghua; Feher, Victoria A.; Walters, W. Patrick; Kuhn, Bernd; Rudolph, Markus G.; Burley, Stephen K.; Gilson, Michael K.; Amaro, Rommie E.

2018-01-01

The Drug Design Data Resource (D3R) ran Grand Challenge 2 (GC2) from September 2016 through February 2017. This challenge was based on a dataset of structures and affinities for the nuclear receptor farnesoid X receptor (FXR), contributed by F. Hoffmann-La Roche. The dataset contained 102 IC50 values, spanning six orders of magnitude, and 36 high-resolution co-crystal structures with representatives of four major ligand classes. Strong global participation was evident, with 49 participants submitting 262 prediction submission packages in total. Procedurally, GC2 mimicked Grand Challenge 2015 (GC2015), with a Stage 1 subchallenge testing ligand pose prediction methods and ranking and scoring methods, and a Stage 2 subchallenge testing only ligand ranking and scoring methods after the release of all blinded co-crystal structures. Two smaller curated sets of 18 and 15 ligands were developed to test alchemical free energy methods. This overview summarizes all aspects of GC2, including the dataset details, challenge procedures, and participant results. We also consider implications for progress in the field, while highlighting methodological areas that merit continued development. Similar to GC2015, the outcome of GC2 underscores the pressing need for methods development in pose prediction, particularly for ligand scaffolds not currently represented in the Protein Data Bank (http://www.pdb.org), and in affinity ranking and scoring of bound ligands.

Generation of pharmacophores and classification of drugs using protein-ligand complexes

Directory of Open Access Journals (Sweden)

Eliana Velasquez

2014-04-01

Full Text Available Pharmacophore identification is a veryimportant step in de novo design, leadoptimization, chemogenomics, and virtualscreening of drugs. Unfortunately,the high cost of comercial software forpharmacophore detection is a commonlimiting factor for researchers with limitedfunding. This paper presents a set offreely available perl routines that weredesigned to help in the process of 3Dpharmacophore identification and QSARstudies. These routines also allowed theclassification of ligands based on theirtridimensional similarity and bindingmechanism. The family of phosphodiesterasesand their inhibitors were used astest model.

Synthesis, physico-chemical properties and complexing abilities of new amphiphilic ligands from D-galacturonic acid.

Science.gov (United States)

Allam, Anas; Behr, Jean-Bernard; Dupont, Laurent; Nardello-Rataj, Véronique; Plantier-Royon, Richard

2010-04-19

This paper describes a convenient and efficient synthesis of new complexing surfactants from d-galacturonic acid and n-octanol as renewable raw materials in a two-step sequence. In the first step, simultaneous O-glycosidation-esterification under Fischer conditions was achieved. The anomeric ratio of the products was studied based on the main experimental parameters and the activation mode (thermal or microwave). In the second step, aminolysis of the n-octyl ester was achieved with various functionalized primary amines under standard thermal or microwave activation. The physico-chemical properties of these new amphiphilic ligands were measured and these compounds were found to exhibit interesting surface properties. Complexing abilities of one uronamide ligand functionalized with a pyridine moiety toward Cu(II) ions was investigated in solution by EPR titrations. A solid compound was also synthesized and characterized, its relative structure was deduced from spectroscopic data. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

Catalposide is a natural agonistic ligand of peroxisome proliferator-activated receptor-{alpha}

Energy Technology Data Exchange (ETDEWEB)

Lee, Ji Hae; Jun, Hee-jin; Hoang, Minh-Hien; Jia, Yaoyao [Division of Food Bioscience and Technology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of); Department of Biotechnology, Graduate School of Life Sciences and Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of); Han, Xiang Hua [College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk 361-763 (Korea, Republic of); Lee, Dong-Ho [Department of Biotechnology, Graduate School of Life Sciences and Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of); Lee, Hak-Ju [Division of Green Business Management, Department of Forest Resources Utilization, Korean Forest Research Institute, Seoul 130-712 (Korea, Republic of); Hwang, Bang Yeon, E-mail: byhwang@chungbuk.ac.kr [College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk 361-763 (Korea, Republic of); Lee, Sung-Joon, E-mail: junelee@korea.ac.kr [Division of Food Bioscience and Technology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of); Department of Biotechnology, Graduate School of Life Sciences and Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of)

2012-06-15

Highlights: Black-Right-Pointing-Pointer Catalposide is a novel ligand for PPAR{alpha}. Black-Right-Pointing-Pointer Cell stimulated with catalposide improved fatty acid uptake, regulated target genes in fatty acid {beta}-oxidation and synthesis. Black-Right-Pointing-Pointer Catalposdie reduces hepatic triacylglycerides. Black-Right-Pointing-Pointer Theses demonstrate catalposide could ameliorate hyperlipidemia and hepatic steatosis. -- Abstract: Peroxisome proliferator-activated receptor-alpha (PPAR{alpha}) is a nuclear receptor that regulates the expression of genes related to cellular lipid uptake and oxidation. Thus, PPAR{alpha} agonists may be important in the treatment of hypertriglyceridemia and hepatic steatosis. In this study, we demonstrated that catalposide is a novel natural PPAR{alpha} agonist, identified from reporter gene assay-based activity screening with approximately 900 natural plant and seaweed extracts. Results of time-resolved fluorescence resonance energy transfer analyses suggested that the compound interacted directly with the ligand-binding domain of PPAR{alpha}. Cultured hepatocytes stimulated with catalposide exhibited significantly reduced cellular triglyceride concentrations, by 21%, while cellular uptake of fatty acids was increased, by 70% (P < 0.05). Quantitative PCR analysis revealed that the increase in cellular fatty acid uptake was due to upregulation of fatty acid transporter protein-4 (+19% vs. the control) in cells stimulated with catalposide. Additionally, expression of genes related to fatty acid oxidation and high-density lipoprotein metabolism were upregulated, while that of genes related to fatty acid synthesis were suppressed. In conclusion, catalposide is hypolipidemic by activation of PPAR{alpha} via a ligand-mediated mechanism that modulates the expression of in lipid metabolism genes in hepatocytes.

Synthesis and characterisation of luminescent rhenium tricarbonyl complexes with axially coordinated 1,2,3-triazole ligands.

Science.gov (United States)

Uppal, Baljinder S; Booth, Rebecca K; Ali, Noreen; Lockwood, Cindy; Rice, Craig R; Elliott, Paul I P

2011-08-07

A series of 1-alkyl-4-aryl-1,2,3-triazoles (1-methyl-4-phenyl-1,2,3-triazole (1a); 1-propyl-4-phenyl-1,2,3-triazole (1b); 1-benzyl-4-phenyl-1,2,3-triazole (1c); 1-propyl-4-p-tolyl-1,2,3-triazole (1d)) have been prepared through a one-pot procedure involving in situ generation of the alkyl azide from a halide precursor followed by copper catalysed alkyne/azide cycloaddition (CuAAC) with the appropriate aryl alkyne. Cationic Re(I) complexes [Re(bpy)(CO)(3)(1a-d)]PF(6) (2a-d) were then prepared by stirring [Re(bpy)(CO)(3)Cl] with AgPF(6) in dichloromethane in the presence of ligands 1a-d. X-ray crystal structures were obtained for 2a and 2b. In the solid state, 2a adopts a highly distorted geometry, which is not seen for 2b, in which the plane of the triazole ligand tilts by 13° with respect to the Re-N bond as a result of a π-stacking interaction between the Ph substituent and one of the rings of the bpy ligand. This π-stacking interaction also results in severe twisting of the bpy ligand. Infrared spectra of 2a-d exhibit ν(CO) bands at ∼2035 and ∼1926 cm(-1) suggesting that these ligands are marginally better donors than pyridine (ν(CO) = 2037, 1932 cm(-1)). The complexes are luminescent in aerated dichloromethane at room temperature with emission maxima at 542 to 552 nm comparable to that of the pyridine analogue (549 nm) and blue shifted relative to the parent chloride complex. Long luminescent lifetimes are observed for the triazole complexes (475 to 513 ns) in aerated dichloromethane solutions at room temperature.

Spectroscopic characterization of ligands on the surface of water dispersible NaGdF4:Ln3+ nanocrystals

International Nuclear Information System (INIS)

Cichos, J.; Karbowiak, M.

2012-01-01

For electronic or biomedical applications it is desirable to have ligand-free water-dispersible nanocrystals (NCs). The commonly used FTIR spectroscopy often provides a direct evidence for molecules on the surface. In some cases, however, the strong bands of solvent molecules may obscure the peaks of surface bounded ligands. We show that in this regard the emission spectroscopy may be used as a more reliable probing tool. The relevant information can be obtained from emission and excitation spectra, emission decay times as well as from analysis of relative efficiency of excitation energy transfer from Gd 3+ to Eu 3+ ions. Using these methods we tested samples obtained by various synthetic routes and indicated that only nitrosonium tetrafluoroborate (NOBF 4 ) removes successfully the organic ligands from the nanocrystals surface, yielding organic ligand-free NCs dispersible in aqueous solutions. The conclusions drawn from emission spectroscopy are useful for interpretation of results of FTIR, Raman and NMR studies. The detailed assignment of FTIR peaks for oleate-capped and oleate-free NCs is also provided. Finally, we point to the risk of drawing erroneous conclusions about colloidal stability of nanocrystals if refractive indexes of NCs and medium are similar.

Spectroscopic characterization of ligands on the surface of water dispersible NaGdF4:Ln3+ nanocrystals

Science.gov (United States)

Cichos, J.; Karbowiak, M.

2012-05-01

For electronic or biomedical applications it is desirable to have ligand-free water-dispersible nanocrystals (NCs). The commonly used FTIR spectroscopy often provides a direct evidence for molecules on the surface. In some cases, however, the strong bands of solvent molecules may obscure the peaks of surface bounded ligands. We show that in this regard the emission spectroscopy may be used as a more reliable probing tool. The relevant information can be obtained from emission and excitation spectra, emission decay times as well as from analysis of relative efficiency of excitation energy transfer from Gd3+ to Eu3+ ions. Using these methods we tested samples obtained by various synthetic routes and indicated that only nitrosonium tetrafluoroborate (NOBF4) removes successfully the organic ligands from the nanocrystals surface, yielding organic ligand-free NCs dispersible in aqueous solutions. The conclusions drawn from emission spectroscopy are useful for interpretation of results of FTIR, Raman and NMR studies. The detailed assignment of FTIR peaks for oleate-capped and oleate-free NCs is also provided. Finally, we point to the risk of drawing erroneous conclusions about colloidal stability of nanocrystals if refractive indexes of NCs and medium are similar.

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

DEFF Research Database (Denmark)

Tekle, Christina; van Deurs, Bo; Sandvig, Kirsten

2008-01-01

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...

Predicting Efficient Antenna Ligands for Tb(III) Emission

Energy Technology Data Exchange (ETDEWEB)

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.

Dynamic ligand-based pharmacophore modeling and virtual ...

Indian Academy of Sciences (India)

Five ligand-based pharmacophore models were generated from 40 different .... the Phase module of the Schrodinger program.35 Each model consisted of six types of ... ligand preparation included the OPLS_2005 force field and to retain the ...

Technology Exhibition

Energy Technology Data Exchange (ETDEWEB)

Anon.

1979-09-15

Linked to the 25th Anniversary celebrations, an exhibition of some of CERN's technological achievements was opened on 22 June. Set up in a new 600 m{sup 2} Exhibition Hall on the CERN site, the exhibition is divided into eight technology areas — magnets, vacuum, computers and data handling, survey and alignment, radiation protection, beam monitoring and handling, detectors, and workshop techniques.

Identification of VDR Antagonists among Nuclear Receptor Ligands Using Virtual Screening

Directory of Open Access Journals (Sweden)

Kelly Teske

2014-04-01

Full Text Available Herein, we described the development of two virtual screens to identify new vitamin D receptor (VDR antagonists among nuclear receptor (NR ligands. Therefore, a database of 14330 nuclear receptor ligands and their NR affinities was assembled using the online available “Binding Database.” Two different virtual screens were carried out in conjunction with a reported VDR crystal structure applying a stringent and less stringent pharmacophore model to filter docked NR ligand conformations. The pharmacophore models were based on the spatial orientation of the hydroxyl functionalities of VDR's natural ligands 1,25(OH2D3 and 25(OH2D3. The first virtual screen identified 32 NR ligands with a calculated free energy of VDR binding of more than -6.0 kJ/mol. All but nordihydroguaiaretic acid (NDGA are VDR ligands, which inhibited the interaction between VDR and coactivator peptide SRC2-3 with an IC50 value of 15.8 μM. The second screen identified 162 NR ligands with a calculated free energy of VDR binding of more than -6.0 kJ/mol. More than half of these ligands were developed to bind VDR followed by ERα/β ligands (26%, TRα/β ligands (7%, and LxRα/β ligands (7%. The binding between VDR and ERα ligand H6036 as well as TRα/β ligand triiodothyronine and a homoserine analog thereof was confirmed by fluorescence polarization.

