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  • High-Throughput Chemical Probing of Full-Length Protein–Protein Interactions
    ACS Comb. Sci. (IF 3.168) Pub Date : 2017-11-14
    James M. Song, Arya Menon, Dylan C. Mitchell, Oleta T. Johnson, Amanda L. Garner
    更新日期:2017-11-15
  • Process-Function Data Mining for the Discovery of Solid-State Iron-Oxide PV
    ACS Comb. Sci. (IF 3.168) Pub Date : 2017-11-09
    Elana Borvick, Assaf Y. Anderson, Hannah-Noa Barad, Maayan Priel, David A. Keller, Adam Ginsburg, Kevin J. Rietwyk, Simcha Meir, Arie Zaban
    更新日期:2017-11-09
  • Microwave-Facilitated SPOT-Synthesis of Antibacterial Dipeptoids
    ACS Comb. Sci. (IF 3.168) Pub Date : 2017-11-07
    Anne C. Schneider, Daniel Fritz, Joseph K. Vasquez, Sidonie B. L. Vollrath, Helen E. Blackwell, Stefan Bräse
    更新日期:2017-11-08
  • Stereoselective Synthesis of Benzo[e][1,4]oxazino[4,3-a][1,4]diazepine-6,12-diones with Two Diversity Positions
    ACS Comb. Sci. (IF 3.168) Pub Date : 2017-11-02
    Petra Králová, Michal Maloň, Miroslav Soural
    更新日期:2017-11-02
  • Efficient Synthesis of 1,9-Substituted Benzo[h][1,6]naphthyridin-2(1H)-ones and Evaluation of their Plasmodium falciparum Gametocytocidal Activities
    ACS Comb. Sci. (IF 3.168) Pub Date : 2017-10-27
    Hao Li, Wei Sun, Xiuli Huang, Xiao Lu, Paresma R. Patel, Myunghoon Kim, Meghan J. Orr, Richard M. Fisher, Takeshi Q Tanaka, John C. McKew, Anton Simeonov, Philip E. Sanderson, Wei Zheng, Kim C. Williamson, Wenwei Huang
    更新日期:2017-10-28
  • Skeletal Diversity in Combinatorial Fashion: A New Format for the Castagnoli–Cushman Reaction
    ACS Comb. Sci. (IF 3.168) Pub Date : 2017-10-26
    Anastasia Lepikhina, Dmitry Dar’in, Olga Bakulina, Evgeny Chupakhin, Mikhail Krasavin
    更新日期:2017-10-26
  • Parallel Synthesis of 1H-Pyrazolo[3,4-d]pyrimidines via Condensation of N-Pyrazolylamides and Nitriles
    ACS Comb. Sci. (IF 3.168) Pub Date : 2017-10-20
    Akshay A. Shah, Lois K. Chenard, Joseph W. Tucker, Christopher J. Helal
    更新日期:2017-10-20
  • Microwave-Assisted Regioselective Synthesis of 3-Functionalized Indole Derivatives via Three-Component Domino Reaction
    ACS Comb. Sci. (IF 3.168) Pub Date : 2017-10-18
    Wei Lin, Yong-Xiang Zheng, Zhan Xun, Zhi-Bin Huang, Da-Qing Shi
    更新日期:2017-10-19
  • Library Design-Facilitated High-Throughput Sequencing of Synthetic Peptide Libraries
    ACS Comb. Sci. (IF 3.168) Pub Date : 2017-09-29
    Alexander A. Vinogradov, Zachary P. Gates, Chi Zhang, Anthony J. Quartararo, Kathryn H. Halloran, Bradley L. Pentelute
    更新日期:2017-09-30
  • How Many Bulk Metallic Glasses Are There?
    ACS Comb. Sci. (IF 3.168) Pub Date : 2017-09-27
    Yanglin Li, Shaofan Zhao, Yanhui Liu, Pan Gong, Jan Schroers
    更新日期:2017-09-28
  • How Many Bulk Metallic Glasses Are There?
    ACS Comb. Sci. (IF 3.168) Pub Date : 2017-09-13
    Yanglin Li, Shaofan Zhao, Yanhui Liu, Pan Gong, Jan Schroers

    Quantitative prediction of glass forming ability using a priori known parameters is highly desired in metallic glass development; however proven to be challenging due to the complexity of glass formation. Here we estimate the number of potential metallic glasses (MGs) and bulk metallic glasses (BMGs) forming systems and alloys, from empirically determined alloy design rules based on a priori known parameters. Specifically, we take into account atomic size ratio, heat of mixing, and liquidus temperature, which we quantify on binary glasses and centimeter-sized BMGs. When expanding into higher order systems that can be formed among 32 practical elements, we reduce the composition space for BMG formation using developed criteria by 106 times and estimate ~3 million binary, ternary, quaternary and quinary BMGs alloys.

