Academic literature on the topic 'Ligand design'
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Journal articles on the topic "Ligand design"
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Apostolakist, J., and A. Caflisch. "Computational Ligand Design." Combinatorial Chemistry & High Throughput Screening 2, no. 2 (April 1999): 91–104. http://dx.doi.org/10.2174/1386207302666220203193501.
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Abstract: A variety of computational tools that are used to assist drug design are reviewed. Particular emphasis is given to the limitations and merits of different methodologies. Recently, a number of general methods have been proposed for clustering compounds in classes of drug like and non-drug-like molecules. The usefulness of this classification for drug design is discussed. The estimation of (relative) binding affinities is from a theoretical point of view the most challenging part of ligand design. We review three methods for the estimation of binding energies. Firstly, quantitative structure-activity relationships (QSAR) are presented. These have gained significantly from recent developments of experimental techniques for combinatorial synthesis and high-throughput screening as well as the use of powerful computational procedures like genetic algorithms and neural networks for the derivation of models. Secondly, empirical energy functions are shown to lead to more general models than standard QSAR, since they are fitted to a variety of complexes. They have been used recently with considerable success. Thirdly, we briefly outline free energy calculations based on molecular dynamics simulations, the method with the most sound theoretical foundation. Recent developments are reestablishing the interest in this approach. In the last part of this review structure-based ligand design programs are described. These are closely related to docking, with the difference that in design, unlike in most docking procedures, ligands are built on a fragment-by-fragment basis. Finally, a short description of our approach to computational combinatorial ligand design is given.
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Caflisch, Amedeo, Rudolf Wälchli, and Claus Ehrhardt. "Computer-Aided Design of Thrombin Inhibitors." Physiology 13, no. 4 (August 1998): 182–89. http://dx.doi.org/10.1152/physiologyonline.1998.13.4.182.
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Computer-aided ligand design is an active, challenging, and multidisciplinary research field that blends knowledge of biochemistry, physics, and computer sciences. Whenever it is possible to experimentally determine or to model the three-dimensional structure of a pharmacologically relevant enzyme or receptor, computational approaches can be used to design specific high-affinity ligands. This article describes methods, applications, and perspectives of computer-assisted ligand design.
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Nash, Jessica A., Matthew D. Manning, Alexey V. Gulyuk, Aleksey E. Kuznetsov, and Yaroslava G. Yingling. "Gold nanoparticle design for RNA compaction." Biointerphases 17, no. 6 (November 2022): 061001. http://dx.doi.org/10.1116/6.0002043.
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RNA-based therapeutics hold a great promise in treating a variety of diseases. However, double-stranded RNAs (dsRNAs) are inherently unstable, highly charged, and stiff macromolecules that require a delivery vehicle. Cationic ligand functionalized gold nanoparticles (AuNPs) are able to compact nucleic acids and assist in RNA delivery. Here, we use large-scale all-atom molecular dynamics simulations to show that correlations between ligand length, metal core size, and ligand excess free volume control the ability of nanoparticles to bend dsRNA far below its persistence length. The analysis of ammonium binding sites showed that longer ligands that bind deep within the major groove did not cause bending. By limiting ligand length and, thus, excess free volume, we have designed nanoparticles with controlled internal binding to RNA's major groove. NPs that are able to induce RNA bending cause a periodic variation in RNA's major groove width. Density functional theory studies on smaller models support large-scale simulations. Our results are expected to have significant implications in packaging of nucleic acids for their applications in nanotechnology and gene delivery.
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Zhang, Bihan, Jishi Chen, Yitao Cao, Osburg Jin Huang Chai, and Jianping Xie. "Ligand Design in Ligand‐Protected Gold Nanoclusters." Small 17, no. 27 (January 28, 2021): 2004381. http://dx.doi.org/10.1002/smll.202004381.
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Hendrati, Diana, Erianti Siska Purnamasari, Syulastri Effendi, and Santhy Wyantuti. "Pemantapan Proses Sintesis Ligan Dibutilditiokarbamat (DBDTK) Sebagai Pengekstrak Logam Tanah Jarang Berdasarkan Desain Eksperimen." ALCHEMY Jurnal Penelitian Kimia 14, no. 2 (September 3, 2018): 219. http://dx.doi.org/10.20961/alchemy.14.2.15006.219-235.
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<p>Gadolinium (Gd) merupakan salah satu logam tanah jarang, dimana logam tanah jarang dapat diekstrak dari mineral salah satunya mineral monasit. Logam Gd biasanya digunakan sebagai bahan dasar <em>contrast agent</em> dalam dunia kesehatan. Ligan dibutilditiokarbamat mampu membentuk senyawa kompleks dengan cara mengikat logam sehingga membentuk khelat yang dapat digunakan untuk ekstraksi. Tujuan dari penelitian ini adalah memantapkan sintesis ligan dibutilditiokarbamat berdasarkan desain eksperimen dan karakterisasi kompleks antara Gd(III) dengan ligan dibutilditiokarbamat hasil sintesis. Penelitian ini diawali dengan pembuatan desain eksperimen untuk sintesis ligan dan ekstraksi Gd(III) dengan ligan, kemudian proses sintesis dan ekstraksi dilakukan sesuai dengan desain eksperimen, hasil sintesis dan ekstraksi dikarakterisasi menggunakan metode spektroskopi serta diuji kelarutannya dalam pelarut organik. Data yang diperoleh menunjukkan bahwa sintesis ligan dibutilditiokarbamat optimal pada suhu 4 °C, perbandingan dibutilamin dan karbondisulfida yaitu 1 : 3 dengan perbandingan mol ammonia terhadap dibutilamin yaitu 1 : 4, sedangkan kondisi optimal untuk ekstraksi Gd(III) dengan ligan yaitu pada pH 6, dengan perbandingan mol Gd(III) dan ligan yaitu 1 : 4 dan lama ekstraksi 60 menit. Oleh karena itu ligan dibutilditiokarbamat hasil sintesis berpotensi digunakan sebagai ekstraktan untuk ekstraksi Gd(III). Hasil prediksi ligan berdasarkan desain eksperimen yaitu sebesar 56,12% sedangkan prediksi ekstraksi Gd(III) dengan ligan hasil sintesis diperoleh sebesar 78,41%.</p><p><strong>The Consolidation of Dibutyldithiocarbamate (DBDTC) Synthesis as Gadolinium Metal Extraction Based On Experimental Design. </strong>Gadolinium (Gd) is one of the rare-earth elements, whereas rare-earth elements can be extracted from monazite. Gd is usually used as raw material for synthesizing contrast agent<em> </em>in medicine field. Dibuthyldithiocarbamate ligand can form a complex compound with metal. This ligand will bind a metal and then forming chelate which is used for extraction. The purpose of this research is to ensure procedure of dibuthyldithiocarbamate ligand synthesis based on the design of experiment and to study the characterization of reaction result between Gd(III) and dibuthyldithiocarbamate ligand which this ligand is synthesis result. This research begins with making design of experiment for ligand synthesis and Gd(III) extraction with ligand, then perform the process of synthesis and extraction according to the design of experiment, the result of synthesis and extraction were characterized by spectroscopy method and solubility tested in organic solvent. The data was collected indicate that the optimal condition of dibuthyldithiocarbamate ligan synthesis at 4 °C (temperature), the ratio of di-n-butylamine and carbon disulphide is 1:3 with the mole ratio of ammonia to the di-n-butylamine 1:4, while the optimal conditions for gadolinium extraction with ligand at pH 6, the mol ratio of gadolinium and ligand is 1:4 and 60 minutes extraction time. Hence, dibuthyldithiocarbamate ligand can be used as extractan for extracting Gd(III). The prediction of ligand based on the experimental design is 56.12% while the prediction of Gd(III) extraction with ligand of the synthesis result is obtained equal to 78.41%. The conclusion of this research is that the synthesis of dibuthyldithiocarbamate ligand based on the experimental design can be developed for large-scale synthesis.</p>
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Hendrati, Diana, Erianti Siska Purnamasari, Syulastri Effendi, and Santhy Wyantuti. "Pemantapan Proses Sintesis Ligan Dibutilditiokarbamat (DBDTK) Sebagai Pengekstrak Logam Tanah Jarang Berdasarkan Desain Eksperimen." ALCHEMY Jurnal Penelitian Kimia 14, no. 1 (February 15, 2018): 195. http://dx.doi.org/10.20961/alchemy.14.1.15006.195-203.
