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Rational Design (rational + design)
Selected AbstractsRational Design of Charge-Neutral, Near-Infrared-Emitting Osmium(II) Complexes and OLED FabricationADVANCED FUNCTIONAL MATERIALS, Issue 16 2009Tsang-Chi Lee Abstract A new series of charge neutral Os(II) isoquinolyl triazolate complexes (1,4) with both trans and cis arrangement of phosphine donors are synthesized, and their structural, electrochemical and photophysical properties are established. In sharp contrast to the cis -arranged complexes 2,4, the trans derivative 1, which shows a planar arrangement of chromophoric N -substituted chelates, offers the most effective extended , -delocalization and hence the lowest excited state energy gap. These complexes exhibit phosphorescence with peak wavelengths ranging from 692,805,nm in degassed CH2Cl2 at room temperature. Near-infrared (NIR)-emitting electroluminescent devices employing 6,wt % of 1 (or 4) doped in Alq3 host material are successfully fabricated. The devices incorporating 1 as NIR phosphor exhibit fairly intense emission with a peak wavelength at 814,nm. Forward radiant emittance reaches as high as 65.02,µW,cm,2, and a peak EQE of ,1.5% with devices employing Alq3, TPBi and/or TAZ as electron-transporting/exciton-blocking layers. Upon switching to phosphor 4, the electroluminescence blue shifts to 718,nm, while the maximum EQE and radiance increase to 2.7% and 93.26 (,W,cm,2) respectively. Their performances are optimized upon using TAZ as the electron transporting and exciton-blocking material. The OLEDs characterized represent the only NIR-emitting devices fabricated using charge-neutral and volatile Os(II) phosphors via thermal vacuum deposition. [source] Rational Design of Conjugated Polymer Supramolecules with Tunable Colorimetric ResponsesADVANCED FUNCTIONAL MATERIALS, Issue 10 2009Dong June Ahn Abstract Polydiacetylenes (PDAs), a family of highly ,-conjugated polymers, have unique characteristics associated with their ability to self-assemble. Disruption of the extensively delocalized enyne backbones of molecularly ordered PDA sidechains induces a blue-to-red color change, which has been elegantly applied in the design of chemosensors. Recently, colorimetrically reversible PDAs have received significant attention, not only to gain a better understanding of the fundamentals of PDA chromism, but also to develop methodologies to overcome limitations associated with their colorimetrically irreversible counterparts. In this article, recent progress made in the field of colorimetrically tunable (reversible, stable, or sensitive) PDAs is described. Major emphasis is given to rational design strategies developed in our group. Relevant mechanistic investigations, a diagnostic method to test colorimetric reversibility, as well as future challenges in this area will be also discussed. [source] Rational Design of Chelating Phosphine Functionalized Os(II) Emitters and Fabrication of Orange Polymer Light-Emitting Diodes Using Solution Process,ADVANCED FUNCTIONAL MATERIALS, Issue 2 2008M. Cheng Abstract A new series of charge neutral Os(II) pyridyl azolate complexes with either bis(diphenylphosphino)methane (dppm) or cis -1,2-bis(diphenylphosphino)ethene (dppee) chelates were synthesized, and their structural, electrochemical, photophysical properties and thermodynamic relationship were established. For the dppm derivatives 3a and 4a, the pyridyl azolate chromophores adopt an eclipse orientation with both azolate segments aligned trans to each other, and with the pyridyl groups resided the sites that are opposite to the phosphorus atoms. In sharp contrast, the reactions with dppee ligand gave rise to the formation of two structural isomers for all three kind of azole chromophores, with both azolate or neutral heterocycles (i.e., pyridyl or isoquinolinyl fragments) located at the mutual trans -disposition around the Os metal (denoted as series of a and b complexes). These chelating phosphines Os(II) complexes show remarkably high thermal stability, among which and several exhibit nearly unitary phosphorescence yield in deaerated solution at RT. A polymer light-emitting device (PLED) prepared using 0.4 mol % of 5a as dopant in a blend of poly(vinylcarbazole) (PVK) and 30 wt % of 2- tert -butylphenyl-5-biphenyl-1,3,4-oxadiazole (PBD) exhibits yellow emission with brightness of 7208 cd m,2, an external quantum efficiency of 10.4 % and luminous efficiency of 36.1 cd A,1 at current density of 20 mA cm,2. Upon changing to 1.6 mol % of 6a, the result showed even better brightness of 9212 cd m,2, external quantum