    更新日期:2017-09-14
  • 更新日期:2017-09-12
  • Library design-facilitated high-throughput sequencing of synthetic peptide libraries
    ACS Comb. Sci. (IF 3.168) Pub Date : 2017-09-11
    Alexander Alexandrovich Vinogradov, Zachary P. Gates, Chi Zhang, Anthony J. Quartararo, Kathryn H. Halloran, Bradley L. Pentelute

    A methodology to achieve high-throughput de novo sequencing of synthetic peptide mixtures is reported. The approach leverages shotgun nano-liquid chromatography coupled with tandem mass spectrometry-based de novo sequencing of library mixtures (up to 2000 peptides), as well as automated data analysis protocols to filter away incorrect assignments, noise and synthetic side-products. To increase the confidence in sequencing results, mass spectrometry-friendly library designs were developed, which enabled unambiguous decoding of up to 600 peptide sequences per hour while maintaining greater than 85% sequence identification rate in most cases. The reliability of the reported decoding strategy was additionally confirmed by matching fragmentation spectra for select authentic peptides identified from library sequencing samples. The methods reported here are directly applicable to screening techniques that yield mixtures of active compounds, including particle sorting of one-bead one-compound libraries, and affinity enrichment of synthetic library mixtures performed in solution.

    更新日期:2017-09-11
  • Array-Based Rational Design of Short Peptide Probe-Derived from an Anti-TNT Monoclonal Antibody
    ACS Comb. Sci. (IF 3.168) Pub Date : 2017-09-08
    Mina Okochi, Masaki Muto, Kentaro Yanai, Masayoshi Tanaka, Takeshi Onodera, Jin Wang, Hiroshi Ueda, Kiyoshi Toko
    更新日期:2017-09-08
  • Gold-Catalyzed Solid-Phase Synthesis of 3,4-Dihydropyrazin-2(1H)-ones: Relevant Pharmacophores and Peptide Backbone Constraints
    ACS Comb. Sci. (IF 3.168) Pub Date : 2017-09-08
    Adam Pribylka, Viktor Krchnak

    Here, we report the efficient solid-phase synthesis of N-propargyl peptides using Fmoc-amino acids and propargyl alcohol as key building blocks. Gold-catalyzed nucleophilic addition to the triple bond induced C‒N bond formation, which triggered intramolecular cyclization, yielding 1,3,4-trisubstituted-5-methyl-3,4-dihydropyrazin-2(1H)-ones. Conformations of acyclic and constrained peptides were compared using a two-step conformer distribution analysis at the molecular mechanics level and density functional theory. The results indicated that the incorporation of heterocyclic molecular scaffold into a short peptide sequence adopted extended conformation of peptide chain. The amide bond adjacent to the constraint did not show significant preference for either cis or trans isomerism. Prepared model compounds demonstrate a proof of concept for gold-catalyzed polymer-supported synthesis of variously substituted 3,4-dihydropyrazin-2(1H)-ones for applications in drug discovery and peptide backbone constraints.