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<p>Gadolinium (Gd) merupakan salah satu logam tanah jarang, dimana logam tanah jarang dapat diekstrak dari mineral salah satunya mineral monasit. Logam Gd biasanya digunakan sebagai bahan dasar <em>contrast agent</em> dalam dunia kesehatan. Ligan dibutilditiokarbamat mampu membentuk senyawa kompleks dengan cara mengikat logam sehingga membentuk khelat yang dapat digunakan untuk ekstraksi. Tujuan dari penelitian ini adalah memantapkan sintesis ligan dibutilditiokarbamat berdasarkan desain eksperimen dan karakterisasi kompleks antara Gd(III) dengan ligan dibutilditiokarbamat hasil sintesis. Penelitian ini diawali dengan pembuatan desain eksperimen untuk sintesis ligan dan ekstraksi Gd(III) dengan ligan, kemudian proses sintesis dan ekstraksi dilakukan sesuai dengan desain eksperimen, hasil sintesis dan ekstraksi dikarakterisasi menggunakan metode spektroskopi serta diuji kelarutannya dalam pelarut organik. Data yang diperoleh menunjukkan bahwa sintesis ligan dibutilditiokarbamat optimal pada suhu 4 °C, perbandingan dibutilamin dan karbondisulfida yaitu 1 : 3 dengan perbandingan mol ammonia terhadap dibutilamin yaitu 1 : 4, sedangkan kondisi optimal untuk ekstraksi Gd(III) dengan ligan yaitu pada pH 6, dengan perbandingan mol Gd(III) dan ligan yaitu 1 : 4 dan lama ekstraksi 60 menit. Oleh karena itu ligan dibutilditiokarbamat hasil sintesis berpotensi digunakan sebagai ekstraktan untuk ekstraksi Gd(III). Hasil prediksi ligan berdasarkan desain eksperimen yaitu sebesar 56,12% sedangkan prediksi ekstraksi Gd(III) dengan ligan hasil sintesis diperoleh sebesar 78,41%. Kesimpulan dari penelitian ini bahwa sintesis ligan dibutilditiokarbamat berdasarkan desain eksperimen dapat dikembangkan untuk sintesis skala besar.</p><p>Gadolinium (Gd) is one of the rare-earth elements, whereas rare-earth elements can be extracted from monazite. Gd is usually used as raw material for synthesizing contrast agent<em> </em>in medicine field. Dibuthyldithiocarbamate ligand can form a complex compound with metal. This ligand will bind a metal and then forming chelate which is used for extraction. The purpose of this research is to ensure procedure of dibuthyldithiocarbamate ligand synthesis based on the design of experiment and to study the characterization of reaction result between Gd(III) and dibuthyldithiocarbamate ligand which this ligand is synthesis result. This research begins with making design of experiment for ligand synthesis and Gd(III) extraction with ligand, then perform the process of synthesis and extraction according to the design of experiment, the result of synthesis and extraction were characterized by spectroscopy method and solubility tested in organic solvent. The data was collected indicate that the optimal condition of dibuthyldithiocarbamate ligan synthesis at 4 °C (temperature), the ratio of di-n-butylamine and carbon disulphide is 1:3 with the mole ratio of ammonia to the di-n-butylamine 1:4, while the optimal conditions for gadolinium extraction with ligand at pH 6, the mol ratio of gadolinium and ligand is 1:4 and 60 minutes extraction time. Hence, dibuthyldithiocarbamate ligand can be used as extractan for extracting Gd(III). The prediction of ligand based on the experimental design is 56.12% while the prediction of Gd(III) extraction with ligand of the synthesis result is obtained equal to 78.41%. The conclusion of this research is that the synthesis of dibuthyldithiocarbamate ligand based on the experimental design can be developed for large-scale synthesis.</p>
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Hendrati, Diana, Erianti Siska Purnamasari, Syulastri Effendi, and Santhy Wyantuti. "Pemantapan Proses Sistesis Ligan Dibutilditiokarbamat (DBDTK) sebagai Pengekstrak Logam Tanah Jarang berdasarkan Desain Eksperimen." ALCHEMY Jurnal Penelitian Kimia 14, no. 1 (February 15, 2018): 84. http://dx.doi.org/10.20961/alchemy.14.1.15006.84-99.
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<p>Gadolinium (Gd) merupakan salah satu logam tanah jarang, dimana logam tanah jarang dapat diekstrak dari mineral salah satunya mineral monasit. Logam Gd biasanya digunakan sebagai bahan dasar <em>contrast agent</em> dalam dunia kesehatan. Ligan dibutilditiokarbamat mampu membentuk senyawa kompleks dengan cara mengikat logam sehingga membentuk khelat yang dapat digunakan untuk ekstraksi. Tujuan dari penelitian ini adalah memantapkan sintesis ligan dibutilditiokarbamat berdasarkan desain eksperimen dan karakterisasi kompleks antara Gd(III) dengan ligan dibutilditiokarbamat hasil sintesis. Penelitian ini diawali dengan pembuatan desain eksperimen untuk sintesis ligan dan ekstraksi Gd(III) dengan ligan, kemudian proses sintesis dan ekstraksi dilakukan sesuai dengan desain eksperimen, hasil sintesis dan ekstraksi dikarakterisasi menggunakan metode spektroskopi serta diuji kelarutannya dalam pelarut organik. Data yang diperoleh menunjukkan bahwa sintesis ligan dibutilditiokarbamat optimal pada suhu 4 °C, perbandingan dibutilamin dan karbondisulfida yaitu 1:3 dengan perbandingan mol ammonia terhadap dibutilamin yaitu 1:4, sedangkan kondisi optimal untuk ekstraksi Gd(III) dengan ligan yaitu pada pH 6, dengan perbandingan mol Gd(III) dan ligan yaitu 1:4 dan lama ekstraksi 60 menit. Oleh karena itu ligan dibutilditiokarbamat hasil sintesis berpotensi digunakan sebagai ekstraktan untuk ekstraksi Gd(III). Hasil prediksi ligan berdasarkan desain eksperimen yaitu sebesar 56,12 % sedangkan prediksi ekstraksi Gd(III) dengan ligan hasil sintesis diperoleh sebesar 78,41 %. Kesimpulan dari penelitian ini bahwa sintesis ligan dibutilditiokarbamat berdasarkan desain eksperimen dapat dikembangkan untuk sintesis skala besar.</p><p>Gadolinium (Gd) is one of the rare-earth elements, whereas rare-earth elements can be extracted from monazite. Gd is usually used as raw material for synthesizing contrast agent<em> </em>in medicine field. Dibuthyldithiocarbamate ligand can form a complex compound with metal. This ligand will bind a metal and then forming chelate which is used for extraction. The purpose of this research is to ensure procedure of dibuthyldithiocarbamate ligand synthesis based on the design of experiment and to study the characterization of reaction result between Gd(III) and dibuthyldithiocarbamate ligand which this ligand is synthesis result. This research begins with making design of experiment for ligand synthesis and Gd(III) extraction with ligand, then perform the process of synthesis and extraction according to the design of experiment, the result of synthesis and extraction were characterized by spectroscopy method and solubility tested in organic solvent. The data was collected indicate that the optimal condition of dibuthyldithiocarbamate ligan synthesis at 4 °C (temperature), the ratio of di-n-butylamine and carbon disulphide is 1:3 with the mole ratio of ammonia to the di-n-butylamine 1:4, while the optimal conditions for gadolinium extraction with ligand at pH 6, the mol ratio of gadolinium and ligand is 1:4 and 60 minutes extraction time. Hence, dibuthyldithiocarbamate ligand can be used as extractan for extracting Gd(III). The prediction of ligand based on the experimental design is 56.12 % while the prediction of Gd(III) extraction with ligand of the synthesis result is obtained equal to 78.41 %. The conclusion of this research is that the synthesis of dibuthyldithiocarbamate ligand based on the experimental design can be developed for large-scale synthesis.</p>
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Date, Richard W., Eva Fernandez Iglesias, Kathryn E. Rowe, James M. Elliott, and Duncan W. Bruce. "Metallomesogens by ligand design." Dalton Trans., no. 10 (2003): 1914–31. http://dx.doi.org/10.1039/b212610a.
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Fryzuk, Michael D. "Ligand Design Virtual Issue." Inorganic Chemistry 54, no. 20 (October 19, 2015): 9671–74. http://dx.doi.org/10.1021/acs.inorgchem.5b02191.