efficiency of 12.5 % and luminous efficiency of 46.1 cd A,1 at 20 mA cm,2, while the max. external quantum efficiency of both devices reaches as high as 11.7 % and 13.3 %, respectively. The high PL quantum efficiency, non-ionic nature, and short radiative lifetime are believed to be the determining factors for this unprecedented achievement. [source] Highly Fluorinated Comb-Shaped Copolymers as Proton Exchange Membranes (PEMs): Improving PEM Properties Through Rational Design,ADVANCED FUNCTIONAL MATERIALS, Issue 14 2006B. Norsten Abstract A new class of comb-shaped polymers for use as a proton conducting membrane is presented. The polymer is designed to combine the beneficial physical, chemical, and structural attributes of fluorinated Nafion-like materials with higher-temperature, polyaromatic-based polymer backbones. The comb-shaped polymer unites a rigid, polyaromatic, hydrophobic backbone with lengthy hydrophilic polymer side chains; this combination affords direct control over the polymer nanostructure within the membrane and results in distinct microphase separation between the opposing domains. The microphase separation serves to compartmentalize water into the hydrophilic polymer side chain domains, resulting in effective membrane water management and excellent proton conductivities. [source] Biofunctionalized pH-Responsive Microgels for Cancer Cell Targeting: Rational Design,ADVANCED MATERIALS, Issue 1 2006M. Das The design of a drug-delivery system based on bioconjugated, pH-responsive microgels is demonstrated. Microgels loaded with the anticancer drug Doxorubicin are introduced into the HeLa tumor cells by means of receptor- mediated endocytosis. Changes in pH within the intracellular environment induce shrinkage of microgels, triggering the drug release into the cells. The microgel described in this work shows enhanced cytotoxicity to HeLa cells (see Figure). [source] Apamin as a Template for Structure-Based Rational Design of Potent Peptide Activators of p53,ANGEWANDTE CHEMIE, Issue 46 2009Chong Li Tumoren wird der Stachel gezogen: Die Onkoproteine MDM2 und MDMX beeinflussen die Aktivität und Stabilität des Tumorsuppressorproteins p53 und sind wichtige molekulare Ziele der Krebstherapie. Das Aufpfropfen von vier für das Binden von MDM2/MDMX wichtigen Resten auf die C-terminale ,-Helix von Apamin (siehe Bild) überführt das Bienengiftneurotoxin in eine neuartige Klasse leistungsfähiger, möglicherweise gegen Krebs wirksamer p53-Aktivatoren. [source] The Role of Flexibility in the Rational Design of Modularly Assembled Ligands Targeting the RNAs that Cause the Myotonic DystrophiesCHEMBIOCHEM, Issue 3 2010Matthew D. Disney Prof. Abstract Modularly assembled ligands were designed to target the RNAs that cause two currently untreatable neuromuscular disorders, myotonic dystrophy types 1 (DM1) and 2 (DM2). DM1 is caused by an expanded repeating sequence of CUG, and DM2 is caused by expanded CCUG repeats. Both are present in noncoding regions and fold into hairpins with either repeating 1×1 nucleotide UU (DM1) or 2×2 nucleotide 5,-CU/3,-UC (DM2) internal loops separated by two GC pairs. The repeats are toxic because they sequester the RNA splicing regulator muscleblind-like 1 protein (MBNL1). Rational design of ligands targeting these RNAs was enabled by a database of RNA motif,ligand partners compiled by using two-dimensional combinatorial screening (2DCS). One 2DCS study found that the 6,,-azido-kanamycin A module binds internal loops similar to those found in DM1 and DM2. In order to further enhance affinity and specificity, the ligand was assembled on a peptoid backbone to precisely control valency and the distance between ligand modules. Designed compounds are more potent and specific binders to the toxic RNAs than MBNL1 and inhibit the formation of the RNA,protein complexes with nanomolar IC50 values. This study shows that three important factors govern potent inhibition: 1) the surface area sequestered by the assembled ligands; 2) the spacing between ligand modules since a longer distance is required to target DM2 RNAs than DM1 RNAs; and 3) flexibility in the modular assembly scaffold used to display the RNA-binding module. These results have impacts on the general design of assembled ligands targeting RNAs present in genomic sequence. [source] Rational Design of an L-Histidine-Derived Minimal Artificial Acylase for the Kinetic Resolution of Racemic Alcohols.CHEMINFORM, Issue 5 2005Kazuaki Ishihara Abstract For Abstract see ChemInform Abstract in Full Text. [source] Rational Design of 6-Methylsulfonylindoles as Selective Cyclooxygenase-2 