    更新日期:2017-09-08
  • 1,3-Dipolar Cycloaddition Reactions for the Synthesis of Novel Oxindole Derivatives and Their Cytotoxic Properties
    ACS Comb. Sci. (IF 3.168) Pub Date : 2017-09-07
    Prakash R. Mali, Prashishkumar K. Shirsat, Navnath Khomane, Lakshama Nayak, Jagadeesh Babu Nanubolu, H. M. Meshram
    更新日期:2017-09-07
  • A Linker for the Solid-Phase Synthesis of Hydroxamic Acids and Identification of HDAC6 Inhibitors
    ACS Comb. Sci. (IF 3.168) Pub Date : 2017-09-06
    Claus G. Bang, Jakob F. Jensen, Emil O’Hanlon Cohrt, Lasse B. Olsen, Saba G. Siyum, Kim T. Mortensen, Tine Skovgaard, Jens Berthelsen, Liang Yang, Michael Givskov, Katrine Qvortrup, Thomas E. Nielsen
    更新日期:2017-09-06
  • Oligonucleotide Hybridization Combined with Competitive Antibody Binding for the Truncation of a High-Affinity Aptamer
    ACS Comb. Sci. (IF 3.168) Pub Date : 2017-09-05
    Cong Quang Vu, Pichayanoot Rotkrua, Yuthana Tantirungrotechai, Boonchoy Soontornworajit
    更新日期:2017-09-06
  • Parallel Chemistry Approach to Identify Novel Nuclear Receptor Ligands Based on the GW0742 Scaffold
    ACS Comb. Sci. (IF 3.168) Pub Date : 2017-09-05
    Kelly A. Teske, Ganesha Rai, Premchendar Nandhikonda, Preetpal S. Sidhu, Belaynesh Feleke, Anton Simeonov, Adam Yasgar, Ajit Jadhav, David J. Maloney, Leggy A. Arnold
    更新日期:2017-09-06
  • Machine Learning Using Combined Structural and Chemical Descriptors for Prediction of Methane Adsorption Performance of Metal Organic Frameworks (MOFs)
    ACS Comb. Sci. (IF 3.168) Pub Date : 2017-09-05
    Maryam Pardakhti, Ehsan Moharreri, David Wanik, Steven L. Suib, Ranjan Srivastava
    更新日期:2017-09-05
  • Polymer-Supported Stereoselective Synthesis of Benzoxazino[4,3-b][1,2,5]thiadiazepinone 6,6-dioxides
    ACS Comb. Sci. (IF 3.168) Pub Date : 2017-08-31
    Petra Králová, Michal Maloň, Tereza Volná, Veronika Ručilová, Miroslav Soural
    更新日期:2017-08-31
  • Array-based rational design of short peptide probe derived from an anti-TNT monoclonal antibody
    ACS Comb. Sci. (IF 3.168) Pub Date : 2017-08-28
    Mina Okochi, Masaki Muto, Kentaro Yanai, Masayoshi Tanaka, Takeshi Onodera, Jin Wang, Hiroshi Ueda, Kiyoshi Toko

    Complementarity-determining regions (CDRs) are sites on the variable chains of antibodies responsible for binding to specific antigens. In this study, a short peptide probe for recognition of 2,4,6-trinitrotoluene (TNT), was identified by testing sequences derived from the CDRs of an anti-TNT monoclonal antibody. The major TNT-binding site in this antibody was identified in the heavy chain CDR3 by antigen docking simulation and confirmed by an immunoassay using a spot-synthesis based peptide array comprising amino acid sequences of six CDRs in the variable region. A peptide derived from heavy chain CDR3 (RGYSSFIYWF) bound to TNT with a dissociation constant of 1.3 μM measured by surface plasmon resonance. Substitution of selected amino acids with basic residues increased TNT binding while substitution with acidic amino acids decreased affinity, an isoleucine to arginine change showed the greatest improvement of 1.8-fold. The ability to create simple peptide binders of volatile organic compounds from sequence information provided by the immune system in the creation of an immune response will be beneficial for sensor developments in the future.

    更新日期:2017-08-28
  • Selection of Effective HTRA3 Activators Using Combinatorial Chemistry
    ACS Comb. Sci. (IF 3.168) Pub Date : 2017-08-24
    Magdalena Wysocka, Kamila Sychowska, Natalia Gruba, Łukasz Winiarski, Marcin Skoreński, Mateusz Psurski, Joanna Makowska, Artur Giełdoń, Tomasz Wenta, Mirosław Jarząb, Przemysław Glaza, Joanna Zdancewicz, Marcin Sieńczyk, Barbara Lipińska, Adam Lesner
    更新日期:2017-08-24
  • Polymer-Supported Stereoselective Synthesis of Benzoxazino[4,3-b][1,2,5]thiadiazepinone 6,6-dioxides
    ACS Comb. Sci. (IF 3.168) Pub Date : 2017-08-21
    Petra Kralova, Michal Malon, Tereza Volna, Veronika Rucilova, Miroslav Soural