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Mehta, Simpi, and Seema R. Pathak. "INSILICO DRUG DESIGN AND MOLECULAR DOCKING STUDIES OF NOVEL COUMARIN DERIVATIVES AS ANTI-CANCER AGENTS." Asian Journal of Pharmaceutical and Clinical Research 10, no. 4 (April 1, 2017): 335. http://dx.doi.org/10.22159/ajpcr.2017.v10i4.16826.
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Objective: Cancer is the major worldwide problem. It arises due to uncontrolled growth of cells. In the present study a series of novel coumarin derivatives were designed and computationallyoptimized to investigate the interaction between designed ligands and 10 pdb files of five selected proteins. The objective here was to analyse in silico anticancerous activity of designed ligands to reduce cost and time for getting novel anticancerous drug with minimum side effects.Methods: Docking studies were performed to find outmaximum interaction between designed ligands and selected five proteins using Schrondinger software Maestro. Capecitabin has been used as reference compound. Structures of selected proteins were downloaded from protein data bank.Results: All the designed ligands showed mild to excellent binding with proteins.Most of the ligands exhibited better interaction compared to reference compoundcapacitabin with all pdb files. Some of designed ligands amongst (1-7) showed excellent docking score with all pdb files(2v5z, 2v60, 2v61) ofAmine oxidase. Conclusion: All the designed ligands were docked with ten pdb files of five different proteins and it was found that out of seven designed ligand, ligand 4 showed best binding (docking score -10.139 ) with pdb 2v5z of protein Amine oxidase. Docked ligand cavity of ligand 4 showed important hydrophobic/non polar residues such asIle199,Ile316,Trp119,Phe168,Ile198,Cys172,Tyr188,Tyr398,Tyr435,Phe343,Tyr60,Leu328,Leu171 and showed pi-pi interaction with Tyr326.Further wet lab studies are continued in our laboratory to confirm and find out efficiency and activity of target compounds.Keywords: Docking, Mono Amine Oxidase, Coumarin derivatives, Anticancerous activity, binding energy, Ramachandran Plot, Hydrophobic residue.
Dissertations / Theses on the topic "Ligand design"
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Kontopidis, George A. "Immunophilin ligand design." Thesis, University of Edinburgh, 2000. http://hdl.handle.net/1842/22386.
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The general aim of the project is predict and select small molecule ligands which may bind to 3D protein templates. Proteins from the Immunophilin family were used. The putative ligands were selected by two different methods, by structure similarity and using the docking program LIDAEUS, which was developed in house by Dr. P. Taylor. Twenty nine small molecules were selected from a small molecule database and were tested with a fluorescence assay, a PPIase assay and x-ray crystallography for binding activity. Six new ligands have been discovered which bind to Cyp-A. In this work the IC<sub>50</sub> (concentration in which half inhibition occurred) of the putative ligands were determined by rotamase inhibition assay. In addition the binding of the ligands was also confirmed by crystallographic experiments. The X-ray structures of 3-acetyl-1 methyl piperidine, ethyl-piperidine glyoxylate, dimethyl sulfoxide, tetramethylene sulfoxide, cyclopentanone and 5,5-dimethyl-1,3-cyclohexanedione bound to Cyp-A have been solved and refined with Rfactor for each structure less than 20%. The structural analysis of the native and ligand structures revealed a hydrophobic pocket surrounded by residues Asn 102, Met 61, Arg 55 and His 122, a hydrogen bond donor site of the main chain nitrogen Asn 102, and another hydrogen bond donor site of the guanidinium of Arg 55. The six novel ligands have been classified into 3 different families of compounds, 3-Acetyl-1 methyl piperidine and ethyl-piperidine glyoxylate belong to the piperidine family and share structural similarities with a natural substrate of Cyp-A the dipeptide Ala-Pro. Dimethyl sulfoxide (DMSO), tetramethylene sulfoxide and cyclopentanone form the DMSO family and they do not share any similarities with known Cyp-A ligand. Only one compound has been discovered in the third family. This compound 5,5-dimethyl-1,3-cyclohexanedione also known as dimedone shows some structural similarities with the Val 11 residue of the Cyp-A ligand cyclosporin.
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Hallman, Kristina. "Asymmetric Catalysis : Ligand Design and Conformational Studies." Doctoral thesis, KTH, Chemistry, 2001. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-3275.
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<p>This thesis deals with the design of ligands for efficientasymmetric catalysis and studies of the conformation of theligands in the catalytically active complexes. All ligandsdeveloped contain chiral oxazoline heterocycles.</p><p>The conformations of hydroxy- and methoxy-substitutedpyridinooxazolines and bis(oxazolines) during Pd-catalysedallylic alkylations were investigated using crystallography,2D-NMR techniques and DFT calculations. A stabilising OH-Pdinteraction was discovered which might explain the differencein reactivity between the hydroxy- and methoxy-containingligands. The conformational change in the ligands due to thisinteraction may explain the different selectivities observed inthe catalytic reaction.</p><p>Polymer-bound pyridinooxazolines and bis(oxazolines) weresynthesised and employed in Pd-catalysed allylic alkylationswith results similar to those of monomeric analogues;enantioselectivities up to 95% were obtained. One polymer-boundligand could be re-used several times after removal of Pd(0).The polymer-bound bis(oxazoline) was also used in Zn-catalysedDiels-Alder reactions, but the heterogenised catalyst gavelower selectivities than a monomeric analogue.</p><p>A series of chiral dendron-containing pyridinooxazolines andbis(oxazolines) were synthesised and evaluated in Pd-catalysedallylic alkylations. The dendrons did not seem to have anyinfluence on the selectivity and little influence on the yieldwhen introduced in the pyridinooxazoline ligands. In thebis(oxazoline) series lower generation dendrimers had a postiveon the selectivity, but the selectivity and the activitydecreased with increasing generation.</p><p>Crown ether-containing ligands were investigated inpalladium-catalysed alkylations. No evidence of a possibleinteraction between the metal in the crown ether and thenucleophile was discovered.</p><p>A new type of catalyst, an oxazoline-containing palladacyclewas found to be very active in oxidations of secondary alcoholsto the corresponding aldehydes or ketones. The reactions wereperformed with air as the re-oxidant. Therefore, this is anenviromentally friendly oxidation method.</p><p><b>Keywords:</b>asymmetric catalysis, chiral ligand,oxazolines, conformational study, allylic substitution,polymer-bound ligands, dendritic ligands, crown ether,oxidations, palladacycle.</p>
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Evans, P. L. "Ligand design for homogenous catalysis." Thesis, University of Oxford, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.376909.
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Green, Jason. "Ligand design for copper(I) catalysis." Thesis, University of Hull, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.318380.
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Frost, Jamie Michael. "Ligand design strategies for molecular nanomagnets." Thesis, University of Edinburgh, 2015. http://hdl.handle.net/1842/17990.
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This thesis describes the synthesis and magnetic characterisation of a series of polynuclear 3d and 3d/4f complexes built using phenolic oxime type ligands. Chapter two describes the reaction of salicylaldoxime and its derivatised analogues (R-saoH2) with the alkoxide containing co-ligands triethanolamine (TeaH3) and 2-(hydroxymethyl)pyridine (Hhmp), in the presence of Mn(II)/Ln(III) salts. This results in the formation of a family of sixteen [MnIII4LnIII2] clusters, which are structurally related to a previously studied [MnIII6] family of Single-Molecule Magnets (SMMs). The magnetic properties of the Ln = Y, Gd and Lu analogues can be qualitatively rationalised on the basis of a magneto-structural correlation (MSC), previously developed for MnIII alkoxide/oxime bridged dimers. Chapter three describes how the combination of two complimentary ligands, the phenolic oximes (R-SaoH2) and the diethanolamines (DeaH3), into one organic framework, creates new ligand types (H3L1 and H4L2) which can be used to construct a hexametallic MnIII wheel; [MnIII6Na(L1)6]Cl, the first example of a ferromagnetically coupled dodecametallic MnIII wheel;[MnIII 12(OMe)16(L2)4(O2CCMe3)4(MeOH)4], and the first example of a dodecametallic MnIII truncated tetrahedron; [MnIII12O4(H3L2)8(H2L2)4(TMA)4 (TMA = trianion of trimesic acid). Single crystal hysteresis measurements reveal both 3.2 and 3.3 to be SMMs at low temperature. Chapter four deals with the use of H4L2 in Cu coordination chemistry. Phenolic oximes are known to form monometallic complexes with CuII ions, as are the diethanolamines. However, the deliberate incorporation of one ligand onto the organic framework of the other permits the preparation of a family of [CuIIn] wheels (n = 4, 6, 8). In each case nearest neighbour interactions between CuII ions are shown to be strongly antiferromagnetic. DFT calculations suggest the origin of this interaction is related to the Cu-O-N-Cu dihedral angle, an observation which allows for the development of a theoretical MSC, that suggests a switch from antiferro- to ferro-magnetic exchange is possible at Cu-O-N-Cu angles > 60o.