Inhibitors.CHEMINFORM, Issue 52 2004Jeffrey A. Campbell Abstract For Abstract see ChemInform Abstract in Full Text. [source] ChemInform Abstract: Rational Design of Chiral 1,1,-Binaphthylazepine-Based Ligands for the Enantioselective Addition of ZnEt2 to Aromatic Aldehydes.CHEMINFORM, Issue 49 2002Stefano Superchi Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source] Rational Design, Synthesis, and Optical Properties of Film-Forming, Near-Infrared Absorbing, and Fluorescent Chromophores with Multidonors and Large Heterocyclic AcceptorsCHEMISTRY - A EUROPEAN JOURNAL, Issue 35 2009Min Luo Abstract A new series of film-forming, low-bandgap chromophores (1,a,b and 2,a,b) were rationally designed with aid of a computational study, and then synthesized and characterized. To realize absorption and emission above the 1000,nm wavelength, the molecular design focuses on lowering the LUMO level by fusing common heterocyclic units into a large conjugated core that acts an electron acceptor and increasing the charge transfer by attaching the multiple electron-donating groups at the appropriate positions of the acceptor core. The chromophores have bandgap levels of 1.27,0.71,eV, and accordingly absorb at 746,1003,nm and emit at 1035,1290,nm in solution. By design, the relatively high molecular weight (up to 2400,g,mol,1) and non-coplanar structure allow these near-infrared (NIR) chromophores to be readily spin-coated as uniform thin films and doped with other organic semiconductors for potential device applications. Doping with [6,6]-phenyl-C61 butyric acid methyl ester leads to a red shift in the absorption only for 1,a and 2,a. An interesting NIR electrochromism was found for 2,a, with absorption being turned on at 1034,nm when electrochemically switched (at 1000,mV) from its neutral state to a radical cation state. Furthermore, a large Stokes shift (256,318,nm) is also unique for this multidonor,acceptor type of chromophore, indicating a significant structural difference between the ground state and the excited state. Photoluminescence of the film of 2,a was further probed at variable temperatures and the results strongly suggest that the restriction of bond rotations certainly helps to diminish non-radiative decay and thus enhance the luminescence of these large chromophores. [source] Rational Design of Sterically and Electronically Easily Tunable Chiral Bisimidazolines and Their Applications in Dual Lewis Acid/Brønsted Base Catalysis for Highly Enantioselective Nitroaldol (Henry) ReactionsCHEMISTRY - A EUROPEAN JOURNAL, Issue 6 2007Kuoyan Ma Abstract A new addition to the rational design of sterically and electrically easily tunable chiral bis(imidazoline) ligands from chiral amino alcohols has been developed. Vast structural variation of chiral bis(imidazoline) ligands can be simply achieved by the choice of both the 1,2-amino alcohol and its N-1 R1 substituent. A small library of chiral bisimidazolines (1,a,h) has been constructed. The method has provided an easy and simplified route to a diverse set of air-stable and water-tolerant chiral bis(imidazoline) ligands on 10,g scales. The dual Lewis Acid/Brønsted base catalytic system generated from the (S)- 1,a/Cu(OTf)2 complex and Et3N was able to catalyze Henry reactions between aldehydes and nitromethane effectively at room temperature, and also to tolerate a wide scope of aldehydes with excellent enantiomeric excesses. Not only aromatic aldehydes but also aliphatic aldehydes afforded the nitroalcohol products, with enantiomeric excesses in the 93,98,% range. This dual catalytic system is among the most effective systems so far reported for the asymmetric parent Henry reactions. This work also represents the first members of the class of chiral bisimidazolines to have been demonstrated to achieve excellent enantioselectivities. [source] Rational Design and Evaluation of a Branched-Chain-Containing Glycolipid Antigen That Binds to CD1dCHEMISTRY - AN ASIAN JOURNAL, Issue 7 2010Dong Jae Baek Circumnavigating or clamping: CD1 molecules recognize glycolipid antigens with a straight alkyl chain moiety. Owing to the presence of the central pole in the A, pocket of the CD1 binding groove, the straight alkyl chain of antigens circles around the pole like a hook. To determine whether CD1 molecules are capable of recognizing structurally dissimilar ligands, we have designed and evaluated branched-chain-containing glycolipid derivatives of the prototypical CD1d ligand ,-GalCer. [source] Rational Design of Ag/TiO2 Nanosystems by a Combined RF-Sputtering/Sol-Gel ApproachCHEMPHYSCHEM, Issue 18 2009Lidia Armelao Dr. Abstract The