    Herein, we report the stereoselective synthesis of trisubstituted benzoxazino[4,3-b][1,2,5]thiadiazepinone 6,6-dioxides from polymer-supported Fmoc-Ser(tBu)-OH and Fmoc-Thr(tBu)-OH. After the solid-phase synthesis of N-alkylated-N-sulfonylated intermediates using various 2-nitrobenzenesulfonyl chlorides and bromoketones, the target compounds were obtained via trifluoroacetic acid (TFA)-mediated cleavage from the resin followed by cyclization of the diazepinone scaffold. Except for the threonine-based intermediates, the inclusion of triethylsilane (TES) in the cleavage cocktail yielded a specific configuration of the newly formed C3 chiral center. The final cyclization resulted in only minor inversion of the C12a stereocenter configuration.

    更新日期:2017-08-22
  • Oligonucleotide Hybridization Combined with Competitive Antibody Binding for the Truncation of a High-Affinity Aptamer
    ACS Comb. Sci. (IF 3.168) Pub Date : 2017-08-21
    Cong Quang Vu, Pichayanoot Rotkrua, Yuthana Tantirungrotechai, Boonchoy Soontornworajit

    Truncation can enhance the affinity of aptamers for their targets by limiting nonessential segments and therefore limiting the molecular degrees of freedom that must be overcome in the binding process. This study demonstrated a truncation protocol relying on competitive antibody binding and the hybridization of complementary oligonucleotides, using platelet derived growth factor BB (PDGF-BB) as the model target. Based on immunoassay results, an initial long aptamer was truncated to a number of sequences with lengths of 36-40 nucleotides (nt). These sequences showed apparent KD values in the picomolar range, with the best case being a 36-nt truncated aptamer with a 150-fold increase in affinity over the full-length aptamer. The observed binding energies correlated well with relative energies calculated by molecular dynamics simulations. The effect of the truncated aptamer on PDGF-BB-stimulated fibroblasts was found to be equivalent to that of the full-length aptamer.

    更新日期:2017-08-21
  • A parallel chemistry approach to identify novel nuclear receptor ligands based on the GW0742 scaffold
    ACS Comb. Sci. (IF 3.168) Pub Date : 2017-08-21
    Kelly A. Teske, Ganesha Rai, Premchendar Nandhikonda, Preetpal Sidhu, Belaynesh D. Feleke, Anton Simeonov, Adam Yasgar, Ajit Jadhav, David J. Maloney, Leggy A. Arnold

    We describe the parallel synthesis of novel analogs of GW0742, a peroxisome proliferator-activated receptor δ (PPARδ) agonist. For that purpose, modified reaction conditions were applied, such as a solid-phase palladium-catalyzed Suzuki coupling. In addition, tetrazole-based compounds were generated as a bioisostere for carboxylic acid-containing ligand GW0742. The new compounds were investigated for their ability to activate PPARδ mediated transcription and their cross-reactivity with the vitamin D receptor (VDR), another member of the nuclear receptor superfamily. We identified many potent PPARδ agonists that were less toxic than GW0742. Sixty five of the compounds synthesized exhibited partial PPARδ activity (23-98%) with EC50 values ranging from 0.007 – 18.2 μM. Some ligands, such as compound 32, were more potent inhibitors of VDR-mediated transcription with significantly reduced PPARδ activity in comparison with GW0742, however, none of the ligands were completely selective for VDR inhibition over PPARδ activation.

    更新日期:2017-08-21
  • 1,3-dipolar cycloaddition reactions for the Synthesis of Novel Oxindole Derivatives and Their Cytotoxic Properties
    ACS Comb. Sci. (IF 3.168) Pub Date : 2017-08-17
    Prakash Rambhau Mali, Prashishkumar Kisan Shirsat, Navnath Bapurao Khomane, V Lakshama Nayak, Jagadeesh Babu Nanubolu, Harshadas Mitaram Meshram

    The multicomponent reaction between isatin, amino acid, but-2-ynedioates and phenacyl bromide has been developed using microwave irradiation under catalyst and base free conditions in aqueous medium. This synthetic protocol is useful for the synthesis of various functionalized spirooxindole derivatives. This MCR exhibits a broad substrate scope with excellent yields and shorter reaction time. Additionally the synthesized spirooxindole derivatives were evaluated for their anticancer activity against three human cancer cell lines; MCF-7 (breast), A549 (lung) and Hela cervical. Most of the compounds showed moderate to potent cytotoxic activity against the tested cell lines.