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Bremberg, Ulf. "Asymmetric catalysis : ligand design and microwave acceleration." Doctoral thesis, KTH, Chemistry, 2000. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-2962.
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<p>This thesis deals partly with the design and synthesis ofligands for use in asymmetric catalysis, and partly with theapplication of microwave heating on metal-based asymmetriccatalytic reactions.</p><p>Enantiomerically pure pyridyl alcohols and bipyridylalcohols were synthesized from the chiral pool for future usein asymmetric catalysis. Lithiated pyridines were reacted withseveral chiral electrophiles, yielding diastereomeric mixturesthat could be separated without the use of resolutiontechniques.</p><p>New pyridino- and quinolinooxazolines were synthesized andtested in palladium-catalyzed asymmetric allylation using1,3-diphenyl-2-propenyl acetate and dimethyl malonate. Theconformational preferences of the ligands in palladiumcomplexes were studied with crystallography, 2D-NMR techniquesand DFT calculations. Conclusions about how the chirality wastransferred from the ligand to the substrate could be drawnfrom the conformational analysis.</p><p>The effect of heating Pd- and Mo-catalyzed asymmetricallylic substitution reactions was investigated with oil bathheating and microwave irradiation. With a few exceptions,ligands with high room temperature selectivity were shown toretain their selectivity on heating. Reaction rates, catalyststability and product selectivities of microwave-heatedreactions were compared with those of reactions performed inoil bath.</p><p>Palladium-catalyzed asymmetric allylation was studied withseveral ligand types, allylic substrates and nucleophiles. Someof the experimental procedures had to be adapted to microwaveheating conditions.</p><p>The procedure for asymmetric allylation catalyzed bybispyridylamide molybdenum complexes was developed into aone-pot microwave-mediated reaction. With microwaves, Mo(CO)<sub>6</sub>could be used as an easily-handled metal sourceand inert conditions could be omitted. Derivatives of thebispyridylamide ligandswere synthesized and tested withmolybdenum as catalysts to investigate the effects ofsubstituents on the pyridine ring.</p><p><b>Keywords</b>: ligand, asymmetric catalysis, pyridylalcohols, oxazolines, conformational study, Pd-allyl, fastchemistry, microwave chemistry, Mo-allyl, bispyridylamides.</p>
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Jabri, Amir. "Mechanism and ligand design in ruthenium catalysis." Thesis, University of Ottawa (Canada), 2005. http://hdl.handle.net/10393/27208.
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The known ruthenium pincer complex RuCl(eta3-dcpx)(PPh 3) (7) (PCP = eta3-2,6-(PCy2CH 2)2C6H3) was transformed into several different hydride products under standard transfer hydrogenation conditions. In situ 31P NMR analysis during thermolysis of 7 in basic isopropanol permitted identification of RuH(eta3-dcpx)(PPh 3)(N2) (8a/b), RuH(eta3-dcpx)(PPh 3) (10), and RuH(eta3-dcpx)(PPh3 )(H2) (9a/b). A spectroscopically unobservable species, Ru(H)2[eta2-PC(H)P] (12), is proposed as the active species in transfer hydrogenation catalysis. The novel precatalyst, RuCl(eta3-dcpx)(py)2 ( 14), which may provide a more active catalyst, was synthesized and characterized.
Several primary and secondary phosphine complexes of ruthenium were synthesized and tested for their activity in catalytic transfer hydrogenation. Of these, only the bulky HPCy2 ligand in RuCl2(HPCy2) 4 (18a/b) provided high catalytic activity. Reaction of RuCl2(PCy3)2(=CHPh) (24) with HPCy2 transforms it cleanly to 18a, potentially opening new opportunities in tandem catalysis. (Abstract shortened by UMI.)
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Rio, Echevarria Iria M. "Applications of surface ligand design to flotation." Thesis, University of Edinburgh, 2007. http://hdl.handle.net/1842/3457.
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This thesis involves the design, synthesis and testing of organic hydrophobic ligands. They would act as co-collectors in froth flotation processes to enhance the recovery of sulfidic minerals which have undergone some oxidation on processing and are not efficiently collected by the commercial reagents used in froth flotation. Strong and selective binding to iron(III) oxide/hydroxide surfaces, e.g. goethite, over unwanted silicaceous material was considered essential criteria for such new cocollectors. A general overview of froth flotation processes is given in Chapter 1 as well as a description of the analytical techniques used in this thesis and the features that the ligands must have to act as co-collectors. On the basis of the strong binding to iron(III) surfaces of the organic ligand Irgacor 419®, used commercially as a corrosion inhibitor for iron, this compound was studied as a potential co-collector. Adsorption isotherms were determined by UV-Vis spectroscopy for two carboxylic acids that may also bind strongly to goethite, the results of which are discussed in Chapter 2. Chapter 3 involves the measurement of the strength of binding of one the most widely used type of collectors for sulfide ores, potassium ethyl xanthate. Complications in the analysis of materials in solution by both ICP-OES and UV-Vis spectroscopy arose due to the instability of potassium ethyl xanthate in solution, making determination and interpretation of isotherms difficult. The determination of adsorption isotherms for 2-mercaptobenzothiazole, which showed weak binding to goethite as well as to silica, and the mode of binding of 2-mercaptobenzothiazole on copper(I) surfaces is reported in Chapter 4. A crystal structure was obtained in which four units of 2-mercaptobenzothiazole bridge two nickel atoms through the nitrogen atom and the exocyclic sulfur and is considered as a model for binding to sulfidic minerals. Chapter 5 looks at the strength of binding to goethite and silica of various hydroxamic acids. Benzohydroxamic acid was initially selected for study since hydroxamates are known to act as collectors for oxidized materials. Unpredictably, benzohydroxamic acid showed strong binding to a goethite surface and did not release any iron from the surface into solution, which would have been predicted due to its known strong chelating abilities to iron(III). The X-ray structure determination of the first example of a dinuclear Fe(III) hydroxamate complex showed this to have -oxo bridge formed by the hydroxamate unit and supports multisite attachment between this ligand and the surface, as suggested by adsoption isotherms. Simple models based on this dinucleating motif provide plausible modes of multisite attachment to a goethite surface. Competitive binding studies provided a way of ranking the ability to bind to goethite of acetohydroxamic acid, which was not suitable for analyses by either ICP-OES or UV-Vis spectroscopy. Of the ligands studied in this chapter acetohydroxamic acid was found to bind most strongly to goethite followed by benzohydroxamic acid. In Chapter 6, the attachment to goethite and silica of a series of phosphonic acids is investigated. All show a very high binding strength to goethite. Froth flotation experiments at a laboratory scale are described in Chapter 7. The types of ligand that showed strong binding to goethite in adsorption isotherms experiments were tested as co-collectors in different ores and conditions. There is not a simple correlation between adsorption isotherm data and flotation performance as co-collectors because other factors, besides strength of binding, affect the system. Benzohydroxamic acid was the ligand that increased the grade/recovery of the process in all the cases studied. Irgacor 419® enhances the grade/recovery curve for Palabora ore and phenyl malonic acid for Kennecott ore. These results support the original proposition that it may be possible to increase the recovery of oxidized particles substantially by using a blend of collectors which includes a compound to target the oxidized sites.
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Boas, F. Edward. "Physics-based design of protein-ligand binding /." May be available electronically:, 2008. http://proquest.umi.com/login?COPT=REJTPTU1MTUmSU5UPTAmVkVSPTI=&clientId=12498.
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Speidel, Joshua A. "Computational approaches to structure based ligand design : an illustration for P/CAF bromodomain ligands /." Access full-text from WCMC, 2007. http://proquest.umi.com/pqdweb?did=1453183061&sid=21&Fmt=2&clientId=8424&RQT=309&VName=PQD.
Full textBooks on the topic "Ligand design"
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Hans-Joachim, Böhm, and Gubernator Klaus, eds. Structure-based ligand design. Weinheim: Wiley-VCH, 1998.