present work is devoted to the preparation of Ag/TiO2 nanosystems by an original synthetic strategy, based on the radio-frequency (RF) sputtering of silver particles on titania-based xerogels prepared by the sol,gel (SG) route. This approach takes advantage of the synergy between the microporous xerogel structure and the infiltration power characterizing RF-sputtering, whose combination enables the obtainment of a tailored dispersion of Ag-containing particles into the titania matrix. In addition, the system,s chemico-physical features can be tuned further through proper ex situ thermal treatments in air at 400 and 600,°C. The synthesized composites are extensively characterized by the joint use of complementary techniques, that is, X-ray photoelectron and X-ray excited Auger electron spectroscopies (XPS, XE-AES), secondary ion mass spectrometry (SIMS), glancing incidence X-ray diffraction (GIXRD), field emission scanning electron microscopy (FE,SEM), transmission electron microscopy (TEM), electron diffraction (ED), high-angle annular dark field scanning TEM (HAADF,STEM), energy-filtered TEM (EF,TEM) and optical absorption spectroscopy. Finally, the photocatalytic performances of selected samples in the decomposition of the azo-dye Plasmocorinth B are preliminarily investigated. The obtained results highlight the possibility of tailoring the system characteristics over a broad range, directly influencing their eventual functional properties. [source] Rational Design of Solid Catalysts for the Selective Use of Glycerol as a Natural Organic Building BlockCHEMSUSCHEM CHEMISTRY AND SUSTAINABILITY, ENERGY & MATERIALS, Issue 7 2008François Jérôme Dr. Abstract Glycerol is the main co-product of the vegetable oils industry (especially biodiesel). With the rapid development of oleochemistry, the production of glycerol is rapidly increasing and chemists are trying to find new applications of glycerol to encourage a better industrial development of vegetable oils. In this Review, attention is focused on the selective use of glycerol as a safe organic building block for organic chemistry. An overview is given of the different heterogeneous catalytic routes developed by chemists for the successful and environmentally friendly use of glycerol in sustainable organic chemistry. In particular, the effects of different catalyst structural parameters are discussed to clearly highlight how catalysis can help organic chemists to overcome the drawbacks stemming from the use of glycerol as a safe organic building block. It is shown that heterogeneous catalysis offers efficient routes for bypassing the traditional use of highly toxic and expensive epichlorohydrin, 3-chloro-1,2-propanediol, or glycidol, which are usually used as a glyceryl donor in organic chemistry. [source] Rational design of new CpG oligonucleotides that combine B cell activation with high IFN-, induction in plasmacytoid dendritic cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 6 2003Gunther Hartmann Abstract Two different types of CpG motif-containing oligonucleotides (CpG ODN) have been described: CpG-A with high induction of IFN-, in plasmacytoid dendritic cells; and CpG-B with little induction of IFN-,, but potent activation of B cells. In this study, we demonstrate that CpG-A fail to activate B cells unless plasmacytoid dendritic cells are present. We identified a new set of CpG ODN sequences which induces high levels of IFN-, in plasmacytoid dendritic cells but remains capable of directly activating B cells. These new CpG ODN (termed CpG-C) are more potent stimulants of B cells than CpG-B due to their ability of directly and indirectly (via plasmacytoid dendritic cells) activating B cells. The sequence of CpG-C combines structural elements of both CpG-A and CpG-B. The most potent sequence, M362, contains a 5,-end ,TCGTCG-motif' and a ,GTCGTT-motif', both of which are present in CpG-B (ODN,2006); a palindromic sequence characteristic for CpG-A (ODN,2216); but no poly,G motif required for CpG-A. In conclusion, we defined the first CpG-containing sequences that potently activate both TLR9-expressing immune cell subsets in humans, the plasmacytoid dendritic cell and the B cell. CpG-C may allow for improved therapeutic immuno-modulation in vivo. [source] A novel method for enzyme designJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 2 2009Xiaolei Zhu Abstract Rational design of enzymes is a stringent test of our understanding of protein structure and function relationship, which also has numerous potential applications. We present a novel method for enzyme design that can find good candidate protein