    更新日期:2017-08-17
  • Shape Memory Micro- and Nanowire Libraries for the High-Throughput Investigation of Scaling Effects
    ACS Comb. Sci. (IF 3.168) Pub Date : 2017-08-14
    Tobias Oellers, Dennis König, Aleksander Kostka, Shenqie Xie, Jürgen Brugger, Alfred Ludwig
    更新日期:2017-08-15
  • High-Throughput Structural and Functional Characterization of the Thin Film Materials System Ni–Co–Al
    ACS Comb. Sci. (IF 3.168) Pub Date : 2017-08-11
    Peer Decker, Dennis Naujoks, Dennis Langenkämper, Christoph Somsen, Alfred Ludwig
    更新日期:2017-08-12
  • Machine learning using combined structural and chemical descriptors for prediction of methane adsorption performance of metal organic frameworks (MOFs)
    ACS Comb. Sci. (IF 3.168) Pub Date : 2017-08-11
    Maryam Pardakhti, Ehsan Moharreri, David Wanik, Steven L. Suib, Ranjan Srivastava

    Using molecular simulation for adsorbent screening is computationally expensive and thus prohibitive to material discovery. Machine learning (ML) algorithms trained on fundamental material properties can potentially provide quick and accurate methods for screening purposes. Prior efforts have focused on structural descriptors for use with ML. In this work, the use of chemical descriptors, in addition to structural descriptors, was introduced for adsorption analysis. Evaluation of structural and chemical descriptors coupled with various ML algorithms, including decision trees, Poisson regression, support vector machine and random forest, were carried out to predict methane uptake on hypothetical metal organic frameworks. To highlight their predictive capabilities, ML models were trained on 8% of a dataset consisting of 130,398 MOFs and then tested on the remaining 92% to predict methane adsorption capacities. When structural and chemical descriptors were jointly used as ML input, the random forest model with 10-fold cross validation proved to be superior to the other ML approaches, with an R2 of 0.98 and a mean average percent error of about 7%. The training and prediction using the random forest algorithm for adsorption capacity estimation of all 130,398 MOFs took approximately two hours on a single personal computer, several orders of magnitude faster than actual molecular simulations on high-performance computing clusters.

    更新日期:2017-08-11
  • Fabrication of a New Lineage of Artificial Luciferases from Natural Luciferase Pools
    ACS Comb. Sci. (IF 3.168) Pub Date : 2017-08-09
    Sung Bae Kim, Ryo Nishihara, Daniel Citterio, Koji Suzuki
    更新日期:2017-08-09
  • 更新日期:2017-08-09
  • An Efficient One-Pot Synthesis of Densely Functionalized Fused-Quinolines via Sequential Ugi4CC and Acid-Mediated Povarov-Type Reaction
    ACS Comb. Sci. (IF 3.168) Pub Date : 2017-08-08
    Anirban Ghoshal, Doddapaneni Yugandhar, Jagadeesh Babu Nanubolu, Ajay Kumar Srivastava
    更新日期:2017-08-08
  • Shape Memory Micro- and Nanowire Libraries for the High-Throughput Investigation of Scaling Effects
    ACS Comb. Sci. (IF 3.168) Pub Date : 2017-07-31
    Tobias Oellers, Dennis König, Aleksander Kostka, Shenqi Xie, Juergen Brugger, Alfred Ludwig

    The scaling behavior of Ti-Ni-Cu shape memory thin film micro- and nanowires of different geometry is investigated with respect to its influence on the martensitic transformation properties. Two processes for the high-throughput fabrication of Ti-Ni-Cu micro- to nanoscale thin film wire libraries and the subsequent investigation of the transformation properties are reported. The libraries are fabricated with compositional and geometrical (wire width) variations to investigate the influence of these parameters on the transformation properties. Interesting behaviors were observed: Phase transformation temperatures change in the range from 1 to 72 °C (Af), 13 to 66 °C (Ms) and the thermal hysteresis from -3.5 to 20 K. It is shown that a vanishing hysteresis can be achieved for special combinations of sample geometry and composition.