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Stradiotto, Mark, and Rylan J. Lundgren, eds. Ligand Design in Metal Chemistry. Chichester, UK: John Wiley & Sons, Ltd, 2016. http://dx.doi.org/10.1002/9781118839621.
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Ballante, Flavio, ed. Protein-Ligand Interactions and Drug Design. New York, NY: Springer US, 2021. http://dx.doi.org/10.1007/978-1-0716-1209-5.
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Stoddard, Barry L., ed. Computational Design of Ligand Binding Proteins. New York, NY: Springer New York, 2016. http://dx.doi.org/10.1007/978-1-4939-3569-7.
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Storr, Tim, ed. Ligand Design in Medicinal Inorganic Chemistry. Chichester, UK: John Wiley & Sons, Ltd, 2014. http://dx.doi.org/10.1002/9781118697191.
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1959-, Merz Kenneth M., Ringe Dagmar, and Reynolds Charles H. 1957-, eds. Drug design: Structure and ligand-based approaches. Cambridge: Cambridge University Press, 2010.
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Didier, Rognan, ed. Ligand design for G protein-coupled receptors. Weinheim: Wiley, 2006.
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Merz, Kenneth M. Drug design: Structure- and ligand-based approaches. Cambridge [U.K.]: Cambridge University Press, 2010.
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Hans-Joachim, Böhm, and Schneider Gisbert 1965-, eds. Protein-ligand interactions from molecular recognition to drug design. Weinheim: Wiley-VCH, 2003.
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M, Rami Reddy, and Erion Mark D, eds. Free energy calculations in rational drug design. New York: Kluwer Academic/Plenum Publishers, 2001.
Find full textBook chapters on the topic "Ligand design"
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Wan, Qian-Hong. "Ligand Design." In Mixed-Mode Chromatography, 181–221. Singapore: Springer Singapore, 2021. http://dx.doi.org/10.1007/978-981-16-5485-5_5.
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Söderhjelm, Pär, Samuel Genheden, and Ulf Ryde. "Quantum Mechanics in Structure-Based Ligand Design." In Protein-Ligand Interactions, 121–43. Weinheim, Germany: Wiley-VCH Verlag GmbH & Co. KGaA, 2012. http://dx.doi.org/10.1002/9783527645947.ch7.
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Gubernator, K., C. Broger, D. Bur, D. M. Doran, P. R. Gerber, K. Müller, and T. M. Schaumann. "Structure-Based Ligand Design." In Computer Aided Drug Design in Industrial Research, 61–77. Berlin, Heidelberg: Springer Berlin Heidelberg, 1995. http://dx.doi.org/10.1007/978-3-662-03141-4_4.
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Lundgren, Rylan J., and Mark Stradiotto. "Key Concepts in Ligand Design." In Ligand Design in Metal Chemistry, 1–14. Chichester, UK: John Wiley & Sons, Ltd, 2016. http://dx.doi.org/10.1002/9781118839621.ch1.
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Cremer, Julian, Tuan Le, Djork-Arné Clevert, and Kristof T. Schütt. "Latent-Conditioned Equivariant Diffusion for Structure-Based De Novo Ligand Generation." In Lecture Notes in Computer Science, 36–46. Cham: Springer Nature Switzerland, 2024. http://dx.doi.org/10.1007/978-3-031-72381-0_4.
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AbstractWe propose PoLiGenX for de novo ligand design using latent-conditioned, target-aware equivariant diffusion. Our model leverages the conditioning of the generation process on reference molecules within a protein pocket to produce shape-similar de novo ligands that can be used for target-aware hit expansion and hit optimization. The results of our study showcase the efficacy of PoLiGenX in ligand design. Docking scores indicate that the generated ligands exhibit superior binding affinity compared to the reference molecule while preserving the shape. At the same time, our model maintains chemical diversity, ensuring the exploration of diverse chemical space. The evaluation of Lipinski’s rule of five suggests that the sampled molecules possess a higher drug-likeness than the reference data. This constitutes an important step towards the controlled generation of therapeutically relevant de novo ligands tailored to specific protein targets.
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Osten, Kimberly M., Dinesh C. Aluthge, and Parisa Mehrkhodavandi. "Ligand Design in Enantioselective Ring-opening Polymerization of Lactide." In Ligand Design in Metal Chemistry, 270–307. Chichester, UK: John Wiley & Sons, Ltd, 2016. http://dx.doi.org/10.1002/9781118839621.ch10.
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Caballero, Ana, M. Mar Díaz-Requejo, Manuel R. Fructos, Juan Urbano, and Pedro J. Pérez. "Modern Applications of Trispyrazolylborate Ligands in Coinage Metal Catalysis." In Ligand Design in Metal Chemistry, 308–29. Chichester, UK: John Wiley & Sons, Ltd, 2016. http://dx.doi.org/10.1002/9781118839621.ch11.
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Mills, David P., and Stephen T. Liddle. "Ligand Design in Modern Lanthanide Chemistry." In Ligand Design in Metal Chemistry, 330–63. Chichester, UK: John Wiley & Sons, Ltd, 2016. http://dx.doi.org/10.1002/9781118839621.ch12.
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Ryken, Scott A., Philippa R. Payne, and Laurel L. Schafer. "Tight Bite AngleN,O-Chelates. Amidates, Ureates and Beyond." In Ligand Design in Metal Chemistry, 364–405. Chichester, UK: John Wiley & Sons, Ltd, 2016. http://dx.doi.org/10.1002/9781118839621.ch13.
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Quigley, Brendan L., and Robert H. Grubbs. "Catalyst Structure andCis-TransSelectivity in Ruthenium-based Olefin Metathesis." In Ligand Design in Metal Chemistry, 15–45. Chichester, UK: John Wiley & Sons, Ltd, 2016. http://dx.doi.org/10.1002/9781118839621.ch2.
Full textConference papers on the topic "Ligand design"
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Hussein, Layth, P. Ilanchezhian, Praveen Kumar Hiremath, V. Sivakumar, and S. Senthil Kumar. "Dual Channel based Convolutional Neural Network based Protein–Ligand Interaction Prediction for Drug Design." In 2024 First International Conference on Software, Systems and Information Technology (SSITCON), 1–5. IEEE, 2024. https://doi.org/10.1109/ssitcon62437.2024.10796432.
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Gao, Yandong, Dana Brantley-Sieders, Devi Majumdar, Jin Chen, Donna Webb, and Deyu Li. "A Simple Approach to Probe the Extracellular Signaling Pathways Using Ligand Traps." In ASME 2012 Third International Conference on Micro/Nanoscale Heat and Mass Transfer. American Society of Mechanical Engineers, 2012. http://dx.doi.org/10.1115/mnhmt2012-75106.
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Cells communicate with one another through a huge variety of extracellular soluble signaling molecules. A common method in biology to investigate the signaling pathways is to inactivate the gene coding the interested ligand or receptor from cells using modern DNA technology, known as gene knockout. Even though very effective, however, gene knockout is a time-consuming and cost-prohibitive process and requires huge amount of efforts to conduct. Here we present a simple method to probe the extracellular signaling pathways through engineering a semi-permeable barrier between two cell populations. In this approach, ligand traps, receptor-coated nano/micro-particles, are embedded inside the nanoporous barrier. Because the receptors have the ability to selectively bind to certain ligand(s) with high affinity, the associated ligands can be ‘trapped’ inside the barrier when they try to perfuse from one cell population to the other. As a result, the targeted soluble ligands can be effectively blocked from the molecular exchange between the two cell populations. We have demonstrated the feasibility of this novel approach using fluorescent proteins. An analytical model has also been developed to guide the design of the ligand-trap-embedded barrier.
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Rakshit, Pratyusha, Amit Konar, Archana Chowdhury, Eunjin Kim, and Atulya K. Nagar. "Muti-objective evolutionary approach of ligand design for protein-ligand docking problem." In 2013 IEEE Congress on Evolutionary Computation (CEC). IEEE, 2013. http://dx.doi.org/10.1109/cec.2013.6557576.
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Ucan, Halil Ismet, and Aslihan Yilmaz Obali. "Design of azide-substitued polypyridine ligand." In 2017 IEEE 7th International Conference "Nanomaterials: Application & Properties" (NAP). IEEE, 2017. http://dx.doi.org/10.1109/nap.2017.8190216.
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Todorov, Nikolay P., and Philip M. Dean. "Computational ligand design by free energy minimization." In The third international symposium on biological physics. AIP, 1999. http://dx.doi.org/10.1063/1.59894.