Water oxidation catalyzed by mononuclear ruthenium complexes with a 2,2'-bipyridine-6,6'-dicarboxylate (bda) ligand: how ligand environment influences the catalytic behavior.

Science.gov (United States)

Staehle, Robert; Tong, Lianpeng; Wang, Lei; Duan, Lele; Fischer, Andreas; Ahlquist, Mårten S G; Sun, Licheng; Rau, Sven

2014-02-03

A new water oxidation catalyst [Ru(III)(bda)(mmi)(OH2)](CF3SO3) (2, H2bda = 2,2'-bipyridine-6,6'-dicarboxylic acid; mmi = 1,3-dimethylimidazolium-2-ylidene) containing an axial N-heterocyclic carbene ligand and one aqua ligand was synthesized and fully characterized. The kinetics of catalytic water oxidation by 2 were measured using stopped-flow technique, and key intermediates in the catalytic cycle were probed by density functional theory calculations. While analogous Ru-bda water oxidation catalysts [Ru(bda)L2] (L = pyridyl ligands) are supposed to catalyze water oxidation through a bimolecular coupling pathway, our study points out that 2, surprisingly, undergoes a single-site water nucleophilic attack (acid-base) pathway. The diversion of catalytic mechanisms is mainly ascribed to the different ligand environments, from nonaqua ligands to an aqua ligand. Findings in this work provide some critical proof for our previous hypothesis about how alternation of ancillary ligands of water oxidation catalysts influences their catalytic efficiency.

Systematic study of ligand structures of metal oxide EUV nanoparticle photoresists

KAUST Repository

Jiang, Jing

2015-03-19

Ligand stabilized metal oxide nanoparticle resists are promising candidates for EUV lithography due to their high sensitivity for high-resolution patterning and high etching resistance. As ligand exchange is responsible for the patterning mechanism, we systematically studied the influence of ligand structures of metal oxide EUV nanoparticles on their sensitivity and dissolution behavior. ZrO2 nanoparticles were protected with various aromatic ligands with electron withdrawing and electron donating groups. These nanoparticles have lower sensitivity compared to those with aliphatic ligands suggesting the structures of these ligands is more important than their pka on resist sensitivity. The influence of ligand structure was further studied by comparing the nanoparticles’ solubility for a single type ligand to mixtures of ligands. The mixture of nanoparticles showed improved pattern quality. © (2015) COPYRIGHT Society of Photo-Optical Instrumentation Engineers (SPIE). Downloading of the abstract is permitted for personal use only.

Sigma-1 and Sigma-2 receptor ligands induce apoptosis and autophagy but have opposite effect on cell proliferation in uveal melanoma.

Science.gov (United States)

Longhitano, Lucia; Castracani, Carlo Castruccio; Tibullo, Daniele; Avola, Roberto; Viola, Maria; Russo, Giuliano; Prezzavento, Orazio; Marrazzo, Agostino; Amata, Emanuele; Reibaldi, Michele; Longo, Antonio; Russo, Andrea; Parrinello, Nunziatina Laura; Volti, Giovanni Li

2017-10-31

Uveal melanoma is the most common primary intraocular tumor in adults, with about 1200-1500 new cases occurring per year in the United States. Metastasis is a frequent occurrence in uveal melanoma, and outcomes are poor once distant spread occurs and no clinically significant chemotherapeutic protocol is so far available. The aim of the present study was to test the effect of various σ 1 and σ 2 receptor ligands as a possible pharmacological strategy for this rare tumor. Human uveal melanoma cells (92.1) were treated with various concentrations of different σ 2 ligands (haloperidol and haloperidol metabolite II) and σ 1 ligand ((+)-pentazocine) at various concentrations (1, 10 and 25 μM) and time points (0, 4 h, 8 h, 24 h and 48 h). Cell proliferation and migration were evaluated respectively by continuous cell monitoring by xCELLigence analysis, clonogenic assay and wound healing. Apoptosis and autophagy were also measured by cytofluorimetric and microscopy analysis. Our results showed that σ 2 receptor ligands significantly reduced cell proliferation whereas (+)-pentazocine exhibited opposite results. All tested ligands showed significant decrease in cell migration. Interestingly, both σ 1 and σ 2 receptor ligands showed significant increase of autophagy and apoptosis at all concentrations. Taken all together these results suggest that sigma receptors mediates opposite biological effects but they also share common pharmacological effect on apoptosis and autophagy in uveal melanoma. In conclusion, these data provide the first evidence that sigma receptors may represent a "druggable" target to develop new chemotherapic agent for uveal melanoma.

Development of pharmacophore similarity-based quantitative activity hypothesis and its applicability domain: applied on a diverse data-set of HIV-1 integrase inhibitors.

Science.gov (United States)

Kumar, Sivakumar Prasanth; Jasrai, Yogesh T; Mehta, Vijay P; Pandya, Himanshu A

2015-01-01

Quantitative pharmacophore hypothesis combines the 3D spatial arrangement of pharmacophore features with biological activities of the ligand data-set and predicts the activities of geometrically and/or pharmacophoric similar ligands. Most pharmacophore discovery programs face difficulties in conformational flexibility, molecular alignment, pharmacophore features sampling, and feature selection to score models if the data-set constitutes diverse ligands. Towards this focus, we describe a ligand-based computational procedure to introduce flexibility in aligning the small molecules and generating a pharmacophore hypothesis without geometrical constraints to define pharmacophore space, enriched with chemical features necessary to elucidate common pharmacophore hypotheses (CPHs). Maximal common substructure (MCS)-based alignment method was adopted to guide the alignment of carbon molecules, deciphered the MCS atom connectivity to cluster molecules in bins and subsequently, calculated the pharmacophore similarity matrix with the bin-specific reference molecules. After alignment, the carbon molecules were enriched with original atoms in their respective positions and conventional pharmacophore features were perceived. Distance-based pharmacophoric descriptors were enumerated by computing the interdistance between perceived features and MCS-aligned 'centroid' position. The descriptor set and biological activities were used to develop support vector machine models to predict the activities of the external test set. Finally, fitness score was estimated based on pharmacophore similarity with its bin-specific reference molecules to recognize the best and poor alignments and, also with each reference molecule to predict outliers of the quantitative hypothesis model. We applied this procedure to a diverse data-set of 40 HIV-1 integrase inhibitors and discussed its effectiveness with the reported CPH model.

A response calculus for immobilized T cell receptor ligands

DEFF Research Database (Denmark)

Andersen, P S; Menné, C; Mariuzza, R A

2001-01-01

determine the level of T cell activation. When fitted to T cell responses against purified ligands immobilized on plastic surfaces, the 2D-affinity model adequately simulated changes in cellular activation as a result of varying ligand affinity and ligand density. These observations further demonstrated...

The Development of Target-Specific Pose Filter Ensembles To Boost Ligand Enrichment for Structure-Based Virtual Screening.

Science.gov (United States)

Xia, Jie; Hsieh, Jui-Hua; Hu, Huabin; Wu, Song; Wang, Xiang Simon

2017-06-26

Structure-based virtual screening (SBVS) has become an indispensable technique for hit identification at the early stage of drug discovery. However, the accuracy of current scoring functions is not high enough to confer success to every target and thus remains to be improved. Previously, we had developed binary pose filters (PFs) using knowledge derived from the protein-ligand interface of a single X-ray structure of a specific target. This novel approach had been validated as an effective way to improve ligand enrichment. Continuing from it, in the present work we attempted to incorporate knowledge collected from diverse protein-ligand interfaces of multiple crystal structures of the same target to build PF ensembles (PFEs). Toward this end, we first constructed a comprehensive data set to meet the requirements of ensemble modeling and validation. This set contains 10 diverse targets, 118 well-prepared X-ray structures of protein-ligand complexes, and large benchmarking actives/decoys sets. Notably, we designed a unique workflow of two-layer classifiers based on the concept of ensemble learning and applied it to the construction of PFEs for all of the targets. Through extensive benchmarking studies, we demonstrated that (1) coupling PFE with Chemgauss4 significantly improves the early enrichment of Chemgauss4 itself and (2) PFEs show greater consistency in boosting early enrichment and larger overall enrichment than our prior PFs. In addition, we analyzed the pairwise topological similarities among cognate ligands used to construct PFEs and found that it is the higher chemical diversity of the cognate ligands that leads to the improved performance of PFEs. Taken together, the results so far prove that the incorporation of knowledge from diverse protein-ligand interfaces by ensemble modeling is able to enhance the screening competence of SBVS scoring functions.

α2A- and α2C-Adrenoceptors as Potential Targets for Dopamine and Dopamine Receptor Ligands.

Science.gov (United States)

Sánchez-Soto, Marta; Casadó-Anguera, Verònica; Yano, Hideaki; Bender, Brian Joseph; Cai, Ning-Sheng; Moreno, Estefanía; Canela, Enric I; Cortés, Antoni; Meiler, Jens; Casadó, Vicent; Ferré, Sergi

2018-03-18

The poor norepinephrine innervation and high density of Gi/o-coupled α 2A - and α 2C -adrenoceptors in the striatum and the dense striatal dopamine innervation have prompted the possibility that dopamine could be an effective adrenoceptor ligand. Nevertheless, the reported adrenoceptor agonistic properties of dopamine are still inconclusive. In this study, we analyzed the binding of norepinephrine, dopamine, and several compounds reported as selective dopamine D 2 -like receptor ligands, such as the D 3 receptor agonist 7-OH-PIPAT and the D 4 receptor agonist RO-105824, to α 2 -adrenoceptors in cortical and striatal tissue, which express α 2A -adrenoceptors and both α 2A - and α 2C -adrenoceptors, respectively. The affinity of dopamine for α 2 -adrenoceptors was found to be similar to that for D 1 -like and D 2 -like receptors. Moreover, the exogenous dopamine receptor ligands also showed high affinity for α 2A - and α 2C -adrenoceptors. Their ability to activate Gi/o proteins through α 2A - and α 2C -adrenoceptors was also analyzed in transfected cells with bioluminescent resonance energy transfer techniques. The relative ligand potencies and efficacies were dependent on the Gi/o protein subtype. Furthermore, dopamine binding to α 2 -adrenoceptors was functional, inducing changes in dynamic mass redistribution, adenylyl cyclase activity, and ERK1/2 phosphorylation. Binding events were further studied with computer modeling of ligand docking. Docking of dopamine at α 2A - and α 2C -adrenoceptors was nearly identical to its binding to the crystallized D 3 receptor. Therefore, we provide conclusive evidence that α 2A - and α 2C -adrenoceptors are functional receptors for norepinephrine, dopamine, and other previously assumed selective D 2 -like receptor ligands, which calls for revisiting previous studies with those ligands.

AMPA receptor ligands

DEFF Research Database (Denmark)

Strømgaard, Kristian; Mellor, Ian

2004-01-01

Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPAR), subtype of the ionotropic glutamate receptors (IGRs), mediate fast synaptic transmission in the central nervous system (CNS), and are involved in many neurological disorders, as well as being a key player in the f......Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPAR), subtype of the ionotropic glutamate receptors (IGRs), mediate fast synaptic transmission in the central nervous system (CNS), and are involved in many neurological disorders, as well as being a key player...... in the formation of memory. Hence, ligands affecting AMPARs are highly important for the study of the structure and function of this receptor, and in this regard polyamine-based ligands, particularly polyamine toxins, are unique as they selectively block Ca2+ -permeable AMPARs. Indeed, endogenous intracellular...

New synthetic routes toward enantiopure nitrogen donor ligands.