    更新日期:2017-07-31
  • Solid-Phase Synthesis of Hydroxamic Acids and Identification of HDAC Inhibitors Using a Chemi-luminescence-based Assay
    ACS Comb. Sci. (IF 3.168) Pub Date : 2017-07-26
    Claus Bang, Jakob Jensen, Emil Cohrt, Lasse Olsen, Saba Siyum, Kim Mortensen, Tine S. Poulsen, Jens Berthelsen, Liang Yang, Michael Givskov, Katrine Qvortrup, Thomas Eiland Nielsen

    We herein present broadly useful, readily available and non-integral hydroxylamine linkers for the routine solid-phase synthesis of hydroxamic acids. The Fmoc-protected linkers are readily made on multi-gram scale from simple starting materials and conveniently attached to solid support through standard amide bond forming reactions. The developed protocols enable the efficient synthesis and release of a wide range of hydroxamic acids from various resins, relying on high control and flexibility with respect to reagents and synthetic processes. The linkers show broad applicability to a range of reactions commonly employed in the solid-phase organic synthesis of molecular libraries, such as amination, acylation, sulfonylation, Cu-catalyzed click reactions, and Wittig reactions. The flexibility for the synthetic process was utilized to generate a proof-of-concept collection of 72 thiophene-based hydroxamic acids. The inhibitory effects of the compounds were examined for seven HDAC enzyme subtypes using a chemiluminescence-based assay, revealing several highly potent, and even subtype-selective, HDAC inhibitors, including single-digit nM inhibitors of HDAC6.

    更新日期:2017-07-28
  • Fabrication of TiO2–Reduced Graphene Oxide Nanorod Composition Spreads Using Combinatorial Hydrothermal Synthesis and Their Photocatalytic and Photoelectrochemical Applications
    ACS Comb. Sci. (IF 3.168) Pub Date : 2017-07-26
    Wen-Chung Lu, Li-Chun Tseng, Kao-Shuo Chang

    This study is the first to employ combinatorial hydrothermal synthesis and facile spin-coating technology to fabricate TiO2–reduced graphene oxide (rGO) nanorod composition spreads. The features of this study are 1) the development of a self-designed spin coating wedge, 2) the systemic investigation of the structure–property relationship of the system, 3) the high-throughput screening of the optimal ratio from a wide range of compositions for photocatalytic and photoelectrochemical (PEC) applications, and 4) the effective coupling between the density gradient TiO2 nanorod array and the thickness gradient rGO. The formation of rGO in the fabricated TiO2–rGO sample was monitored through Fourier transform infrared spectrometry. Transmission electron microscopy images also suggested that the TiO2 nanorod surfaces were covered with a thin layer of amorphous rGO. The rutile TiO2 plane evolution along the composition variation was verified through X-ray diffraction. Location 5 (7% TiO2–93% rGO) on the nanorod composition spread exhibited the most promising photocatalytic ability (k  12.7  10−3 min−1), which was also superior to a similar system described in the literature. The excellent performance was attributed to the effective coupling between the TiO2 and rGO, which improved the charge carrier transport, thus inhibiting electron-hole pair recombination. A cycling test implied that Location 5 is a reliable photocatalyst. A photoluminescence spectroscopy study also supported the superior photocatalytic ability of the sample, which was attributed to its markedly poorer recombination behavior. In addition, without further treatment, the sample exhibited excellent PEC stability; the photocurrent density was more than three times higher than that exhibited by the density gradient TiO2 nanorods.