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Maccallum, Rob, and Geoff Nitschke. "Automated Ligand Design in Simulated Molecular Docking." In The 2022 Conference on Artificial Life. Cambridge, MA: MIT Press, 2022. http://dx.doi.org/10.1162/isal_a_00482.
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Velo-Heleno, Isabel, Sandra Fernández-Fariña, Uxía Barreiro-Sisto, Laura Rodríguez-Silva, and Rosa Pedrido. "Design, Synthesis and Characterization of a Bicompartmental bisthiosemicarbazone Ligand." In ECSOC 2023. Basel Switzerland: MDPI, 2023. http://dx.doi.org/10.3390/ecsoc-27-16093.
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Barreiro-Sisto, Uxía, Marcelino Maneiro, and Rosa Pedrido. "Design, Synthesis and Characterization of a Phosphino-Azine Ligand." In ECSOC 2024, 105. Basel Switzerland: MDPI, 2024. https://doi.org/10.3390/ecsoc-28-20129.
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Jomeh, Sina, and Mina Hoorfar. "Numerical Investigation of the Effect of Geometric and Physiochemical Parameters on Biomolecule Capture Efficiency." In ASME 2010 8th International Conference on Nanochannels, Microchannels, and Minichannels collocated with 3rd Joint US-European Fluids Engineering Summer Meeting. ASMEDC, 2010. http://dx.doi.org/10.1115/fedsm-icnmm2010-30531.
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This paper presents and compares three different designs including open channel, circular pillar and screen-plate microreactors for capturing and detection of biomolecules in a buffer liquid. In general, these capturing/detection devices consist of a flow cell containing one or several reactive surfaces loaded with ligand molecules. The critical issue in the design of an efficient device is the proximity of the biomolecules to the ligands in the capturing stage since the latter is immobilized on the reactive surface and the former is freely moving in the flow. The flow pattern and the geometry of the device are the key factors in this regard. The presented designs are numerically modeled and compared in terms of capture efficiency. Immersed biomolecules are assumed to behave like a continuum medium. The Navier-Stokes and advection-diffusion equations are solved in two dimensions and the concentration profile is found after a certain sampling period. The chemical reaction between the ligand and the biomolecule is included in the model through solving the first order kinetic equation at the boundaries. The average surface concentrations of the adsorbed molecules are plotted and compared for all the geometries to determine the most efficient one. Considering the performance, ease of fabrication, and detection, the screen plates are found to be the best option for the purpose of biomolecule removal. The effects of the change in the geometric parameters (e.g., the flow path width in the microchannels) and physicochemical parameters (e.g., the diffusion constant, ligand surface density, and forward and backward reaction rates) involved in the problem on the adsorbed concentration are thoroughly inspected and the corresponding results are plotted.
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Mladenović, Milan P., Nevena M. Tomašević, Sanja Lj Matić, Tamara M. Mladenović, and Rino Ragno. "Computer-aided design of new drugs against breast cancer." In 2nd International Conference on Chemo and Bioinformatics. Institute for Information Technologies, University of Kragujevac, 2023. http://dx.doi.org/10.46793/iccbi23.641m.
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Computational medicinal chemistry, if used properly and in accordance with the available experimental data, may provide significant support to rational drug design. Herein, an overview of the computational approaches that have been applied to an estrogen receptor α (ERα) and endowed in the rational design of pM ERα antagonists with profound anti-breast cancer activity either in vitro or in vivo, will be presented. ERα is a 17β-estradiol inducible transcriptional regulator that initiates the RNA polymerase II-dependent transcriptional machinery, pointed for breast cancer (BC) development via either genomic direct or genomic indirect (i.e., tethered) pathway. To develop innovative ligands, structure-based (SB) 3-D QSAR, ComBinE, and 3-D Pharmacophore studies have been undertaken from experimentally resolved partial agonists, SERMs, and SERDs within either wild-type or mutated ERα receptors. SB and ligand-based (LB) alignments gave rules to align the untested compounds. The protocols led to the development of 3DQs, CBEs, and 3DPQs compounds, further synthesized and submitted to either in vitro or in vivo assessments, upon which new leads were revealed as candidates for clinical trials.
Reports on the topic "Ligand design"
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Szigethy, Geza. Rational Ligand Design for U(VI) and Pu(IV). Office of Scientific and Technical Information (OSTI), August 2009. http://dx.doi.org/10.2172/972716.
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Rafaeli, Ada, and Russell Jurenka. Molecular Characterization of PBAN G-protein Coupled Receptors in Moth Pest Species: Design of Antagonists. United States Department of Agriculture, December 2012. http://dx.doi.org/10.32747/2012.7593390.bard.
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The proposed research was directed at determining the activation/binding domains and gene regulation of the PBAN-R’s thereby providing information for the design and screening of potential PBAN-R-blockers and to indicate possible ways of preventing the process from proceeding to its completion. Our specific aims included: (1) The identification of the PBAN-R binding domain by a combination of: (a) in silico modeling studies for identifying specific amino-acid side chains that are likely to be involved in binding PBAN with the receptor and; (b) bioassays to verify the modeling studies using mutant receptors, cell lines and pheromone glands (at tissue and organism levels) against selected, designed compounds to confirm if compounds are agonists or antagonists. (2) The elucidation ofthemolecular regulationmechanisms of PBAN-R by:(a) age-dependence of gene expression; (b) the effect of hormones and; (c) PBAN-R characterization in male hair-pencil complexes. Background to the topic Insects have several closely related G protein-coupled receptors (GPCRs) belonging to the pyrokinin/PBAN family, one with the ligand pheromone biosynthesis activating neuropeptide or pyrokinin-2 and another with diapause hormone or pyrokinin-1 as a ligand. We were unable to identify the diapause hormone receptor from Helicoverpa zea despite considerable effort. A third, related receptor is activated by a product of the capa gene, periviscerokinins. The pyrokinin/PBAN family of GPCRs and their ligands has been identified in various insects, such as Drosophila, several moth species, mosquitoes, Triboliumcastaneum, Apis mellifera, Nasoniavitripennis, and Acyrthosiphon pisum. Physiological functions of pyrokinin peptides include muscle contraction, whereas PBAN regulates pheromone production in moths plus other functions indicating the pleiotropic nature of these ligands. Based on the alignment of annotated genomic sequences, the primary and secondary structures of the pyrokinin/PBAN family of receptors have similarity with the corresponding structures of the capa or periviscerokinin receptors of insects and the neuromedin U receptors found in vertebrates. Major conclusions, solutions, achievements Evolutionary trace analysisof receptor extracellular domains exhibited several class-specific amino acid residues, which could indicate putative domains for activation of these receptors by ligand recognition and binding. Through site-directed point mutations, the 3rd extracellular domain of PBAN-R was shown to be critical for ligand selection. We identified three receptors that belong to the PBAN family of GPCRs and a partial sequence for the periviscerokinin receptor from the European corn borer, Ostrinianubilalis. Functional expression studies confirmed that only the C-variant of the PBAN-R is active. We identified a non-peptide agonist that will activate the PBAN-receptor from H. zea. We determined that there is transcriptional control of the PBAN-R in two moth species during the development of the pupa to adult, and we demonstrated that this transcriptional regulation is independent of juvenile hormone biosynthesis. This transcriptional control also occurs in male hair-pencil gland complexes of both moth species indicating a regulatory role for PBAN in males. Ultimate confirmation for PBAN's function in the male tissue was revealed through knockdown of the PBAN-R using RNAi-mediated gene-silencing. Implications, both scientific and agricultural The identification of a non-peptide agonist can be exploited in the future for the design of additional compounds that will activate the receptor and to elucidate the binding properties of this receptor. The increase in expression levels of the PBAN-R transcript was delineated to occur at a critical period of 5 hours post-eclosion and its regulation can now be studied. The mysterious role of PBAN in the males was elucidated by using a combination of physiological, biochemical and molecular genetics techniques.
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Clark, Aurora Sue, Nathalie Wall, and Paul Benny. Rapid Computer Aided Ligand Design and Screening of Precious Metal Extractants from TRUEX Raffinate with Experimental Validation. Office of Scientific and Technical Information (OSTI), November 2015. http://dx.doi.org/10.2172/1232661.
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Jha, Ramesh, Sang-Min Shin, and Taraka Dale. Rosetta Comparative Modeling and Ligand Docking for a Transcription Factor Library Design to Select Biosensor for an Anthropogenic Molecule. Office of Scientific and Technical Information (OSTI), June 2022. http://dx.doi.org/10.2172/1871442.