Science.gov (United States)

Sala, Xavier; Rodríguez, Anna M; Rodríguez, Montserrat; Romero, Isabel; Parella, Teodor; von Zelewsky, Alexander; Llobet, Antoni; Benet-Buchholz, Jordi

2006-12-08

New polypyridylic chiral ligands, having either C3 or lower symmetry, have been prepared via a de novo construction of the pyridine nucleus by means of Kröhnke methodology in the key step. The chiral moieties of these ligands originate from the monoterpen chiral pool, namely (-)-alpha-pinene ((-)-14, (-)-15) and (-)-myrtenal ((-)-9, (-)-10). Extension of the above-mentioned asymmetric synthesis procedure to the preparation of enantiopure derivatives of some commonly used polypyridylic ligands has been achieved through a new aldehyde building block ((-)-16). As an example, the synthesis of a chiral derivative of N,N-bis(2-pyridylmethyl)ethylamine (bpea) ligand, (-)-19, has been performed to illustrate the viability of the method. The coordinative ability of the ligands has been tested through the synthesis and characterization of complexes [Mn((-)-19)Br2], (-)-20, and [RuCl((-)-10)(bpy)](BF4), (-)-21. Some preliminary results related to the enantioselective catalytic epoxidation of styrene with the ruthenium complex are also presented.

Automated ligand fitting by core-fragment fitting and extension into density

International Nuclear Information System (INIS)

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

2006-01-01

An automated ligand-fitting procedure has been developed and tested on 9327 ligands and (F o − F c )exp(iϕ c ) difference density from macromolecular structures in the Protein Data Bank. A procedure for fitting of ligands to electron-density maps by first fitting a core fragment of the ligand to density and then extending the remainder of the ligand into density is presented. The approach was tested by fitting 9327 ligands over a wide range of resolutions (most are in the range 0.8-4.8 Å) from the Protein Data Bank (PDB) into (F o − F c )exp(iϕ c ) difference density calculated using entries from the PDB without these ligands. The procedure was able to place 58% of these 9327 ligands within 2 Å (r.m.s.d.) of the coordinates of the atoms in the original PDB entry for that ligand. The success of the fitting procedure was relatively insensitive to the size of the ligand in the range 10–100 non-H atoms and was only moderately sensitive to resolution, with the percentage of ligands placed near the coordinates of the original PDB entry for fits in the range 58–73% over all resolution ranges tested

Evaluation of DNA binding, DNA cleavage, protein binding, radical scavenging and in vitro cytotoxic activities of ruthenium(II) complexes containing 2,4-dihydroxy benzylidene ligands

Energy Technology Data Exchange (ETDEWEB)

Mohanraj, Maruthachalam; Ayyannan, Ganesan; Raja, Gunasekaran; Jayabalakrishnan, Chinnasamy, E-mail: drcjbstar@gmail.com

2016-12-01

The new ruthenium(II) complexes with hydrazone ligands, 4-Methyl-benzoic acid (2,4-dihydroxy-benzylidene)-hydrazide (HL{sup 1}), 4-Methoxy-benzoic acid (2,4-dihydroxy-benzylidene)-hydrazide (HL{sup 2}), 4-Bromo-benzoic acid (2,4-dihydroxy-benzylidene)-hydrazide (HL{sup 3}), were synthesized and characterized by various spectro analytical techniques. The molecular structures of the ligands were confirmed by single crystal X-ray diffraction technique. The DNA binding studies of the ligands and complexes were examined by absorption, fluorescence, viscosity and cyclic voltammetry methods. The results indicated that the ligands and complexes could interact with calf thymus DNA (CT-DNA) through intercalation. The DNA cleavage activity of the complexes was evaluated by gel electrophoresis assay, which revealed that the complexes are good DNA cleaving agents. The binding interaction of the ligands and complexes with bovine serum albumin (BSA) was investigated using fluorescence spectroscopic method. Antioxidant studies showed that the complexes have a strong radical scavenging properties. Further, the cytotoxic effect of the complexes examined on cancerous cell lines showed that the complexes exhibit significant anticancer activity. - Highlights: • Synthesis of ruthenium(II) hydrazone complexes • Molecular structure of the ligands was elucidated by single crystal X-ray diffraction method. • The ligands and complexes interact with CT-DNA via intercalation. • The complexes possess significant antioxidant activity against DPPH, OH and NO radicals. • The complex 6 shows higher IC{sub 50} value than the other complexes against cancer cells.

Synthesis, Characterization and Biological Evaluation of Transition Metal Complexes Derived from N, S Bidentate Ligands

Directory of Open Access Journals (Sweden)

Enis Nadia Md Yusof

2015-05-01

Full Text Available Two bidentate NS ligands were synthesized by the condensation reaction of S-2-methylbenzyldithiocarbazate (S2MBDTC with 2-methoxybenzaldehyde (2MB and 3-methoxybenzaldehyde (3MB. The ligands were reacted separately with acetates of Cu(II, Ni(II and Zn(II yielding 1:2 (metal:ligand complexes. The metal complexes formed were expected to have a general formula of [M(NS2] where M = Cu2+, Ni2+, and Zn2+. These compounds were characterized by elemental analysis, molar conductivity, magnetic susceptibility and various spectroscopic techniques. The magnetic susceptibility measurements and spectral results supported the predicted coordination geometry in which the Schiff bases behaved as bidentate NS donor ligands coordinating via the azomethine nitrogen and thiolate sulfur. The molecular structures of the isomeric S2M2MBH (1 and S2M3MBH (2 were established by X-ray crystallography to have very similar l-shaped structures. The Schiff bases and their metal complexes were evaluated for their biological activities against estrogen receptor-positive (MCF-7 and estrogen receptor-negative (MDA-MB-231 breast cancer cell lines. Only the Cu(II complexes showed marked cytotoxicity against the cancer cell lines. Both Schiff bases and other metal complexes were found to be inactive. In concordance with the cytotoxicity studies, the DNA binding studies indicated that Cu(II complexes have a strong DNA binding affinity.

Mixed-ligand Al complex-a new approach for more high efficient OLEDs

Energy Technology Data Exchange (ETDEWEB)

Petrova, Petia K., E-mail: petia@clf.bas.bg [Institute of Optical Materials and Technologies ' Acad. J. Malinowski' , Bulgarian Academy of Sciences, Acad. G Bonchev st., bl. 109, 1113 Sofia (Bulgaria); Tomova, Reni L.; Stoycheva-Topalova, Rumiana T. [Institute of Optical Materials and Technologies ' Acad. J. Malinowski' , Bulgarian Academy of Sciences, Acad. G Bonchev st., bl. 109, 1113 Sofia (Bulgaria); Kaloyanova, Stefka S.; Deligeorgiev, Todor G. [Applied Organic Chemistry, Faculty of Chemistry, University of Sofia, Sofia 1164 (Bulgaria)

2012-02-15

The mixed-ligand Aluminum bis(8-hydroxyquinoline) acetylacetonate (Alq{sub 2}Acac) complex was presented and its performance as electroluminescent and electron transporting layer for OLED was studied. The photophysical properties of the novel complex were investigated and compared with the properties of the parent Alq{sub 3}. Highly efficient OLED based on the mixed-ligand Al complex was developed with two times higher luminescence and efficiency compared to the identical OLED based on the conventional Alq{sub 3} The better performance of the devices make the novel Al complex a very promising material for OLEDs. - Highlights: Black-Right-Pointing-Pointer A novel electroluminescent Alq{sub 2}Acac complex is presented as material for OLED. Black-Right-Pointing-Pointer Electroluminescent emission of Alq{sub 2}Acac is very similar to that of commercial Alq{sub 3}. Black-Right-Pointing-Pointer Devices with Alq{sub 2}Acac show better characteristics compared to those with Alq{sub 3}.

Elucidation of Ligand-Dependent Modulation of Disorder-Order Transitions in the Oncoprotein MDM2.

Directory of Open Access Journals (Sweden)

Juan A Bueren-Calabuig

2015-06-01

Full Text Available Numerous biomolecular interactions involve unstructured protein regions, but how to exploit such interactions to enhance the affinity of a lead molecule in the context of rational drug design remains uncertain. Here clarification was sought for cases where interactions of different ligands with the same disordered protein region yield qualitatively different results. Specifically, conformational ensembles for the disordered lid region of the N-terminal domain of the oncoprotein MDM2 in the presence of different ligands were computed by means of a novel combination of accelerated molecular dynamics, umbrella sampling, and variational free energy profile methodologies. The resulting conformational ensembles for MDM2, free and bound to p53 TAD (17-29 peptide identify lid states compatible with previous NMR measurements. Remarkably, the MDM2 lid region is shown to adopt distinct conformational states in the presence of different small-molecule ligands. Detailed analyses of small-molecule bound ensembles reveal that the ca. 25-fold affinity improvement of the piperidinone family of inhibitors for MDM2 constructs that include the full lid correlates with interactions between ligand hydrophobic groups and the C-terminal lid region that is already partially ordered in apo MDM2. By contrast, Nutlin or benzodiazepinedione inhibitors, that bind with similar affinity to full lid and lid-truncated MDM2 constructs, interact additionally through their solubilizing groups with N-terminal lid residues that are more disordered in apo MDM2.

Interaction between alkaline earth cations and oxo-ligands. DFT study of the affinity of the Ca2+ cation for carbonyl ligands.

Science.gov (United States)

da Costa, Leonardo Moreira; Carneiro, José Walkimar de Mesquita; Romeiro, Gilberto Alves; Paes, Lilian Weitzel Coelho

2011-02-01

The affinity of the Ca(2+) ion for a set of substituted carbonyl ligands was analyzed with both the DFT (B3LYP/6-31+G(d)) and semi-empirical (PM6) methods. Two types of ligands were studied: a set of monosubstituted [O=CH(R)] and a set of disubstituted ligands [O=C(R)(2)] (R=H, F, Cl, Br, OH, OCH(3), CH(3), CN, NH(2) and NO(2)), with R either directly bound to the carbonyl carbon atom or to the para position of a phenyl ring. The interaction energy was calculated to quantify the affinity of the Ca(2+) cation for the ligands. Geometric and electronic parameters were correlated with the intensity of the metal-ligand interaction. The electronic nature of the substituent is the main parameter that determines the interaction energy. Donor groups make the interaction energy more negative (stabilizing the complex formed), while acceptor groups make the interaction energy less negative (destabilizing the complex formed).

Computer-aided design of multi-target ligands at A1R, A2AR and PDE10A, key proteins in neurodegenerative diseases.

Science.gov (United States)

Kalash, Leen; Val, Cristina; Azuaje, Jhonny; Loza, María I; Svensson, Fredrik; Zoufir, Azedine; Mervin, Lewis; Ladds, Graham; Brea, José; Glen, Robert; Sotelo, Eddy; Bender, Andreas

2017-12-30

Compounds designed to display polypharmacology may have utility in treating complex diseases, where activity at multiple targets is required to produce a clinical effect. In particular, suitable compounds may be useful in treating neurodegenerative diseases by promoting neuronal survival in a synergistic manner via their multi-target activity at the adenosine A 1 and A 2A receptors (A 1 R and A 2A R) and phosphodiesterase 10A (PDE10A), which modulate intracellular cAMP levels. Hence, in this work we describe a computational method for the design of synthetically feasible ligands that bind to A 1 and A 2A receptors and inhibit phosphodiesterase 10A (PDE10A), involving a retrosynthetic approach employing in silico target prediction and docking, which may be generally applicable to multi-target compound design at several target classes. This approach has identified 2-aminopyridine-3-carbonitriles as the first multi-target ligands at A 1 R, A 2A R and PDE10A, by showing agreement between the ligand and structure based predictions at these targets. The series were synthesized via an efficient one-pot scheme and validated pharmacologically as A 1 R/A 2A R-PDE10A ligands, with IC 50 values of 2.4-10.0 μM at PDE10A and K i values of 34-294 nM at A 1 R and/or A 2A R. Furthermore, selectivity profiling of the synthesized 2-amino-pyridin-3-carbonitriles against other subtypes of both protein families showed that the multi-target ligand 8 exhibited a minimum of twofold selectivity over all tested off-targets. In addition, both compounds 8 and 16 exhibited the desired multi-target profile, which could be considered for further functional efficacy assessment, analog modification for the improvement of selectivity towards A 1 R, A 2A R and PDE10A collectively, and evaluation of their potential synergy in modulating cAMP levels.

What a difference a 5f element makes: trivalent and tetravalent uranium halide complexes supported by one and two bis[2-(diisopropylphosphino)-4-methylphenyl]amido (PNP) ligands.