    更新日期:2017-07-28
  • Bias-Free Chemically Diverse Test Sets from Machine Learning
    ACS Comb. Sci. (IF 3.168) Pub Date : 2017-07-27
    Ellen T. Swann, Michael Fernandez, Michelle L. Coote, Amanda S. Barnard
    更新日期:2017-07-28
  • Poisson Statistics of Combinatorial Library Sampling Predict False Discovery Rates of Screening
    ACS Comb. Sci. (IF 3.168) Pub Date : 2017-07-26
    Andrew B. MacConnell, Brian M. Paegel
    更新日期:2017-07-28
  • Microwave-Assisted Synthesis of Diversely Substituted Quinoline-Based Dihydropyridopyrimidine and Dihydropyrazolopyridine Hybrids
    ACS Comb. Sci. (IF 3.168) Pub Date : 2017-07-26
    Daniel Insuasty, Rodrigo Abonia, Braulio Insuasty, Jairo Quiroga, Kenneth K. Laali, Manuel Nogueras, Justo Cobo
    更新日期:2017-07-28
  • Systematic First-Principles Study of Binary Metal Hydrides
    ACS Comb. Sci. (IF 3.168) Pub Date : 2017-07-25
    Natacha Bourgeois, Jean-Claude Crivello, Pierre Cenedese, Jean-Marc Joubert
    更新日期:2017-07-26
  • Selection of effective HTRA3 activators using combinatorial chemistry
    ACS Comb. Sci. (IF 3.168) Pub Date : 2017-07-25
    Magdalena Wysocka, Kamila Sychowska, Natalia Gruba, Łukasz Winiarski, Marcin Skoreński, Mateusz Psurski, Joanna Makowska, Artur Gieldon, Tomasz Wenta, Mirosław Jarząb, Przemyslaw Glaza, Joanna Zdacewicz, Marcin Sieńczyk, Barbara Lipinska, Adam Lesner

    Herein we report selection, synthesis and enzymatic evaluation of a peptidomimetic library able to increase proteolytic activity of HtrA3 (high temperature requirement A) protease. Iterative deconvolution in solution of synthesized modified pentapeptides yielded two potent HtrA3 activators acting in the micromolar range (HCOO-CH2O-C6H4-OCH2-CO-Tyr-Asn-Phe-His-Asn-OH and HCOO-CH2O-C6H4-OCH2-CO-Tyr-Asn-Phe-His-Glu-OH). Both compounds increased proteolysis of an artificial HtrA3 substrate over 40-fold in a selective manner. Based on molecular modeling, the selected compounds bind strongly to the PDZ domain.

    更新日期:2017-07-26
  • Fabrication of a New Lineage of Artificial Luciferases from Natural Luciferase Pools
    ACS Comb. Sci. (IF 3.168) Pub Date : 2017-07-25
    Sung Bae Kim, Ryo Nishihara, Daniel Citterio, Koji Suzuki

    The fabrication of artificial luciferases (ALucs) with unique optical properties can have a fundamental impact on bioassays and molecular imaging. In this study, we developed a new lineage of ALucs with unique substrate preferences by extracting consensus amino acids from the alignment of 25 copepod luciferase sequences available in published databases. The primary sequence was first created with a sequence logo generator resulting in a total of 11 sibling sequences. Phylogenetic analysis shows that the newly fabricated ALucs form an independent branch, genetically isolated from the natural luciferases and from a prior series of ALucs produced by our laboratory using a smaller basis set. The new lineage of ALucs were strongly luminescent in living mammalian cells with specific substrate selectivity to native coelenterazine. A single-residue-level comparison of the C-terminal sequences of new ALucs reveals that some amino acids in the C-terminal ends are greatly influential on the optical intensities, but limited in the color variance. The success of this approach guides on how to engineer and functionalize marine luciferases for bioluminescence imaging and assays.

    更新日期:2017-07-26
  • An Efficient One-Pot Synthesis of Densely Functionalized Fused-Quinolines via Sequential Ugi4CC and Acid-mediated Povarov-Type Reaction
    ACS Comb. Sci. (IF 3.168) Pub Date : 2017-07-25
    Anirban Ghoshal, Doddapaneni Yugandhar, Jagadeesh Babu Nanubolu, Ajay Kumar Srivastava

    A divergent synthesis of fused-quinolines has been explored by performing Ugi four-component condensation and sulfuric acid promoted deprotection/Povarov-type reaction in one-pot. The process involves Ugi condensation of propiolic acids, aldehydes/ketones, aminoaldehyde acetals and isocyanides followed by sulfuric acid promoted deprotection and Povarov-type reaction with anilines in ethanol. This method enables straightforward access to the structurally diverse 2,3-dihydro-1H-pyrrolo[3,4-b]quinolin-1-ones (DHPQ), 3,4-dihydrobenzo[b][1,6]naphthyridin-1(2H)-ones (DHBN) and 2,3,4,5-tetrahydro-1H-azepino[4,3-b]quinolin-1-ones (THAQ), starting from readily available starting materials.