scaffolds in a protein-ligand database based on vector matching of key residues. Residues in the vicinity of the active site were also compared according to a similarity score between the scaffold protein and the target enzyme. Suitable scaffold proteins were selected, and the side chains of residues around the active sites were rebuilt using a previously developed side-chain packing program. Triose phosphate isomerase (TIM) was used as a validation test for enzyme design. Selected scaffold proteins were found to accommodate the enzyme active sites and successfully form a good transition state complex. This method overcomes the limitations of the current enzyme design methods that use limited number of protein scaffold and based on the position of ligands. As there are a large number of protein scaffolds available in the Protein Data Band, this method should be widely applicable for various types of enzyme design. © 2008 Wiley Periodicals, Inc. J Comput Chem, 2009 [source] Rational design of shape selective separations and catalysis: Lattice relaxation and effective aperture sizeAICHE JOURNAL, Issue 3 2010Chrysanthos E. Gounaris Abstract Gounaris et al. presented a computational method that can be used for the quick screening of zeolite structures and provide predictions regarding which of them have the potential to exhibit high selectivity among a set of molecules of interest. This article builds upon this earlier work and furthers our understanding of diffusion processes in zeolites and other microporous metal oxides. We first present an augmented formulation to account for the flexibility of the zeolitic portal and conduct an analysis to assess the effect of varying the parameters of the associated quadratic potential. We then introduce a methodology to map the energetic landscape, identify all locally optimal conformations, and probabilistically account for the multiplicity of conformers. Finally, we conduct sensitivity analysis on the effective size of the aperture, and show how the methodology can be fine,tuned through experimental observations. A comprehensive database of 290 molecules of industrial interest and a total of 123 different zeolite structures were used in this study. © 2009 American Institute of Chemical Engineers AIChE J, 2010 [source] Toward a Cohesive Theory of Polymerization Volume Change, 1MACROMOLECULAR THEORY AND SIMULATIONS, Issue 2 2005Andrew J. Holder Abstract Summary: Rational design of polymer-based composites must include an understanding of how and why polymerization volume change occurs. Computational chemistry methods offer significant leverage in such processes. An obstacle to their use has been the meager amount of systematic volume change data collected under the same conditions and using the same methods. This work provides volume change data for eight oxiranes using the mercury dilatometry method. Densities of pure monomers are often unknown for newly synthesized compounds, but are required for the correction of the composite to monomer volume change. The densities have been estimated here by the application of a newly-developed quantum mechanically-based quantitative structure property relationship (QMQSPR). This computational chemistry model can be used to estimate densities of a large array of organic compounds with sufficient accuracy for most routine purposes. These results are presented herein. Correspondence between experimental and QMQSPR calculated results for densities. [source] Recent advances in rational gene transfer vector design based on poly(ethylene imine) and its derivativesTHE JOURNAL OF GENE MEDICINE, Issue 8 2005Michael Neu Abstract The continually increasing wealth of knowledge about the role of genes involved in acquired or hereditary diseases renders the delivery of regulatory genes or nucleic acids into affected cells a potentially promising strategy. Apart from viral vectors, non-viral gene delivery systems have recently received increasing interest, due to safety concerns associated with insertional mutagenesis of retro-viral vectors. Especially cationic polymers may be particularly attractive for the delivery of nucleic acids, since they allow a vast synthetic modification of their structure enabling the investigation of structure-function relationships. Successful clinical application of synthetic polycations for gene delivery will depend primarily on three factors, namely (1) an enhancement of the transfection efficiency, (2) a reduction in toxicity and (3) an ability of the vectors to overcome numerous biological barriers after systemic or local administration. Among the polycations