Science.gov (United States)

Cantat, Thibault; Scott, Brian L; Morris, David E; Kiplinger, Jaqueline L

2009-03-02

electronic influence of replacing the C5Me5 ligands with PNP was investigated using electronic absorption spectroscopy and electrochemistry. For 12 and 13, a chemically reversible wave corresponding to the UIV/UIII redox transformation comparable to that for 3 and 4 was observed. However, a 350 mV shift of this couple to more negative potentials was observed on substitution of the bis(C5Me5) by the bis(PNP) framework, therefore pointing to a greater electronic density at the metal center in the PNP complexes. The UV-visible region of the electronic spectra for the mono(PNP) and bis(PNP) complexes appear to be dominated by PNP ligand-based transitions that are shifted to higher energy in the uranium complexes than in the simple ligand anion (6) spectrum, for both the UVI and UIII oxidation states. The near IR region in complexes 1-4 and 7, 9, 11-13 is dominated by f-f transitions derived from the 5f3 and 5f2 valence electronic configuration of the metal center. Though complexes of both ligand sets exhibit similar intensities in their f-f bands, a somewhat larger ligand-field splitting was observed for the PNP system, consistent with its higher electron donating ability.

Structure and thermal behavior of a nickel complex based on a V-shaped bis(4-(1H-imidazol-1-yl)phenyl)amine ligand

Energy Technology Data Exchange (ETDEWEB)

Jiao, Yan, E-mail: felixjiao@163.com; Wang, Zhe; Qiu, Yu; He, Jing-Man; Chen, Min-dong [Nanjing University of Information Science & Technology, Jiangsu Key Laboratory of Atmospheric Environment Monitoring and Pollution Control, Innovative Research Laboratory of Energy & Environmental Catalysis, School of Environmental Science and Engineering (China)

2015-12-15

A new coordination polymer ([Ni(BIPA)(bpdc)(H{sub 2}O){sub 2}]){sub n} has been prepared based on a new V-shaped bis(4-(1H-imidazol-1-yl)phenyl)amine (BIPA) ligand. Complex was characterized by elemental analysis, IR spectra, X-ray powder diffraction, thermal analysis and single crystal X-ray analysis. Complex exhibits a 1D → 3D structure. Hydrogen bonds play an important role in the formation of supramolecular network structure. Thermal analysis indicates that complex exhibits a high thermal stability.

Models of protein–ligand crystal structures: trust, but verify

Science.gov (United States)

Deller, Marc C.

2015-01-01

X-ray crystallography provides the most accurate models of protein–ligand structures. These models serve as the foundation of many computational methods including structure prediction, molecular modelling, and structure-based drug design. The success of these computational methods ultimately depends on the quality of the underlying protein–ligand models. X-ray crystallography offers the unparalleled advantage of a clear mathematical formalism relating the experimental data to the protein–ligand model. In the case of X-ray crystallography, the primary experimental evidence is the electron density of the molecules forming the crystal. The first step in the generation of an accurate and precise crystallographic model is the interpretation of the electron density of the crystal, typically carried out by construction of an atomic model. The atomic model must then be validated for fit to the experimental electron density and also for agreement with prior expectations of stereochemistry. Stringent validation of protein–ligand models has become possible as a result of the mandatory deposition of primary diffraction data, and many computational tools are now available to aid in the validation process. Validation of protein–ligand complexes has revealed some instances of overenthusiastic interpretation of ligand density. Fundamental concepts and metrics of protein–ligand quality validation are discussed and we highlight software tools to assist in this process. It is essential that end users select high quality protein–ligand models for their computational and biological studies, and we provide an overview of how this can be achieved. PMID:25665575

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

Science.gov (United States)

Deller, Marc C; Rupp, Bernhard

2015-09-01

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

SPOT-ligand 2: improving structure-based virtual screening by binding-homology search on an expanded structural template library.

Science.gov (United States)

Litfin, Thomas; Zhou, Yaoqi; Yang, Yuedong

2017-04-15

The high cost of drug discovery motivates the development of accurate virtual screening tools. Binding-homology, which takes advantage of known protein-ligand binding pairs, has emerged as a powerful discrimination technique. In order to exploit all available binding data, modelled structures of ligand-binding sequences may be used to create an expanded structural binding template library. SPOT-Ligand 2 has demonstrated significantly improved screening performance over its previous version by expanding the template library 15 times over the previous one. It also performed better than or similar to other binding-homology approaches on the DUD and DUD-E benchmarks. The server is available online at http://sparks-lab.org . yaoqi.zhou@griffith.edu.au or yuedong.yang@griffith.edu.au. Supplementary data are available at Bioinformatics online. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

Quantitative analysis of protein-ligand interactions by NMR.

Science.gov (United States)

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

Diimine triscarbonyl Re(I) of isomeric pyridyl-fulvene ligands: an electrochemical, spectroscopic, and computational investigation.

Science.gov (United States)

Chartrand, Daniel; Castro Ruiz, Carlos A; Hanan, Garry S

2012-12-03

The synthesis and characterization of a novel family of positively charged fac-[Re(bpy)(CO)(3)(L)]PF(6) (bpy = 2,2'-bipyridine) complexes are reported, where L is a pyridine functionalized in para or meta position with a fulvene moiety, namely, 4-fluoren-9-ylidenemethyl-pyridine (pFpy) and 3-fluoren-9-ylidenemethyl-pyridine (mFpy). The complexes were prepared in high yield (86%) by direct addition at room temperature of the corresponding pyridine to the tetrahydrofuran (THF) adduct fac-[Re(bpy)(CO)(3)(THF)][PF(6)] precursor. Both ligand and complex structures were fully characterized by a variety of techniques including X-ray crystallography. The complexes did not exhibit the expected triplet mixed metal-ligand-to-ligand charge transfer (MLLCT) emission, because of its deactivation by the non-emissive triplet excited state of fulvene. The absorption profile shows that the MLLCT is overshadowed by the fulvene centered π-π* transition of higher molar absorptivity as shown by time dependent density functional theory (TD-DFT) calculations. The position of the fulvene on the pyridyl ring has a large effect on this transition, the para position displaying a much higher absorption coefficient (21.3 × 10(3) M(-1) cm(-1)) at lower energy (364 nm) than the meta position (331 nm, 16.0 × 10(3) M(-1) cm(-1)).

New synthetic routes toward enantiopure nitrogen donor ligands

OpenAIRE

Sala, Xavier; Rodríguez, Anna M.; Rodríguez, Montserrat; Romero, Isabel; Parella, Teodor; Zelewsky, Alexander von; Llobet, Antoni; Benet-Buchholz, Jordi

2008-01-01

New polypyridylic chiral ligands, having either C₃ or lower symmetry, have been prepared via a de novo construction of the pyridine nucleus by means of Kröhnke methodology in the key step. The chiral moieties of these ligands originate from the monoterpen chiral pool, namely (-)-α-pinene ((-)-14, (-)-15) and (-)-myrtenal ((-)-9, (-)-10). Extension of the above-mentioned asymmetric synthesis procedure to the preparation of enantiopure derivatives of some commonly used polypyridylic ligands has...

Effects of PPARγ ligands on vascular tone.

Science.gov (United States)

Salomone, Salvatore; Drago, Filippo

2012-06-01

Peroxisome Proliferator-Activated Receptor γ (PPARγ), originally described as a transcription factor for genes of carbohydrate and lipid metabolism, has been more recently studied in the context of cardiovascular pathophysiology. Here, we review the available data on PPARγ ligands as modulator of vascular tone. PPARγ ligands include: thiazolidinediones (used in the treatment of type 2 diabetes mellitus), glitazars (bind and activate both PPARγ and PPARα), and other experimental drugs (still in development) that exploit the chemistry of thiazolidinediones as a scaffold for PPARγ-independent pharmacological properties. In this review, we examine both short (mostly from in vitro data)- and long (mostly from in vivo data)-term effects of PPARγ ligands that extend from PPARγ-independent vascular effects to PPARγ-dependent gene expression. Because endothelium is a master regulator of vascular tone, we have attempted to differentiate between endothelium-dependent and endothelium-independent effects of PPARγ ligands. Based on available data, we conclude that PPARγ ligands appear to influence vascular tone in different experimental paradigms, most often in terms of vasodilatation (potentially increasing blood flow to some tissues). These effects on vascular tone, although potentially beneficial, must be weighed against specific cardiovascular warnings that may apply to some drugs, such as rosiglitazone.

Explicit all-atom modeling of realistically sized ligand-capped nanocrystals

KAUST Repository

Kaushik, Ananth P.

2012-01-01

We present a study of an explicit all-atom representation of nanocrystals of experimentally relevant sizes (up to 6 nm), capped with alkyl chain ligands, in vacuum. We employ all-atom molecular dynamics simulation methods in concert with a well-tested intermolecular potential model, MM3 (molecular mechanics 3), for the studies presented here. These studies include determining the preferred conformation of an isolated single nanocrystal (NC), pairs of isolated NCs, and (presaging studies of superlattice arrays) unit cells of NC superlattices. We observe that very small NCs (3 nm) behave differently in a superlattice as compared to larger NCs (6 nm and above) due to the conformations adopted by the capping ligands on the NC surface. Short ligands adopt a uniform distribution of orientational preferences, including some that lie against the face of the nanocrystal. In contrast, longer ligands prefer to interdigitate. We also study the effect of changing ligand length and ligand coverage on the NCs on the preferred ligand configurations. Since explicit all-atom modeling constrains the maximum system size that can be studied, we discuss issues related to coarse-graining the representation of the ligands, including a comparison of two commonly used coarse-grained models. We find that care has to be exercised in the choice of coarse-grained model. The data provided by these realistically sized ligand-capped NCs, determined using explicit all-atom models, should serve as a reference standard for future models of coarse-graining ligands using united atom models, especially for self-assembly processes. © 2012 American Institute of Physics.

Regulation mechanisms of the FLT3-ligand after irradiation

International Nuclear Information System (INIS)

Prat-Lepesant, M.

2005-06-01

The hematopoietic compartment is one of the most severely damaged after chemotherapy, radiotherapy or accidental irradiations. Whatever its origin, the resulting damage to the bone marrow remains difficult to evaluate. Thus, it would be of great interest to get a biological indicator of residual hematopoiesis in order to adapt the treatment to each clinical situation. Recent results indicated that the plasma Flt3 ligand concentration was increased in patients suffering from either acquired or induced aplasia, suggesting that Flt3 ligand might be useful as a biological indicator of bone marrow status. We thus followed in a mouse model as well as in several clinical situations the variations in plasma Flt3 ligand concentration, after either homogeneous or heterogeneous irradiations. These variations were correlated to the number of hematopoietic progenitors and to other parameters such as duration and depth of pancytopenia. The results indicated that the concentration of Flt3 ligand in the blood reflects the bone marrow status, and that the follow-up of plasma Flt3 ligand concentration could give predictive information about the bone marrow function and the duration and severity of pancytopenia and thrombocytopenia. Nevertheless, the clinical use of Flt3 ligand as a biological indicator of bone marrow damage require the knowledge of the mechanisms regulating the variations in plasma Flt3 ligand concentration. We thus developed a study in the mouse model. The results indicated that the variations in plasma Flt3 ligand variations were not solely due to a balance between its production by lymphoid cells and its consumption by hematopoietic cells. Moreover, we showed that T lymphocytes are not the main regulator of plasma Flt3 ligand concentration as previously suggested, and that other cell types, possibly including bone marrow stromal cells, might be strongly implicated. These results also suggest that the Flt3 ligand is a main systemic regulator of hematopoiesis

ASIC3 Channels Integrate Agmatine and Multiple Inflammatory Signals through the Nonproton Ligand Sensing Domain

Directory of Open Access Journals (Sweden)

Cao Hui

2010-12-01

Full Text Available Abstract Background Acid-sensing ion channels (ASICs have long been known to sense extracellular protons and contribute to sensory perception. Peripheral ASIC3 channels represent natural sensors of acidic and inflammatory pain. We recently reported the use of a synthetic compound, 2-guanidine-4-methylquinazoline (GMQ, to identify a novel nonproton sensing domain in the ASIC3 channel, and proposed that, based on its structural similarity with GMQ, the arginine metabolite agmatine (AGM may be an endogenous nonproton ligand for ASIC3 channels. Results Here, we present further evidence for the physiological correlation between AGM and ASIC3. Among arginine metabolites, only AGM and its analog arcaine (ARC activated ASIC3 channels at neutral pH in a sustained manner similar to GMQ. In addition to the homomeric ASIC3 channels, AGM also activated heteromeric ASIC3 plus ASIC1b channels, extending its potential physiological relevance. Importantly, the process of activation by AGM was highly sensitive to mild acidosis, hyperosmolarity, arachidonic acid (AA, lactic acid and reduced extracellular Ca2+. AGM-induced ASIC3 channel activation was not through the chelation of extracellular Ca2+ as occurs with increased lactate, but rather through a direct interaction with the newly identified nonproton ligand sensing domain. Finally, AGM cooperated with the multiple inflammatory signals to cause pain-related behaviors in an ASIC3-dependent manner. Conclusions Nonproton ligand sensing domain might represent a novel mechanism for activation or sensitization of ASIC3 channels underlying inflammatory pain-sensing under in vivo conditions.