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Leeladee, Pannee. Cooperative small-molecule activation toward sustainable catalysis. Faculty of Science, Chulalongkorn University, 2018. https://doi.org/10.58837/chula.res.2018.47.
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In this research, a series of copper complexes containing polypyridyl ligands were designed to study the influence from ligands, nuclearity, solvents and secondary coordination on reactivity toward small-molecule activation. This structure-reactivity relationship was used in investigation for oxygen reduction reactions (ORR), and applied in detection of ascorbic acid (AsH₂). Firstly, copper (II) complexes containing polypyridyl derivatives ligands (i.e., Cu(dpa), Cu(adpa) and Cu₂ (addpa)) were synthesized and fully characterized by elemental analysis, mass spectrometry and X-ray crystallography. Their electrochemical behaviors were studied by cyclic voltammetry. The Cu(I) complexes which are active species for ORR were generated using AsH₂ as a reducing agent. Redox states of the metal were examined by UV-Vis, NMR and EPR. It was found that copper complexes with various ligand topologies exhibited different reactivity toward O₂. Anthracence moiety in Cu(adpa) and Cu₂ (addpa) played a vital role in facilitating reduction of Cu(II) as well as stability enhancement of Cu(I). The dinuclear complex, Cu₂ (addpa) showed significantly higher ORR activity than that of the mononuclear analogue. The product of ORR was found to be H₂O₂, indicating 2e, 2H⁺ reduction process. Being stable and inactive towards ORR, Cu(adpa) was further investigated as a fluorescence sensor for AsH₂. Reaction of [Cu(adpa)]²⁺ with AsH₂ in CH3CN resulted in turn-on fluorescence due to [Cu(adpa)]⁺ formation.However, when the same reaction was carried out in aqueous solution, the Cu(I) species was gradually oxidized to Cu(II) which hampered the accurate measurement. Notably, addition of Zn(II) in combination with acetate anions helped to stabilize the Cu(I) complex and allowed an accurate detection of ascorbic acids in vitamin C tablets. Secondary coordination sphere modulation of the copper center was proposed to account for this stability enhancement. Overall, the findings obtained from this research have been shown to be applicable in various fields. Also, this can be further used in design for efficient catalysts as well as molecular sensors in the future.
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Altstein, Miriam, and Ronald J. Nachman. Rational Design of Insect Control Agent Prototypes Based on Pyrokinin/PBAN Neuropeptide Antagonists. United States Department of Agriculture, August 2013. http://dx.doi.org/10.32747/2013.7593398.bard.
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The general objective of this study was to develop rationally designed mimetic antagonists (and agonists) of the PK/PBAN Np class with enhanced bio-stability and bioavailability as prototypes for effective and environmentally friendly pest insect management agents. The PK/PBAN family is a multifunctional group of Nps that mediates key functions in insects (sex pheromone biosynthesis, cuticular melanization, myotropic activity, diapause and pupal development) and is, therefore, of high scientific and applied interest. The objectives of the current study were: (i) to identify an antagonist biophores (ii) to develop an arsenal of amphiphilic topically active PK/PBAN antagonists with an array of different time-release profiles based on the previously developed prototype analog; (iii) to develop rationally designed non-peptide SMLs based on the antagonist biophore determined in (i) and evaluate them in cloned receptor microplate binding assays and by pheromonotropic, melanotropic and pupariation in vivo assays. (iv) to clone PK/PBAN receptors (PK/PBAN-Rs) for further understanding of receptor-ligand interactions; (v) to develop microplate binding assays for screening the above SMLs. In the course of the granting period A series of amphiphilic PK/PBAN analogs based on a linear lead antagonist from the previous BARD grant was synthesized that incorporated a diverse array of hydrophobic groups (HR-Suc-A[dF]PRLa). Others were synthesized via the attachment of polyethylene glycol (PEG) polymers. A hydrophobic, biostablePK/PBAN/DH analog DH-2Abf-K prevented the onset of the protective state of diapause in H. zea pupae [EC50=7 pmol/larva] following injection into the preceding larval stage. It effectively induces the crop pest to commit a form of ‘ecological suicide’. Evaluation of a set of amphiphilic PK analogs with a diverse array of hydrophobic groups of the formula HR-Suc-FTPRLa led to the identification of analog T-63 (HR=Decyl) that increased the extent of diapause termination by a factor of 70% when applied topically to newly emerged pupae. Another biostablePK analog PK-Oic-1 featured anti-feedant and aphicidal properties that matched the potency of some commercial aphicides. Native PK showed no significant activity. The aphicidal effects were blocked by a new PEGylated PK antagonist analog PK-dF-PEG4, suggesting that the activity is mediated by a PK/PBAN receptor and therefore indicative of a novel and selective mode-of-action. Using a novel transPro mimetic motif (dihydroimidazole; ‘Jones’) developed in previous BARD-sponsored work, the first antagonist for the diapause hormone (DH), DH-Jo, was developed and shown to block over 50% of H. zea pupal diapause termination activity of native DH. This novel antagonist development strategy may be applicable to other invertebrate and vertebrate hormones that feature a transPro in the active core. The research identifies a critical component of the antagonist biophore for this PK/PBAN receptor subtype, i.e. a trans-oriented Pro. Additional work led to the molecular cloning and functional characterization of the DH receptor from H. zea, allowing for the discovery of three other DH antagonist analogs: Drosophila ETH, a β-AA analog, and a dF analog. The receptor experiments identified an agonist (DH-2Abf-dA) with a maximal response greater than native DH. ‘Deconvolution’ of a rationally-designed nonpeptide heterocyclic combinatorial library with a cyclic bis-guanidino (BG) scaffold led to discovery of several members that elicited activity in a pupariation acceleration assay, and one that also showed activity in an H. zea diapause termination assay, eliciting a maximal response of 90%. Molecular cloning and functional characterization of a CAP2b antidiuretic receptor from the kissing bug (R. prolixus) as well as the first CAP2b and PK receptors from a tick was also achieved. Notably, the PK/PBAN-like receptor from the cattle fever tick is unique among known PK/PBAN and CAP2b receptors in that it can interact with both ligand types, providing further evidence for an evolutionary relationship between these two NP families. In the course of the granting period we also managed to clone the PK/PBAN-R of H. peltigera, to express it and the S. littoralis-R Sf-9 cells and to evaluate their interaction with a variety of PK/PBAN ligands. In addition, three functional microplate assays in a HTS format have been developed: a cell-membrane competitive ligand binding assay; a Ca flux assay and a whole cell cAMP ELISA. The Ca flux assay has been used for receptor characterization due to its extremely high sensitivity. Computer homology studies were carried out to predict both receptor’s SAR and based on this analysis 8 mutants have been generated. The bioavailability of small linear antagonistic peptides has been evaluated and was found to be highly effective as sex pheromone biosynthesis inhibitors. The activity of 11 new amphiphilic analogs has also been evaluated. Unfortunately, due to a problem with the Heliothis moth colony we were unable to select those with pheromonotropic antagonistic activity and further check their bioavailability. Six peptides exhibited some melanotropic antagonistic activity but due to the low inhibitory effect the peptides were not further tested for bioavailability in S. littoralis larvae. Despite the fact that no new antagonistic peptides were discovered in the course of this granting period the results contribute to a better understanding of the interaction of the PK/PBAN family of Nps with their receptors, provided several HT assays for screening of libraries of various origin for presence of PK/PBAN-Ragonists and antagonists and provided important practical information for the further design of new, peptide-based insecticide prototypes aimed at the disruption of key neuroendocrine physiological functions in pest insects.
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Rafaeli, Ada, Russell Jurenka, and Chris Sander. Molecular characterisation of PBAN-receptors: a basis for the development and screening of antagonists against Pheromone biosynthesis in moth pest species. United States Department of Agriculture, January 2008. http://dx.doi.org/10.32747/2008.7695862.bard.