presently used for gene delivery, poly(ethylene imine), PEI, takes a prominent position, due to its potential for endosomal escape. PEI as well as derivatives of PEI currently under investigation for DNA and RNA delivery will be discussed. This review focuses on structure-function relationships and the physicochemical aspects of polyplexes which influence basic characteristics, such as complex formation, stability or in vitro cytotoxicity, to provide a basis for their application under in vivo conditions. Rational design of optimized polycations is an objective for further research and may provide the basis for a successful cationic polymer-based gene delivery system in the future. Copyright © 2005 John Wiley & Sons, Ltd. [source] Design Optimization of Blood Shearing Instrument by Computational Fluid DynamicsARTIFICIAL ORGANS, Issue 6 2005Jingchun Wu Abstract:, Rational design of blood-wetted devices requires a careful consideration of shear-induced trauma and activation of blood elements. Critical levels of shear exposure may be established in vitro through the use of devices specifically designed to prescribe both the magnitude and duration of shear exposure. However, it is exceptionally difficult to create a homogeneous shear-exposure history by conventional means. This study was undertaken to develop a Blood Shearing Instrument (BSI) with an optimized flow path which localized shear exposure within a rotating outer ring and a stationary conical spindle. By adjustment of the rotational speed and the gap dimension, the BSI is designed to generate shear stress magnitudes up to 1500 Pa for exposure time between 0.0015 and 0.20 s with a pressure drop of 100 mm Hg. Computational fluid dynamics (CFD) revealed that a flow path designed by first-order analysis and intuition exhibited unfavorable pressure gradient, vortices, and undesirable regions of reverse flow. An optimized design was evolved utilizing a parameterized geometric model and automatic mesh generation to eliminate vortices and reversal flow and to avoid unfavorable pressure gradients. Analysis of the flow and shear fields for the extreme limits of the shear gap demonstrated an improvement in homogeneity due to shape optimization and the limitations of an annular shear device for achieving completely uniform shear exposure. [source] Rational design of novel red-shifted BRET pairs: Platforms for real-time single-chain protease biosensorsBIOTECHNOLOGY PROGRESS, Issue 2 2009Seth T. Gammon Abstract Bioluminescence resonance energy transfer (BRET) systems to date have been dominated by use of blue-green Renilla luciferase (Rluc) as the energy donor. Although effective in many cases, the expense and unfavorable biochemical attributes of the substrate (phenylcoelenterazine) limit utility of Rluc-based BRET systems. Herein we report a series of novel BRET pairs based on luciferases that utilize D -luciferin, resulting in red-shifted photonic outputs, favorable biochemical attributes, and increased efficacy. We developed a modified Förster equation to predict optimal BRET luciferase donor-fluorophore pairs and identified tdTomato as the optimal red fluorophore acceptor for click beetle green luciferase (CBG). A prototypical single-chain protease biosensor, capable of reporting on executioner caspase activity in live cells and in real-time, was generated by inserting a DEVD linker between CBG and tdTomato and validated in vitro with recombinant caspases and in cellulo with apoptosis-sensitive and -resistant cell lines. High signal-to-noise ratios (,33) and Z, factors (0.85) were observed in live cell longitudinal studies, sufficient for high-throughput screening. Thus, we illustrate a general methodology for the rational design of new BRET systems and provide a novel single-chain BRET protease biosensor that is long lived, red-shifted, and utilizes D -luciferin. © 2009 American Institute of Chemical Engineers Biotechnol. Prog., 2009 [source] The Role of Flexibility in the Rational Design of Modularly Assembled Ligands Targeting the RNAs that Cause the Myotonic DystrophiesCHEMBIOCHEM, Issue 3 2010Matthew D. Disney Prof. Abstract Modularly assembled ligands were designed to target the RNAs that cause two currently untreatable neuromuscular disorders, myotonic dystrophy types 1 (DM1) and 2 (DM2). DM1 is caused by an expanded repeating sequence of CUG, and DM2 is caused by expanded CCUG repeats. Both are present in noncoding regions and fold into hairpins with either repeating 1×1 nucleotide UU (DM1) or 2×2 nucleotide 5,-CU/3,-UC (DM2) internal loops separated by two GC pairs. The repeats are toxic because they