Photochemical Properties and Reactivity of a Ru Compound Containing an NAD/NADH-Functionalized 1,10-Phenanthroline Ligand.

Science.gov (United States)

Kobayashi, Katsuaki; Ohtsu, Hideki; Nozaki, Koichi; Kitagawa, Susumu; Tanaka, Koji

2016-03-07

An NAD/NADH-functionalized ligand, benzo[b]pyrido[3,2-f][1,7]-phenanthroline (bpp), was newly synthesized. A Ru compound containing the bpp ligand, [Ru(bpp)(bpy)2](2+), underwent 2e(-) and 2H(+) reduction, generating the NADH form of the compound, [Ru(bppHH)(bpy)2](2+), in response to visible light irradiation in CH3CN/TEA/H2O (8/1/1). The UV-vis and fluorescent spectra of both [Ru(bpp)(bpy)2](2+) and [Ru(bppHH)(bpy)2](2+) resembled the spectra of [Ru(bpy)3](2+). Both complexes exhibited strong emission, with quantum yields of 0.086 and 0.031, respectively; values that are much higher than those obtained from the NAD/NADH-functionalized complexes [Ru(pbn)(bpy)2](2+) and [Ru(pbnHH)(bpy)2](2+) (pbn = (2-(2-pyridyl)benzo[b]-1.5-naphthyridine, pbnHH = hydrogenated form of pbn). The reduction potential of the bpp ligand in [Ru(bpp)(bpy)2](2+) (-1.28 V vs SCE) is much more negative than that of the pbn ligand in [Ru(pbn)(bpy)2](2+) (-0.74 V), although the oxidation potentials of bppHH and pbnHH are essentially equal (0.95 V). These results indicate that the electrochemical oxidation of the dihydropyridine moiety in the NADH-type ligand was independent of the π system, including the Ru polypyridyl framework. [Ru(bppHH)(bpy)2](2+) allowed the photoreduction of oxygen, generating H2O2 in 92% yield based on [Ru(bppHH)(bpy)2](2+). H2O2 production took place via singlet oxygen generated by the energy transfer from excited [Ru(bppHH)(bpy)2](2+) to triplet oxygen.

Retinal Ligand Mobility Explains Internal Hydration and Reconciles Active Rhodopsin Structures

Science.gov (United States)

Leioatts, Nicholas; Mertz, Blake; Martínez-Mayorga, Karina; Romo, Tod D.; Pitman, Michael C.; Feller, Scott E.; Grossfield, Alan; Brown, Michael F.

2014-01-01

Rhodopsin, the mammalian dim-light receptor, is one of the best-characterized G-protein-coupled receptors, a pharmaceutically important class of membrane proteins that has garnered a great deal of attention because of the recent availability of structural information. Yet the mechanism of rhodopsin activation is not fully understood. Here, we use microsecond-scale all-atom molecular dynamics simulations, validated by solid-state 2H nuclear magnetic resonance spectroscopy, to understand the transition between the dark and metarhodopsin I (Meta I) states. Our analysis of these simulations reveals striking differences in ligand flexibility between the two states. Retinal is much more dynamic in Meta I, adopting an elongated conformation similar to that seen in the recent activelike crystal structures. Surprisingly, this elongation corresponds to both a dramatic influx of bulk water into the hydrophobic core of the protein and a concerted transition in the highly conserved Trp2656.48 residue. In addition, enhanced ligand flexibility upon light activation provides an explanation for the different retinal orientations observed in X-ray crystal structures of active rhodopsin. PMID:24328554

Structural properties of MHC class II ligands, implications for the prediction of MHC class II epitopes.

Directory of Open Access Journals (Sweden)

Kasper Winther Jørgensen

2010-12-01

Full Text Available Major Histocompatibility class II (MHC-II molecules sample peptides from the extracellular space allowing the immune system to detect the presence of foreign microbes from this compartment. Prediction of MHC class II ligands is complicated by the open binding cleft of the MHC class II molecule, allowing binding of peptides extending out of the binding groove. Furthermore, only a few HLA-DR alleles have been characterized with a sufficient number of peptides (100-200 peptides per allele to derive accurate description of their binding motif. Little work has been performed characterizing structural properties of MHC class II ligands. Here, we perform one such large-scale analysis. A large set of SYFPEITHI MHC class II ligands covering more than 20 different HLA-DR molecules was analyzed in terms of their secondary structure and surface exposure characteristics in the context of the native structure of the corresponding source protein. We demonstrated that MHC class II ligands are significantly more exposed and have significantly more coil content than other peptides in the same protein with similar predicted binding affinity. We next exploited this observation to derive an improved prediction method for MHC class II ligands by integrating prediction of MHC- peptide binding with prediction of surface exposure and protein secondary structure. This combined prediction method was shown to significantly outperform the state-of-the-art MHC class II peptide binding prediction method when used to identify MHC class II ligands. We also tried to integrate N- and O-glycosylation in our prediction methods but this additional information was found not to improve prediction performance. In summary, these findings strongly suggest that local structural properties influence antigen processing and/or the accessibility of peptides to the MHC class II molecule.

Prediction of ligand effects in platinum-amyloid-β coordination.

Science.gov (United States)

Turner, Matthew; Deeth, Robert J; Platts, James A

2017-08-01

Ligand field molecular mechanics (LFMM) and semi-empirical Parametric Model 7 (PM7) methods are applied to a series of six Pt II -Ligand systems binding to the N-terminal domain of the amyloid-β (Aβ) peptide. Molecular dynamics using a combined LFMM/Assisted Model Building with Energy Refinement (AMBER) approach is used to explore the conformational freedom of the peptide fragment, and identifies favourable platinum binding modes and peptide conformations for each ligand investigated. Platinum coordination is found to depend on the nature of the ligand, providing evidence that binding mode may be controlled by suitable ligand design. Boltzmann populations at 310K indicate that each Pt-Aβ complex has a small number of thermodynamically accessible states. Ramachandran maps are constructed for the sampled Pt-Aβ conformations and secondary structural analysis of the obtained complex structures is performed and contrasted with the free peptide; coordination of these platinum complexes disrupts existing secondary structure in the Aβ peptide and promotes formation of ligand-specific turn-type secondary structure. Copyright © 2017 Elsevier Inc. All rights reserved.

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

Directory of Open Access Journals (Sweden)

Julia Müller

Full Text Available 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/TC³ (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.

A grand unified model for liganded gold clusters

Science.gov (United States)

Xu, Wen Wu; Zhu, Beien; Zeng, Xiao Cheng; Gao, Yi

2016-12-01

A grand unified model (GUM) is developed to achieve fundamental understanding of rich structures of all 71 liganded gold clusters reported to date. Inspired by the quark model by which composite particles (for example, protons and neutrons) are formed by combining three quarks (or flavours), here gold atoms are assigned three `flavours' (namely, bottom, middle and top) to represent three possible valence states. The `composite particles' in GUM are categorized into two groups: variants of triangular elementary block Au3(2e) and tetrahedral elementary block Au4(2e), all satisfying the duet rule (2e) of the valence shell, akin to the octet rule in general chemistry. The elementary blocks, when packed together, form the cores of liganded gold clusters. With the GUM, structures of 71 liganded gold clusters and their growth mechanism can be deciphered altogether. Although GUM is a predictive heuristic and may not be necessarily reflective of the actual electronic structure, several highly stable liganded gold clusters are predicted, thereby offering GUM-guided synthesis of liganded gold clusters by design.

Capture Matrices Handbook

Science.gov (United States)

2014-04-01

materials, the affinity ligand would need identification , as well as chemistries that graft the affinity ligand onto the surface of magnetic...ACTIVE CAPTURE MATRICES FOR THE DETECTION/ IDENTIFICATION OF PHARMACEUTICALS...6 As shown in Figure 2.3-1a, the spectra exhibit similar baselines and the spectral peaks lineup . Under these circumstances, the spectral

Reversible Size Control of Silver Nanoclusters via Ligand-exchange

KAUST Repository

Bootharaju, Megalamane Siddaramappa

2015-05-21

The properties of atomically monodisperse noble metal nanoclusters (NCs) are intricately intertwined with their precise molecular formula. The vast majority of size-specific NC syntheses start from the reduction of the metal salt and thiol ligand mixture. Only in gold was it recently shown that ligand-exchange could induce the growth of NCs from one atomically precise species to another; a process of yet unknown reversibility. Here, we present a process for the ligand-exchange-induced growth of atomically precise silver NCs, in a biphasic liquid-liquid system, which is particularly of interest because of its complete reversibility and ability to occur at room temperature. We explore this phenomenon in-depth using Ag35(SG)18 [SG= glutathionate] and Ag44(4-FTP)30 [4-FTP= 4-fluorothiophenol] as model systems. We show that the ligand-exchange conversion of Ag35(SG)18 into Ag44(4-FTP)30 is rapid (< 5 min) and direct, while the reverse process proceeds slowly through intermediate cluster sizes. We adapt a recently developed theory of reverse Ostwald ripening to model the NCs’ interconvertibility. The model’s predictions are in good agreement with the experimental observations, and they highlight the importance of small changes in the ligand-metal binding energy in determining the final equilibrium NC size. Based on the insight provided by this model, we demonstrated experimentally that by varying the choice of ligands, ligand-exchange can be used to obtain different sized NCs. The findings in this work establish ligand-exchange as a versatile tool for tuning cluster sizes.

Reversible Size Control of Silver Nanoclusters via Ligand-exchange

KAUST Repository

Bootharaju, Megalamane Siddaramappa; Burlakov, Victor M.; Besong, Tabot M.D.; Joshi, Chakra Prasad; AbdulHalim, L; Black, David; Whetten, Robert; Goriely, Alain; Bakr, Osman

2015-01-01

The properties of atomically monodisperse noble metal nanoclusters (NCs) are intricately intertwined with their precise molecular formula. The vast majority of size-specific NC syntheses start from the reduction of the metal salt and thiol ligand mixture. Only in gold was it recently shown that ligand-exchange could induce the growth of NCs from one atomically precise species to another; a process of yet unknown reversibility. Here, we present a process for the ligand-exchange-induced growth of atomically precise silver NCs, in a biphasic liquid-liquid system, which is particularly of interest because of its complete reversibility and ability to occur at room temperature. We explore this phenomenon in-depth using Ag35(SG)18 [SG= glutathionate] and Ag44(4-FTP)30 [4-FTP= 4-fluorothiophenol] as model systems. We show that the ligand-exchange conversion of Ag35(SG)18 into Ag44(4-FTP)30 is rapid (< 5 min) and direct, while the reverse process proceeds slowly through intermediate cluster sizes. We adapt a recently developed theory of reverse Ostwald ripening to model the NCs’ interconvertibility. The model’s predictions are in good agreement with the experimental observations, and they highlight the importance of small changes in the ligand-metal binding energy in determining the final equilibrium NC size. Based on the insight provided by this model, we demonstrated experimentally that by varying the choice of ligands, ligand-exchange can be used to obtain different sized NCs. The findings in this work establish ligand-exchange as a versatile tool for tuning cluster sizes.

Glutamate receptor ligands

DEFF Research Database (Denmark)

Guldbrandt, Mette; Johansen, Tommy N; Frydenvang, Karla Andrea

2002-01-01

Homologation and substitution on the carbon backbone of (S)-glutamic acid [(S)-Glu, 1], as well as absolute stereochemistry, are structural parameters of key importance for the pharmacological profile of (S)-Glu receptor ligands. We describe a series of methyl-substituted 2-aminoadipic acid (AA...

RigFit: a new approach to superimposing ligand molecules.