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The original objectives of the approved proposal included: (a) The determination of species- and tissue-specificity of the PBAN-R; (b) the elucidation of the role of juvenile hormone in gene regulation of the PBAN-R; (c) the identificationof the ligand binding domains in the PBAN-R and (d) the development of efficient screening assays in order to screen potential antagonists that will block the PBAN-R. Background to the topic: Moths constitute one of the major groups of pest insects in agriculture and their reproductive behavior is dependent on chemical communication. Sex-pheromone blends are utilised by a variety of moth species to attract conspecific mates. In most of the moth species sex-pheromone biosynthesis is under circadian control by the neurohormone, PBAN (pheromone-biosynthesis-activating neuropeptide). In order to devise ideal strategies for mating disruption/prevention, we proposed to study the interactions between PBAN and its membrane-bound receptor in order to devise potential antagonists. Major conclusions: Within the framework of the planned objectives we have confirmed the similarities between the two Helicoverpa species: armigera and zea. Receptor sequences of the two Helicoverpa spp. are 98% identical with most changes taking place in the C-terminal. Our findings indicate that PBAN or PBAN-like receptors are also present in the neural tissues and may represent a neurotransmitter-like function for PBAN-like peptides. Surprisingly the gene encoding the PBAN-receptor was also present in the male homologous tissue, but it is absent at the protein level. The presence of the receptor (at the gene- and protein-levels), and the subsequent pheromonotropic activity are age-dependent and up-regulated by Juvenile Hormone in pharate females but down-regulated by Juvenile Hormone in adult females. Lower levels of pheromonotropic activity were observed when challenged with pyrokinin-like peptides than with HezPBAN as ligand. A model of the 3D structure of the receptor was created using the X-ray structure of rhodopsin as a template after sequence alignment of the HezPBAN-R with several other GPCRs and computer simulated docking with the model predicted putative binding sites. Using in silico mutagenesis the predicted docking model was validated with experimental data obtained from expressed chimera receptors in Sf9 cells created by exchanging between the three extracellular loops of the HezPBAN-R and the Drosophila Pyrokinin-R (CG9918). The chimera receptors also indicated that the 3ʳᵈ extracellular loop is important for recognition of PBAN or Diapause hormone ligands. Implications: The project has successfully completed all the objectives and we are now in a position to be able to design and screen potential antagonists for pheromone production. The successful docking simulation-experiments encourage the use of in silico experiments for initial (high-throughput) screening of potential antagonists. However, the differential responses between the expressed receptor (Sf9 cells) and the endogenous receptor (pheromone glands) emphasize the importance of assaying lead compounds using several alternative bioassays (at the cellular, tissue and organism levels). The surprising discovery of the presence of the gene encoding the PBAN-R in the male homologous tissue, but its absence at the protein level, launches opportunities for studying molecular regulation pathways and the evolution of these GPCRs. Overall this research will advance research towards the goal of finding antagonists for this important class of receptors that might encompass a variety of essential insect functions.
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Yedidia, I., H. Senderowitz, and A. O. Charkowski. Small molecule cocktails designed to impair virulence targets in soft rot Erwinias. Israel: United States-Israel Binational Agricultural Research and Development Fund, 2020. http://dx.doi.org/10.32747/2020.8134165.bard.
Full textAbstract:
Chemical signaling between beneficial or pathogenic bacteria and plants is a central factor in determining the outcome of plant-microbe interactions. Pectobacterium and Dickeya (soft rot Erwinias) are the major cause of soft rot, stem rot, and blackleg formed on potato and ornamentals, currently with no effective control. Our major aim was to establish and study specific bacterial genes/proteins as targets for anti-virulence compounds, by combining drug design tools and bioinformatics with experimental work. The approach allowed us to identify and test compounds (small molecules) that specifically interfere with the activities of these targets, by this impairing bacterial virulence. Two main targets were selected within the frame of the BARD project. The first is the ATP-binding cassette (ABC) transporters and methyl-accepting chemotaxis proteins (MCP) that have been characterized here for the first time in Pectobacteriaceae, and the second is the quorum sensing (QS) machinery of Pectobacterium with its major proteins and in particular, the AHL synthase ExpI that was identified as the preferred target for inhibition. Both systems are strongly associated with bacterial virulence and survival in planta. We found that Pectobacteriaceae, namely Dickeya and Pectobacterium, encode more ABC transporters and MCP in their genomes, compared to other bacteria in the order. For MCP, soft rot Pectobacteriaceae not only contain more than 30 MCP genes per strain, but also have more diverse ligand binding domains than other species in the Enterobacteriales. These findings suggest that both ABC transporters and MCP are important for soft rot Pectobacteriaceae pathogenicity. We now have a selection of mutants in these proteins that may be further explored to understand their direct involvement in virulence. In parallel, we studied the QS central proteins in pectobacteria, the signaling molecule N-acyl-homoserine lactone synthase, ExpI, and the response regulator ExpR, and established their phylogenetic relations within plant pathogenic Gram negative bacteria. Next, these proteins were used for virtual screening of millions of compounds in order to discover new compounds with potential to interfere with the QS machinery. Several natural compounds were tested for their interference with virulence related traits in Pectobacterium and their capability to minimize soft rot infections. Our findings using microcalorimetric binding studies have established for the first time direct interaction between the protein ExpI and two natural ligands, the plant hormone salicylic acid and the volatile compound carvacrol. These results supported a model by which plants interfere with bacterial communication through interkingdom signaling. The collaborative project yielded two research papers and a comprehensive review, which included new computational and bioinformatics data, in Annu. Rev. Phytopathol., the highest ranked journal in phytopathology. Additional two papers are in preparation. In order to transform the fundamental knowledge that have been gained during this collaborative BARD project into agricultural practice, to control soft rot bacteria, we have submitted a continual project.
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Eyal, Yoram, and Sheila McCormick. Molecular Mechanisms of Pollen-Pistil Interactions in Interspecific Crossing Barriers in the Tomato Family. United States Department of Agriculture, May 2000. http://dx.doi.org/10.32747/2000.7573076.bard.
Full textAbstract:
During the evolutionary process of speciation in plants, naturally occurring barriers to reproduction have developed that affect the transfer of genes within and between related species. These barriers can occur at several different levels beginning with pollination-barriers and ending with hybrid-breakdown. The interaction between pollen and pistils presents one of the major barriers to intra- and inter-specific crosses and is the focus of this research project. Our long-term goal in this research proposal was defined to resolve questions on recognition and communication during pollen-pistil interactions in the extended tomato family. In this context, this work was initiated and planned to study the potential involvement of tomato pollen-specific receptor-like kinases (RLK's) in the interaction between pollen and pistils. By special permission from BARD the objectives of this research were extended to include studies on pollen-pistil interactions and pollination barriers in horticultural crops with an emphasis on citrus. Functional characterization of 2 pollen-specific RLK's from tomato was carried out. The data shows that both encode functional kinases that were active as recombinant proteins. One of the kinases was shown to accumulate mainly after pollen germination and to be phosphorylated in-vitro in pollen membranes as well as in-vivo. The presence of style extract resulted in dephosphorylation of the RLK, although no species specificity was observed. This data implies a role for at least one RLK in pollination events following pollen germination. However, a transgenic plant analysis of the RLK's comprising overexpression, dominant-negative and anti-sense constructs failed to provide answers on their role in pollination. While genetic effects on some of the plants were observed in both the Israeli and American labs, no clear functional answers were obtained. An alternative approach to addressing function was pursued by screening for an artificial ligand for the receptor domain using a peptide phage display library. An enriched peptide sequence was obtained and will be used to design a peptide-ligand to be tested for its effect o pollen germination and tube growth. Self-incompatibility (SI) in citrus was studied on 3 varieties of pummelo. SI was observed using fluorescence microscopy in each of the 3 varieties and compatibility relations between varieties was determined. An initial screen for an S-RNase SI mechanism yielded only a cDNA homologous to the group of S-like RNases, suggesting that SI results from an as yet unknown mechanism. 2D gel electrophoresis was applied to compare pollen and style profiles of different compatibility groups. A "polymorphic" protein band from style extracts was observed, isolated and micro-sequenced. Degenerate primers designed based on the peptide sequence date will be used to isolate the relevant genes i order to study their potential involvement in SI. A study on SI in the apple cultivar Top red was initiated. SI was found, as previously shown, to be complete thus requiring a compatible pollinator variety. A new S-RNase allele was discovered fro Top red styles and was found to be highly homologous to pear S-RNases, suggesting that evolution of these genes pre-dated speciation into apples and pears but not to other Rosaceae species. The new allele provides molecular-genetic tools to determine potential pollinators for the variety Top red as well as a tool to break-down SI in this important variety.
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Marshall, G. R. De novo design of ligands for metal separation. 1998 annual progress report. Office of Scientific and Technical Information (OSTI), June 1998. http://dx.doi.org/10.2172/13746.
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