sequester the RNA splicing regulator muscleblind-like 1 protein (MBNL1). Rational design of ligands targeting these RNAs was enabled by a database of RNA motif,ligand partners compiled by using two-dimensional combinatorial screening (2DCS). One 2DCS study found that the 6,,-azido-kanamycin A module binds internal loops similar to those found in DM1 and DM2. In order to further enhance affinity and specificity, the ligand was assembled on a peptoid backbone to precisely control valency and the distance between ligand modules. Designed compounds are more potent and specific binders to the toxic RNAs than MBNL1 and inhibit the formation of the RNA,protein complexes with nanomolar IC50 values. This study shows that three important factors govern potent inhibition: 1) the surface area sequestered by the assembled ligands; 2) the spacing between ligand modules since a longer distance is required to target DM2 RNAs than DM1 RNAs; and 3) flexibility in the modular assembly scaffold used to display the RNA-binding module. These results have impacts on the general design of assembled ligands targeting RNAs present in genomic sequence. [source] Computational Design and Discovery of Conformationally Flexible Inhibitors of Acetohydroxyacid Synthase to Overcome Drug Resistance Associated with the W586L MutationCHEMMEDCHEM, Issue 8 2008Feng-Qin Ji Rational design: A series of 2-aroxyl-1,2,4-triazolo[1,5- c]pyrimidine derivatives were computationally designed (see scheme) and synthesized as conformationally flexible AHAS inhibitors. These compounds could find use as new leads for combating drug resistance. [source] Novel therapeutic targets in multiple myelomaEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 6 2000Faith E. Davies The aim of this review is to focus on a number of key areas where recent advances in the biology of the disease have not only yielded an understanding of the disease pathogenesis but have also suggested novel treatment approaches. Factors mediating myeloma cell growth, survival and the complex interaction of myeloma cells with the bone marrowmicroenvironment have provided a framework for the rational design of therapeutic agents. The development of such biologically based treatments which target both the tumour cell and the microenvironment, in order to achieve more complete and selective eradication of myeloma cells and the maintenance of minimal residual disease states, may ultimately lead to improved disease-free survivial and potentially a cure. [source] Sequence-Selective Peptide Recognition with Designed ModulesEUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 1 2006Mark Wehner Abstract A concept for the rational design of sequence-selective peptide receptors has been extended: in addition to recognition modules for polar, aromatic and basic amino acids, the series has now been completed with new receptor units for apolar and acidic amino acids. The underlying strategy uses the intermolecular ,-sheet stabilization of a dipeptide as a prerequisite to bind its N-terminal amino acid side chain through a strategically placed recognition tip at the end of a U-turn protruding from the receptor moiety. Thus, a diaminopyrazole has been covalently attached to Kemp's triacid by way of a cyclic imide, while a meta -substituted aniline was coupled as an amide to the pendant third carboxylate arm, bringing the two aromatic units into a sub-van der Waals distance in a tight conformational lock. NMR titrations, Karplus analyses and Monte-Carlo simulations demonstrate the effective sequence-selective recognition of alanine-containing dipeptides. No example of such a rationally designed set of peptide receptors had existed previously. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006) [source] Chromokinetics of metabolic pathwaysFEBS JOURNAL, Issue 13 2004Jörg W. Stucki Some methods to study and intuitively understand steady-state flows in complicated metabolic pathways are discussed. For this purpose, a suitable decomposition of complex metabolic schemes into smaller subsystems is used. These independent subsystems are then interpreted as basic colors of a chromatic coloring scheme. The mixture of these basic colors allows an intuitive picture of how a steady state in a metabolic pathway can be understood. Furthermore, actions of drugs can be more easily investigated on this basis. An anaerobic variant of pyruvate metabolism in rat liver mitochondria is presented as a simple example. This experiment allows measurement of the percentage that each basic color contributes to the steady states resulting from different experimental conditions. Possible