Science.gov (United States)

Lemmen, C; Hiller, C; Lengauer, T

1998-09-01

If structural knowledge of a receptor under consideration is lacking, drug design approaches focus on similarity or dissimilarity analysis of putative ligands. In this context the mutual ligand superposition is of utmost importance. Methods that are rapid enough to facilitate interactive usage, that allow to process sets of conformers and that enable database screening are of special interest here. The ability to superpose molecular fragments instead of entire molecules has proven to be helpful too. The RIGFIT approach meets these requirements and has several additional advantages. In three distinct test applications, we evaluated how closely we can approximate the observed relative orientation for a set of known crystal structures, we employed RIGFIT as a fragment placement procedure, and we performed a fragment-based database screening. The run time of RIGFIT can be traded off against its accuracy. To be competitive in accuracy with another state-of-the-art alignment tool, with which we compare our method explicitly, computing times of about 6 s per superposition on a common day workstation are required. If longer run times can be afforded the accuracy increases significantly. RIGFIT is part of the flexible superposition software FLEXS which can be accessed on the WWW [http:/(/)cartan.gmd.de/FlexS].

Calculating the knowledge-based similarity of functional groups using crystallographic data

Science.gov (United States)

Watson, Paul; Willett, Peter; Gillet, Valerie J.; Verdonk, Marcel L.

2001-09-01

A knowledge-based method for calculating the similarity of functional groups is described and validated. The method is based on experimental information derived from small molecule crystal structures. These data are used in the form of scatterplots that show the likelihood of a non-bonded interaction being formed between functional group A (the `central group') and functional group B (the `contact group' or `probe'). The scatterplots are converted into three-dimensional maps that show the propensity of the probe at different positions around the central group. Here we describe how to calculate the similarity of a pair of central groups based on these maps. The similarity method is validated using bioisosteric functional group pairs identified in the Bioster database and Relibase. The Bioster database is a critical compilation of thousands of bioisosteric molecule pairs, including drugs, enzyme inhibitors and agrochemicals. Relibase is an object-oriented database containing structural data about protein-ligand interactions. The distributions of the similarities of the bioisosteric functional group pairs are compared with similarities for all the possible pairs in IsoStar, and are found to be significantly different. Enrichment factors are also calculated showing the similarity method is statistically significantly better than random in predicting bioisosteric functional group pairs.

Molecular interactions of agonist and inverse agonist ligands at serotonin 5-HT2C G protein-coupled receptors: computational ligand docking and molecular dynamics studies validated by experimental mutagenesis results

Science.gov (United States)

Córdova-Sintjago, Tania C.; Liu, Yue; Booth, Raymond G.

2015-02-01

To understand molecular determinants for ligand activation of the serotonin 5-HT2C G protein-coupled receptor (GPCR), a drug target for obesity and neuropsychiatric disorders, a 5-HT2C homology model was built according to an adrenergic β2 GPCR (β2AR) structure and validated using a 5-HT2B GPCR crystal structure. The models were equilibrated in a simulated phosphatidyl choline membrane for ligand docking and molecular dynamics studies. Ligands included (2S, 4R)-(-)-trans-4-(3'-bromo- and trifluoro-phenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalene-2-amine (3'-Br-PAT and 3'-CF3-PAT), a 5-HT2C agonist and inverse agonist, respectively. Distinct interactions of 3'-Br-PAT and 3'-CF3-PAT at the wild-type (WT) 5-HT2C receptor model were observed and experimental 5-HT2C receptor mutagenesis studies were undertaken to validate the modelling results. For example, the inverse agonist 3'-CF3-PAT docked deeper in the WT 5-HT2C binding pocket and altered the orientation of transmembrane helices (TM) 6 in comparison to the agonist 3'-Br-PAT, suggesting that changes in TM orientation that result from ligand binding impact function. For both PATs, mutation of 5-HT2C residues S3.36, T3.37, and F5.47 to alanine resulted in significantly decreased affinity, as predicted from modelling results. It was concluded that upon PAT binding, 5-HT2C residues T3.37 and F5.47 in TMs 3 and 5, respectively, engage in inter-helical interactions with TMs 4 and 6, respectively. The movement of TMs 5 and 6 upon agonist and inverse agonist ligand binding observed in the 5-HT2C receptor modelling studies was similar to movements reported for the activation and deactivation of the β2AR, suggesting common mechanisms among aminergic neurotransmitter GPCRs.

Automated identification of crystallographic ligands using sparse-density representations

International Nuclear Information System (INIS)

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

2014-01-01

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

CXCR4 Ligands : The Next Big Hit?

NARCIS (Netherlands)

Walenkamp, Annemiek M. E.; Lapa, Constantin; Herrmann, Ken; Wester, Hans-Juergen

2017-01-01

The G protein-coupled protein receptor C-X-C chemokine receptor 4 (CXCR4) is an attractive target for cancer diagnosis and treatment, as it is overexpressed in many solid and hematologic cancers. Binding of its ligand, C-X-C chemokine ligand 12 (CXCL12), results in receptor internalization and

Polymerization catalysts containing electron-withdrawing amide ligands

Science.gov (United States)

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.

Immobilisation of ligands by radio-derivatized polymers

International Nuclear Information System (INIS)

Varga, J.M.; Fritsch, P.

1995-01-01

The invention relates to radio-derivatized polymers and a method of producing them by contacting non-polymerizable conjugands with radiolysable polymers in the presence of irradiation. The resulting radio-derivatized polymers can be further linked with ligand of organic or inorganic nature to immobilize such ligands. 2 figs., 5 tabs

Conical angles of ligands - compounds of elements of the 6(16) and 7(17) groups. Levelling effect

International Nuclear Information System (INIS)

Imyanitov, N.S.

1991-01-01

In the framework of development of a unified system of electron and steric effects of ligand conical angles of 176 compounds R 2 X and RHal, where X=O, S, Se, Te; Hal=F, Cl, Br, I; R=H, Hal (only in the case of R 2 X), Alk or Ar, were calculated. A levelling effect of large X and Hal was pointed out: in the beginning of steric series the conical angles are determined by dimensions of X and Hal and not by R ones. Similar levelled values of conical angles for previously considered ligands on the basis of N, P, As, Sb, Bi, C, Si, Ge, Sn were also calculated

Synthesis and study of new oxazoline-based ligands

OpenAIRE

Tilliet, Mélanie

2008-01-01

This thesis deals with the study of oxazoline-based ligands in metal-catalyzed asymmetric reactions. The first part describes the synthesis of six new bifunctinal pyridine-bis(oxazoline) ligands and their applications in asymmetric metal-catalysis. These ligands, in addition to a Lewis acid coordination site, are equipped with a Lewis basic part in the 4-position of the oxazoline rings. Dual activation by means of this system was probed in cyanide addition to aldehydes. The second part is con...

Selectivity in ligand recognition of G-quadruplex loops.

Science.gov (United States)

Campbell, Nancy H; Patel, Manisha; Tofa, Amina B; Ghosh, Ragina; Parkinson, Gary N; Neidle, Stephen

2009-03-03

A series of disubstituted acridine ligands have been cocrystallized with a bimolecular DNA G-quadruplex. The ligands have a range of cyclic amino end groups of varying size. The crystal structures show that the diagonal loop in this quadruplex results in a large cavity for these groups, in contrast to the steric constraints imposed by propeller loops in human telomeric quadruplexes. We conclude that the nature of the loop has a significant influence on ligand selectivity for particular quadruplex folds.

Synthesis and characterization of [{sup 76}Br]-labeled high-affinity A{sub 3} adenosine receptor ligands for positron emission tomography

Energy Technology Data Exchange (ETDEWEB)

Kiesewetter, Dale O. [Positron Emission Tomography Radiochemistry Group, NIBIB, Clinical Center, National Institutes of Health, Bethesda, MD 20892 (United States)], E-mail: dk7k@nih.gov; Lang Lixin; Ma Ying; Bhattacharjee, Abesh Kumar [Positron Emission Tomography Radiochemistry Group, NIBIB, Clinical Center, National Institutes of Health, Bethesda, MD 20892 (United States); Gao, Zhan-Guo; Joshi, Bhalchandra V.; Melman, Artem; Castro, Sonia de; Jacobson, Kenneth A. [Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892 (United States)

2009-01-15

Introduction: Bromine-76-radiolabeled analogues of previously reported high-affinity A{sub 3} adenosine receptor (A{sub 3}AR) nucleoside ligands have been prepared as potential radiotracers for positron emission tomography. Methods: The radiosyntheses were accomplished by oxidative radiobromination on the N{sup 6}-benzyl moiety of trimethyltin precursors. Biodistribution studies of the kinetics of uptake were conducted in awake rats. Results: We prepared an agonist ligand {l_brace}[{sup 76}Br](1'S,2'R,3'S,4'R,5'S)-4'-{l_brace}2-chloro-6-[(3-bromophenylmethyl)amino] purin-9-yl{r_brace}-1'-(methylaminocarbonyl)bicyclo[3.1.0]hexane-2',3'-diol (MRS3581){r_brace} in 59% radiochemical yield with a specific activity of 19.5 GBq/{mu}mol and an antagonist ligand {l_brace}[{sup 76}Br](1'R,2'R,3'S,4'R,5'S)-4'-(6-(3-bromobenzylamino) -2-chloro-9H-purin-9-yl)bicyclo[3.1.0]hexane-2',3'-diol (MRS5147){r_brace} in 65% radiochemical yield with a specific activity of 22 GBq/{mu}mol. The resultant products exhibited the expected high affinity (K{sub i}{approx}0.6 nM) and specific binding at the human A{sub 3}AR in vitro. Biodistribution studies in the rat showed uptake in the organs of excretion and metabolism. The antagonist MRS5147 exhibited increasing uptake in testes, an organ that contains significant quantities of A{sub 3}AR, over a 2-h time course, which suggests the presence of a specific A{sub 3}AR retention mechanism. Conclusion: We were able to compare uptake of the [{sup 76}Br]-labeled antagonist MRS5147 to [{sup 76}Br]agonist MRS3581. The antagonist MRS5147 shows increasing uptake in the testes, an A{sub 3}AR-rich tissue, suggesting that this ligand may have promise as a molecular imaging agent.

Nickel(II) and palladium(II) triphenylphosphine complexes incorporating tridentate Schiff base ligands: Synthesis, characterization and biocidal activities

Science.gov (United States)

Shabbir, Muhammad; Akhter, Zareen; Ashraf, Ahmad Raza; Ismail, Hammad; Habib, Anum; Mirza, Bushra

2017-12-01

Nickel(II) and palladium(II) triphenylphosphine complexes incorporating tridentate Schiff bases have been prepared and characterized by elemental analysis as well as by spectroscopic techniques (FTIR & NMR). The synthesized compounds were assessed to check their potential biocidal activity by using different biological assays (brine shrimp cytotoxicity, antimicrobial, antioxidant, antitumor and drug-DNA interaction). Results of brine shrimp cytotoxicity assay showed that ligand molecules are more bioactive than metal complexes with LD50 as low as 12.4 μg/mL. The prominent antitumor activity was shown by nickel complexes while the palladium complexes exhibited moderate activity. The synthesized compounds have shown high propensity for DNA binding either through intercalation or groove binding which represents the mechanism of antitumor effect of these compounds. Additionally, ligand molecules and nickel metal complexes showed significant antioxidant activity with IC50 values as low as 3.1 μg/mL and 18.9 μg/mL respectively while palladium complexes exhibited moderate activity. Moreover, in antimicrobial assays H2L1, Ni(L1)PPh3 and H2L3 showed dual inhibition against bacterial and fungal strains while for the rest of the compounds varying degree of activity was recorded against different strains. Overall comparison of results suggests that the synthesized compounds can be promising candidate for drug formulation and development.

Organotellurium ligands – designing and complexation reactions

Indian Academy of Sciences (India)

Unknown

membered rings it is negative and ~30 ppm only. Keywords. Organotellurium ligands; hybrid telluroether; platinum metal complexes; tellurium-125 NMR. 1. Introduction. Tellurium is the noblest metalloid which may act as a Lewis acid as well as Lewis base. The ligand chemistry of tellurium, which acts as a 'soft' donor, was ...

Ligand complex structures of l-amino acid oxidase/monooxygenase from Pseudomonas sp. AIU 813 and its conformational change.