implementations of existing algorithms and rational design of new drugs are discussed. A mathematica program, based on a new algorithm for finding all basic colors of stoichiometric networks, is included. [source] Crystal structure of Fab198, an efficient protector of the acetylcholine receptor against myasthenogenic antibodiesFEBS JOURNAL, Issue 13 2001Konstantinos Poulas The crystal structure of the Fab fragment of the rat monoclonal antibody 198, with protective activity for the main immunogenic region of the human muscle acetylcholine receptor against the destructive action of myasthenic antibodies, has been determined and refined to 2.8 Å resolution by X-ray crystallographic methods. The mouse anti-lysozyme Fab D1.3 was used as a search model in molecular replacement with the amore software. The complementarity determining regions (CDR)-L2, CDR-H1 and CDR-H2 belong to canonical groups. Loops CDR-L3, CDR-H2 and CDR-H3, which seem to make a major contribution to binding, were analyzed and residues of potential importance for antigen-binding are examined. The antigen-binding site was found to be a long crescent-shaped crevice. The structure should serve as a model in the rational design of very high affinity humanized mutants of Fab198, appropriate for therapeutic approaches in the model autoimmune disease myasthenia gravis. [source] Interplay of Properties and Functions upon Introduction of Mesoporosity in ITQ-4 ZeoliteADVANCED FUNCTIONAL MATERIALS, Issue 9 2010Danny Verboekend Abstract The introduction of mesoporosity in zeolites is often directly coupled to changes in their overall catalytic performance without the detailed assessment of other key functions required for the rational design of the catalytic process such as accessibility, adsorption, and transport. This study presents an integrated approach to study property,function relationships in hierarchical zeolites. Accordingly, desilication of the 1D ITQ-4 zeolite in alkaline medium is applied to develop different degrees of mesoporosity. Along with porosity modification, significant changes in composition, structure, and acidity occur. Relationships are established between the physicochemical properties of the zeolites and their characteristics in the adsorption and elution of light hydrocarbons (C2 to C5, alkanes and alkenes) as well as in the catalytic activity in low-density polyethylene (LDPE) pyrolysis. The recently introduced hierarchy factor can appropriately relate porosity changes to catalytic performance. [source] Current status of malaria chemotherapy and the role of pharmacology in antimalarial drug research and developmentFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 4 2009Kesara Na-Bangchang Abstract Antimalarial drugs have played a mainstream role in controlling the spread of malaria through the treatment of patients infected with the plasmodial parasites and controlling its transmissibility. The inadequate armory of drugs in widespread use for the treatment of malaria, development of strains resistant to currently used antimalarials, and the lack of affordable new drugs are the limiting factors in the fight against malaria. In addition, other problems with some existing agents include unfavorable pharmacokinetic properties and adverse effects/toxicity. These factors underscore the continuing need of research for new classes of antimalarial agents, and a re-examination of the existing antimalarial drugs that may be effective against resistant strains. In recent years, major advances have been made in the pharmacology of several antimalarial drugs both in pharmacokinetics and pharmacodynamics aspects. These include the design, development, and optimization of appropriate dosage regimens of antimalarials, basic knowledge in metabolic pathways of key antimalarials, as well as the elucidation of mechanisms of action and resistance of antimalarials. Pharmacologists have been working in close collaboration with scientists in other disciplines of science/biomedical sciences for more understanding on the biology of the parasite, host, in order to exploit rational design of drugs. Multiple general approaches to the identification of new antimalarials are being pursued at this time. All should be implemented in parallel with focus on the rational development of new agents directed against newly identified parasite targets. With major advances in our understanding of malaria parasite biology coupled with the completion of the malaria genome, has presented exciting opportunities for target-based antimalarial drug discovery. [source] | ||||||||||||||||||||||||||||||||||||||||||||||