Science.gov (United States)

Im, Dohyun; Matsui, Daisuke; Arakawa, Takatoshi; Isobe, Kimiyasu; Asano, Yasuhisa; Fushinobu, Shinya

2018-03-01

l-Amino acid oxidase/monooxygenase from Pseudomonas sp. AIU 813 (l-AAO/MOG) catalyzes both the oxidative deamination and oxidative decarboxylation of the α-group of l-Lys to produce a keto acid and amide, respectively. l-AAO/MOG exhibits limited specificity for l-amino acid substrates with a basic side chain. We previously determined its ligand-free crystal structure and identified a key residue for maintaining the dual activities. Here, we determined the structures of l-AAO/MOG complexed with l-Lys, l-ornithine, and l-Arg and revealed its substrate recognition. Asp238 is located at the ceiling of a long hydrophobic pocket and forms a strong interaction with the terminal, positively charged group of the substrates. A mutational analysis on the D238A mutant indicated that the interaction is critical for substrate binding but not for catalytic control between the oxidase/monooxygenase activities. The catalytic activities of the D238E mutant unexpectedly increased, while the D238F mutant exhibited altered substrate specificity to long hydrophobic substrates. In the ligand-free structure, there are two channels connecting the active site and solvent, and a short region located at the dimer interface is disordered. In the l-Lys complex structure, a loop region is displaced to plug the channels. Moreover, the disordered region in the ligand-free structure forms a short helix in the substrate complex structures and creates the second binding site for the substrate. It is assumed that the amino acid substrate enters the active site of l-AAO/MOG through this route. The atomic coordinates and structure factors (codes 5YB6, 5YB7, and 5YB8) have been deposited in the Protein Data Bank (http://wwpdb.org/). 1.4.3.2 (l-amino acid oxidase), 1.13.12.2 (lysine 2-monooxygenase).

Fluoroalkyl and Alkyl Chains Have Similar Hydrophobicities in Binding to the “Hydrophobic Wall” of Carbonic Anhydrase

Energy Technology Data Exchange (ETDEWEB)

J Mecinovic; P Snyder; K Mirica; S Bai; E Mack; R Kwant; D Moustakas; A Heroux; G Whitesides

2011-12-31

The hydrophobic effect, the free-energetically favorable association of nonpolar solutes in water, makes a dominant contribution to binding of many systems of ligands and proteins. The objective of this study was to examine the hydrophobic effect in biomolecular recognition using two chemically different but structurally similar hydrophobic groups, aliphatic hydrocarbons and aliphatic fluorocarbons, and to determine whether the hydrophobicity of the two groups could be distinguished by thermodynamic and biostructural analysis. This paper uses isothermal titration calorimetry (ITC) to examine the thermodynamics of binding of benzenesulfonamides substituted in the para position with alkyl and fluoroalkyl chains (H{sub 2}NSO{sub 2}C{sub 6}H{sub 4}-CONHCH{sub 2}(CX{sub 2}){sub n}CX{sub 3}, n = 0-4, X = H, F) to human carbonic anhydrase II (HCA II). Both alkyl and fluoroalkyl substituents contribute favorably to the enthalpy and the entropy of binding; these contributions increase as the length of chain of the hydrophobic substituent increases. Crystallography of the protein-ligand complexes indicates that the benzenesulfonamide groups of all ligands examined bind with similar geometry, that the tail groups associate with the hydrophobic wall of HCA II (which is made up of the side chains of residues Phe131, Val135, Pro202, and Leu204), and that the structure of the protein is indistinguishable for all but one of the complexes (the longest member of the fluoroalkyl series). Analysis of the thermodynamics of binding as a function of structure is compatible with the hypothesis that hydrophobic binding of both alkyl and fluoroalkyl chains to hydrophobic surface of carbonic anhydrase is due primarily to the release of nonoptimally hydrogen-bonded water molecules that hydrate the binding cavity (including the hydrophobic wall) of HCA II and to the release of water molecules that surround the hydrophobic chain of the ligands. This study defines the balance of enthalpic and

Speciation of Co(II) and Ni(II) in anaerobic bioreactors measured by competitive ligand exchange - adsorptive stripping voltammetry

NARCIS (Netherlands)

Jansen, S.; Steffen, F.; Threels, W.F.; Leeuwen, van H.P.

2005-01-01

Competitive ligand exchange-adsorptive stripping voltammetry is applied to speciation analysis of dissolved Ni(II) and Co(II) in an anaerobic bioreactor and similar batch media. Co and Ni speciation in these media can be measured down to concentration levels of ca. 1 nM. Sulfide interference is

Free-energy relationships in ion channels activated by voltage and ligand

Science.gov (United States)

Chowdhury, Sandipan

2013-01-01

Many ion channels are modulated by multiple stimuli, which allow them to integrate a variety of cellular signals and precisely respond to physiological needs. Understanding how these different signaling pathways interact has been a challenge in part because of the complexity of underlying models. In this study, we analyzed the energetic relationships in polymodal ion channels using linkage principles. We first show that in proteins dually modulated by voltage and ligand, the net free-energy change can be obtained by measuring the charge-voltage (Q-V) relationship in zero ligand condition and the ligand binding curve at highly depolarizing membrane voltages. Next, we show that the voltage-dependent changes in ligand occupancy of the protein can be directly obtained by measuring the Q-V curves at multiple ligand concentrations. When a single reference ligand binding curve is available, this relationship allows us to reconstruct ligand binding curves at different voltages. More significantly, we establish that the shift of the Q-V curve between zero and saturating ligand concentration is a direct estimate of the interaction energy between the ligand- and voltage-dependent pathway. These free-energy relationships were tested by numerical simulations of a detailed gating model of the BK channel. Furthermore, as a proof of principle, we estimate the interaction energy between the ligand binding and voltage-dependent pathways for HCN2 channels whose ligand binding curves at various voltages are available. These emerging principles will be useful for high-throughput mutagenesis studies aimed at identifying interaction pathways between various regulatory domains in a polymodal ion channel. PMID:23250866

A key agonist-induced conformational change in the cannabinoid receptor CB1 is blocked by the allosteric ligand Org 27569.

Science.gov (United States)

Fay, Jonathan F; Farrens, David L

2012-09-28

Allosteric ligands that modulate how G protein-coupled receptors respond to traditional orthosteric drugs are an exciting and rapidly expanding field of pharmacology. An allosteric ligand for the cannabinoid receptor CB1, Org 27569, exhibits an intriguing effect; it increases agonist binding, yet blocks agonist-induced CB1 signaling. Here we explored the mechanism behind this behavior, using a site-directed fluorescence labeling approach. Our results show that Org 27569 blocks conformational changes in CB1 that accompany G protein binding and/or activation, and thus inhibit formation of a fully active CB1 structure. The underlying mechanism behind this behavior is that simultaneous binding of Org 27569 produces a unique agonist-bound conformation, one that may resemble an intermediate structure formed on the pathway to full receptor activation.

Identification and characterization of PPARα ligands in the hippocampus.

Science.gov (United States)

Roy, Avik; Kundu, Madhuchhanda; Jana, Malabendu; Mishra, Rama K; Yung, Yeni; Luan, Chi-Hao; Gonzalez, Frank J; Pahan, Kalipada

2016-12-01

Peroxisome proliferator-activated receptor-α (PPARα) regulates hepatic fatty acid catabolism and mediates the metabolic response to starvation. Recently we found that PPARα is constitutively activated in nuclei of hippocampal neurons and controls plasticity via direct transcriptional activation of CREB. Here we report the discovery of three endogenous PPARα ligands-3-hydroxy-(2,2)-dimethyl butyrate, hexadecanamide, and 9-octadecenamide-in mouse brain hippocampus. Mass spectrometric detection of these compounds in mouse hippocampal nuclear extracts, in silico interaction studies, time-resolved FRET analyses, and thermal shift assay results clearly indicated that these three compounds served as ligands of PPARα. Site-directed mutagenesis studies further revealed that PPARα Y464 and Y314 are involved in binding these hippocampal ligands. Moreover, these ligands activated PPARα and upregulated the synaptic function of hippocampal neurons. These results highlight the discovery of hippocampal ligands of PPARα capable of modulating synaptic functions.

Ab initio calculation of transport properties between PbSe quantum dots facets with iodide ligands

Science.gov (United States)

Wang, B.; Patterson, R.; Chen, W.; Zhang, Z.; Yang, J.; Huang, S.; Shrestha, S.; Conibeer, G.

2018-01-01

The transport properties between Lead Selenide (PbSe) quantum dots decorated with iodide ligands has been studied using density functional theory (DFT). Quantum conductance at each selected energy levels has been calculated along with total density of states and projected density of states. The DFT calculation is carried on using a grid-based planar augmented wave (GPAW) code incorporated with the linear combination of atomic orbital (LCAO) mode and Perdew Burke Ernzerhof (PBE) exchange-correlation functional. Three iodide ligand attached low index facets including (001), (011), (111) are investigated in this work. P-orbital of iodide ligand majorly contributes to density of state (DOS) at near top valence band resulting a significant quantum conductance, whereas DOS of Pb p-orbital shows minor influence. Various values of quantum conductance observed along different planes are possibly reasoned from a combined effect electrical field over topmost surface and total distance between adjacent facets. Ligands attached to (001) and (011) planes possess similar bond length whereas it is significantly shortened in (111) plane, whereas transport between (011) has an overall low value due to newly formed electric field. On the other hand, (111) plane with a net surface dipole perpendicular to surface layers leading to stronger electron coupling suggests an apparent increase of transport probability. Apart from previously mentioned, the maximum transport energy levels located several eVs (1 2 eVs) from the edge of valence band top.

Using chemical shift perturbation to characterise ligand binding.

Science.gov (United States)

Williamson, Mike P

2013-08-01

Chemical shift perturbation (CSP, chemical shift mapping or complexation-induced changes in chemical shift, CIS) follows changes in the chemical shifts of a protein when a ligand is added, and uses these to determine the location of the binding site, the affinity of the ligand, and/or possibly the structure of the complex. A key factor in determining the appearance of spectra during a titration is the exchange rate between free and bound, or more specifically the off-rate koff. When koff is greater than the chemical shift difference between free and bound, which typically equates to an affinity Kd weaker than about 3μM, then exchange is fast on the chemical shift timescale. Under these circumstances, the observed shift is the population-weighted average of free and bound, which allows Kd to be determined from measurement of peak positions, provided the measurements are made appropriately. (1)H shifts are influenced to a large extent by through-space interactions, whereas (13)Cα and (13)Cβ shifts are influenced more by through-bond effects. (15)N and (13)C' shifts are influenced both by through-bond and by through-space (hydrogen bonding) interactions. For determining the location of a bound ligand on the basis of shift change, the most appropriate method is therefore usually to measure (15)N HSQC spectra, calculate the geometrical distance moved by the peak, weighting (15)N shifts by a factor of about 0.14 compared to (1)H shifts, and select those residues for which the weighted shift change is larger than the standard deviation of the shift for all residues. Other methods are discussed, in particular the measurement of (13)CH3 signals. Slow to intermediate exchange rates lead to line broadening, and make Kd values very difficult to obtain. There is no good way to distinguish changes in chemical shift due to direct binding of the ligand from changes in chemical shift due to allosteric change. Ligand binding at multiple sites can often be characterised, by

Ruthenium(II carbonyl compounds with the 4′-chloro-2,2′:6′,2′′-terpyridine ligand

Directory of Open Access Journals (Sweden)

Rajendhraprasad Tatikonda

2017-04-01

Full Text Available Two ruthenium carbonyl complexes with the 4′-chloro-2,2′:6′,2′′-terpyridine ligand (tpy-Cl, C15H10ClN3, i.e. [RuCl(tpy-Cl(CO2][RuCl3(CO3] (I [systematic name: cis-dicarbonylchlorido(4′-chloro-2,2′:6′,2′′-terpyridine-κ3Nruthenium(II fac-tricarbonyltrichloridoruthenate(II], and [RuCl2(tpy-Cl(CO2] (II [cis-dicarbonyl-trans-dichlorido(4′-chloro-2,2′:6′,2′′-terpyridine-κ2N1,N1′ruthenium(II], were synthesized and characterized by single-crystal X-ray diffraction. The RuII atoms in both centrosymmetric structures (I and (II display similar, slightly distorted octahedral coordination spheres. The coordination sphere in the complex cation in compound (I is defined by three N atoms of the tridentate tpy-Cl ligand, two carbonyl carbon atoms and one chlorido ligand; the charge is balanced by an octahedral [Ru(CO3Cl3]− counter-anion. In the neutral compound (II, the tpy-Cl ligand coordinates to the metal only through two of its N atoms. The coordination sphere of the RuII atom is completed by two carbonyl and two chlorido ligands. In the crystal structures of both (I and (II, weak C—H...Cl interactions are observed.

Adaptability and selectivity of human peroxisome proliferator-activated receptor (PPAR) pan agonists revealed from crystal structures

International Nuclear Information System (INIS)

Oyama, Takuji; Toyota, Kenji; Waku, Tsuyoshi; Hirakawa, Yuko; Nagasawa, Naoko; Kasuga, Jun-ichi; Hashimoto, Yuichi; Miyachi, Hiroyuki; Morikawa, Kosuke

2009-01-01

The structures of the ligand-binding domains (LBDs) of human peroxisome proliferator-activated receptors (PPARα, PPARγ and PPARδ) in complexes with a pan agonist, an α/δ dual agonist and a PPARδ-specific agonist were determined. The results explain how each ligand is recognized by the PPAR LBDs at an atomic level. Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear hormone receptor family, which is defined as transcriptional factors that are activated by the binding of ligands to their ligand-binding domains (LBDs). Although the three PPAR subtypes display different tissue distribution patterns and distinct pharmacological profiles, they all are essentially related to fatty-acid and glucose metabolism. Since the PPARs share similar three-dimensional structures within the LBDs, synthetic ligands which simultaneously activate two or all of the PPARs could be potent candidates in terms of drugs for the treatment of abnormal metabolic homeostasis. The structures of several PPAR LBDs were determined in complex with synthetic ligands, derivatives of 3-(4-alkoxyphenyl)propanoic acid, which exhibit unique agonistic activities. The PPARα and PPARγ LBDs were complexed with the same pan agonist, TIPP-703, which activates all three PPARs and their crystal structures were determined. The two LBD–ligand complex structures revealed how the pan agonist is adapted to the similar, but significantly different, ligand-binding pockets of the PPARs. The structures of the PPARδ LBD in complex with an α/δ-selective ligand, TIPP-401, and with a related δ-specific ligand, TIPP-204, were also determined. The comparison between the two PPARδ complexes revealed how each ligand exhibits either a ‘dual selective’ or ‘single specific’ binding mode

Complexation studies of actinides (U, Pu, Am) with linear polyamino-carboxylate ligands and sidero-chelates

International Nuclear Information System (INIS)

Nguyen, L.V.

2010-01-01

As part of our research endeavour aimed at developing and improving decontamination processes of wastewater containing alpha emitters, physico-chemical complexation studies of actinides (U, Pu, Am) with organic open-chain ligands such as poly-aminocarboxylic acids (H 4 EDTA) and sidero-chelates (di-hydroxamic acids and desferrioxamine B) have been carried out. Gaining a clear understanding of the coordination properties of the targeted actinides is an essential step towards the selection of the most appropriate chelating agents that will exhibit high uptake efficiencies. EXAFS (Extended X-ray Absorption Fine Structure) measurements at the ESRF synchrotron enabled to elucidate the coordination scheme of uranium and plutonium complexes. Solution thermodynamic investigations were intended to provide valuable information about the nature and the stability of the uranium(VI) and americium(III) complexes prevailing at a given pH in solution. The set of stability constants determined from potentiometric and UV-visible spectrophotometric titrations, allowed to predict the speciation of the selected actinides in presence of the aforementioned ligands and to determine the pH range required for achieving 'ultimate' decontamination. (author) [fr

Correlation between social proximity and mobility similarity.

Science.gov (United States)

Fan, Chao; Liu, Yiding; Huang, Junming; Rong, Zhihai; Zhou, Tao

2017-09-20

Human behaviors exhibit ubiquitous correlations in many aspects, such as individual and collective levels, temporal and spatial dimensions, content, social and geographical layers. With rich Internet data of online behaviors becoming available, it attracts academic interests to explore human mobility similarity from the perspective of social network proximity. Existent analysis shows a strong correlation between online social proximity and offline mobility similarity, namely, mobile records between friends are significantly more similar than between strangers, and those between friends with common neighbors are even more similar. We argue the importance of the number and diversity of common friends, with a counter intuitive finding that the number of common friends has no positive impact on mobility similarity while the diversity plays a key role, disagreeing with previous studies. Our analysis provides a novel view for better understanding the coupling between human online and offline behaviors, and will help model and predict human behaviors based on social proximity.

Exhibition

CERN Document Server

Staff Association

2017-01-01

A Look of Hope Islam Mahmoud Sweity From 19 to 30 June 2017 CERN Meyrin, Main Building Islam Mahmoud Sweity Islam Mahmoud Sweity was born in 1997 at Beit Awwa, Palestine. She is currently following a course to get an Art diploma of Painting at the college of Fine Arts at An-Najah National University under the supervision of Esmat Al As'aad. Her portraits, landscapes and still life paintings are full of life and shining colours. Charged of emotional empathy they catch the attention of the viewer and are reminding us that life is beautiful and worth living in spite of all difficulties we have to go through. She participated in many exhibitions and has exposed her drawings in 2015 at CERN and in France in the framework of the exhibition "The Origin“, and in 2017 in the Former Yugoslav Republic of Macedonia, Palestina and Jordan. In this exhibition the oil paintings made in the past year will be presented. For more information : staff.association@cern.ch | T&eacu...

Development of melanoma-targeted polymer micelles by conjugation of a melanocortin 1 receptor (MC1R) specific ligand.

Science.gov (United States)

Barkey, Natalie M; Tafreshi, Narges K; Josan, Jatinder S; De Silva, Channa R; Sill, Kevin N; Hruby, Victor J; Gillies, Robert J; Morse, David L; Vagner, Josef

2011-12-08

The incidence of malignant melanoma is rising faster than that of any other cancer in the United States. Because of its high expression on the surface of melanomas, MC1R has been investigated as a target for selective imaging and therapeutic agents against melanoma. Eight ligands were screened against cell lines engineered to overexpress MC1R, MC4R, or MC5R. Of these, compound 1 (4-phenylbutyryl-His-dPhe-Arg-Trp-NH(2)) exhibited high (0.2 nM) binding affinity for MC1R and low (high nanomolar) affinities for MC4R and MC5R. Functionalization of the ligand at the C-terminus with an alkyne for use in Cu-catalyzed click chemistry was shown not to affect the binding affinity. Finally, formation of the targeted polymer, as well as the targeted micelle formulation, also resulted in constructs with low nanomolar binding affinity.

In vitro evaluation of biodegradable microspheres with surface-bound ligands.

Science.gov (United States)

Keegan, Mark E; Royce, Sara M; Fahmy, Tarek; Saltzman, W Mark

2006-02-21

Protein ligands were conjugated to the surface of biodegradable microspheres. These microsphere-ligand conjugates were then used in two in vitro model systems to evaluate the effect of conjugated ligands on microsphere behavior. Microsphere retention in agarose columns was increased by ligands on the microsphere surface specific for receptors on the agarose matrix. In another experiment, conjugating the lectin Ulex europaeus agglutinin 1 to the microsphere surface increased microsphere adhesion to Caco-2 monolayers compared to control microspheres. This increase in microsphere adhesion was negated by co-administration of l-fucose, indicating that the increase in adhesion is due to specific interaction of the ligand with carbohydrate receptors on the cell surface. These results demonstrate that the ligands conjugated to the microspheres maintain their receptor binding activity and are present on the microsphere surface at a density sufficient to target the microspheres to both monolayers and three-dimensional matrices bearing complementary receptors.

QSAR and docking studies of anthraquinone derivatives by similarity cluster prediction.

Science.gov (United States)

Harsa, Alexandra M; Harsa, Teodora E; Diudea, Mircea V

2016-01-01

Forty anthraquinone derivatives have been downloaded from PubChem database and investigated in a quantitative structure-activity relationships (QSAR) study. The models describing log P and LD50 of this set were built up on the hypermolecule scheme that mimics the investigated receptor space; the models were validated by the leave-one-out procedure, in the external test set and in a new version of prediction by using similarity clusters. Molecular docking approach using Lamarckian Genetic Algorithm was made on this class of anthraquinones with respect to 3Q3B receptor. The best scored molecules in the docking assay were used as leaders in the similarity clustering procedure. It is demonstrated that the LD50 data of this set of anthraquinones are related to the binding energies of anthraquinone ligands to the 3Q3B receptor.

Distinct Iron-binding Ligands in the Upper Water Column at Station ALOHA

Science.gov (United States)

Bundy, R.; Boiteau, R.; Repeta, D.

2016-02-01

The distribution and chemical properties of iron-binding organic ligands at station ALOHA were examined using a combination of solid phase extraction (SPE) followed by high pressure liquid chromatography-inductively coupled plasma mass spectrometry (HPLC-ICPMS). HPLC-ICPMS ligand measurements were complemented by competitive ligand exchange adsorptive cathodic stripping voltammetry (CLE-ACSV) analysis using salicylaldoxime as the added ligand. By HPLC-ICPMS, we find enhanced concentrations of distinct naturally-occurring polar iron-binding ligands present at the surface and in the chlorophyll maximum. Lower concentrations were found in the subsurface, where a suite of non-polar ligands was detected. Siderophores were present at the deepest depths sampled at station ALOHA, down to 400m. Incubation studies provided evidence for the production of iron-binding ligands associated with nutrient amended phytoplankton growth in surface waters, and as a result of microbial particle remineralization in the subsurface water column. Ligands classes identified via SPE were then compared to CLE-ACSV ligand measurements, as well as the conditional stability constants measured from model polar and non-polar siderophores, yielding insight to the sources of iron-binding ligands throughout the water column at station ALOHA.

Mutation of the His ligand in mitoNEET stabilizes the 2Fe–2S cluster despite conformational heterogeneity in the ligand environment

Energy Technology Data Exchange (ETDEWEB)

Conlan, Andrea R.; Paddock, Mark L.; Homer, Christina [University of California at San Diego, La Jolla, CA 92093 (United States); Axelrod, Herbert L.; Cohen, Aina E. [Stanford Synchrotron Radiation Laboratory, 2575 Sand Hill Road, Menlo Park, CA 94025 (United States); Abresch, Edward C.; Zuris, John A. [University of California at San Diego, La Jolla, CA 92093 (United States); Nechushtai, Rachel [Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram, Jerusalem 91904 (Israel); Jennings, Patricia A., E-mail: pajennin@ucsd.edu [University of California at San Diego, La Jolla, CA 92093 (United States)

2011-06-01

The spectroscopic and stability properties and X-ray crystal structure of the H87C mutant of the 2Fe–2S ligand mitoNEET are reported. Strikingly, the single point mutation leads to changes in its absorbance and CD spectra and an increase of around sixfold in the stability of the 2Fe–2S clusters over the pH range 5–7. However, the crystal structure of the H87C mutant displays heterogeneity in a few key residues, including the introduced cysteine ligand. Nonetheless, the cluster is highly stabilized from release. MitoNEET is the only identified Fe–S protein localized to the outer mitochondrial membrane and a 1.5 Å resolution X-ray analysis has revealed a unique structure [Paddock et al. (2007 ▶), Proc. Natl Acad. Sci. USA, 104, 14342–14347]. The 2Fe–2S cluster is bound with a 3Cys–1His coordination which defines a new class of 2Fe–2S proteins. The hallmark feature of this class is the single noncysteine ligand His87, which when replaced by Cys decreases the redox potential (E{sub m}) by ∼300 mV and increases the stability of the cluster by around sixfold. Unexpectedly, the pH dependence of the lifetime of the 2Fe–2S cluster remains the same as in the wild-type protein. Here, the crystal structure of H87C mitoNEET was determined to 1.7 Å resolution (R factor = 18%) to investigate the structural basis of the changes in the properties of the 2Fe–2S cluster. In comparison to the wild type, structural changes are localized to the immediate vicinity of the cluster-binding region. Despite the increased stability, Cys87 displays two distinct conformations, with distances of 2.3 and 3.2 Å between the S{sup γ} and the outer Fe of the 2Fe–2S cluster. In addition, Lys55 exhibits multiple conformations in the H87C mutant protein. The structure and distinct characteristics of the H87C mutant provide a framework for further studies investigating the effects of mutation on the properties of the 2Fe–2S cluster in this new class of proteins.

Synthesis of meta-substituted monodentate phosphinite ligands and ...

Indian Academy of Sciences (India)

SATEJ S DESHMUKH

from organic synthesis, phosphinite ligands find appli- cations in a variety of ... thesis of meta-substituted phosphinite ligands is rarely reported.18 This is most ... 1.9 μm; mobile phase used, 90% methanol + 10% water +. 0.1% formic acid) ...

Rule of five in 2015 and beyond: Target and ligand structural limitations, ligand chemistry structure and drug discovery project decisions.

Science.gov (United States)

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. Copyright © 2016 Elsevier B.V. All rights reserved.