    更新日期:2017-07-26
  • High-throughput structural and functional characterization of the thin film materials system Ni-Co-Al
    ACS Comb. Sci. (IF 3.168) Pub Date : 2017-07-24
    Peer Decker, Dennis Naujoks, Dennis Langenkaemper, Christoph Somsen, Alfred Ludwig

    High-throughput methods were used to investigate a Ni-Co-Al thin film materials library. This material system is of interest for superalloys and shape memory alloys. High resolution grazing incidence x-ray diffraction (XRD) measurements were carried out to identify the library’s phase regions; d-spacing maps, based on peak fitting, were used to determine more precisely the compositional existence regions of phases. Thin film texture, which was observed in XRD, was also addressed. Finally, magneto-optical measurements were performed to confirm the results of the XRD measurements. Magnetic hysteresis loops were only present in compositions where XRD revealed ferromagnetic phases. All results were combined in a ternary thin film phase diagram of the Ni-Co-Al thin film system, which was then assessed by comparing with data from literature phase diagrams.

    更新日期:2017-07-25
  • Bias-free chemically diverse test sets from machine learning
    ACS Comb. Sci. (IF 3.168) Pub Date : 2017-07-19
    Ellen Swann, Michael Fernandez, Michelle L. Coote, Amanda S. Barnard

    Current benchmarking methods in quantum chemistry rely on databases that are built using a chemist’s intuition. It is not fully understood how diverse or representative these databases truly are. Multivariate statistical techniques like archetypal analysis and K-means clustering have previously been used to summarise large sets of nanoparticles however molecules are more diverse and not as easily characterised by descriptors. In this work we compare three sets of descriptors based on the one-, two- and three-dimensional structure of a molecule. Using data from the NIST Computational Chemistry Comparison and Benchmark Database and machine learning techniques we demonstrate the functional relationship between these structural descriptors and the electronic energy of molecules. Archetypes and prototypes found with topological or Coulomb matrix descriptors can be used to identify smaller, statistically significant test sets that better capture the diversity of chemical space. We apply this same method to find a diverse subset of organic molecules to demonstrate how the methods can easily be re-applied to individual research projects. Finally we use our bias-free test sets to assess the performance of density functional theory and quantum Monte Carlo methods.

    更新日期:2017-07-20
  • Microwave-assisted synthesis of diversely substituted quinoline-based dihydropyridopyrimidine and dihydropyrazolopyridine hybrids
    ACS Comb. Sci. (IF 3.168) Pub Date : 2017-07-19
    Daniel Insuasty, Rodrigo Abonia, Braulio Insuasty, Jairo Quiroga, Kenneth K Laali, Manuel Nogueras, Justo Cobo

    An efficient, catalyst-free and one-pot three-component procedure for the synthesis of novel and nitrogen rich dihydropyrido[2,3-d]pyrimidines and dihydro-1H-pyrazolo[3,4-b]pyridines bearing a quinoline pharmacophore fragment is provided. Reactions proceeded in DMF under microwave irradiation of three-component mixtures of formyl-quinoline derivatives, primary heterocyclic amines and cyclic 1,3-diketones. Interestingly, when conventional heating at reflux was used for the starting 5-amino-1-phenylpyrazole, the corresponding aromatized pyrazolopyridines were obtained as the main products. Single crystal X-ray analysis confirmed unequivocally the structure of both the dihydro- and aromatized products.

    更新日期:2017-07-20
  • Identification of Biologically Active Pyrimido[5,4-b]indoles That Prolong NF-κB Activation without Intrinsic Activity
    ACS Comb. Sci. (IF 3.168) Pub Date : 2017-07-13
    Michael Chan, Alast Ahmadi, Shiyin Yao, Fumi Sato-Kaneko, Karen Messer, Minya Pu, Brandon Nguyen, Tomoko Hayashi, Maripat Corr, Dennis A. Carson, Howard B. Cottam, Nikunj M. Shukla
    更新日期:2017-07-14
  • 更新日期:2017-07-11
  • A systematic first principles study of binary metal hydrides
    ACS Comb. Sci. (IF 3.168) Pub Date : 2017-07-11
    Natacha Bourgeois, Jean-Claude Crivello, Pierre Cénédèse, Jean-Marc Joubert

    First principles calculations were systematically performed for 31 binary metal-hydrogen (M-H) systems on a set of 30 potential crystal structures selected on the basis of experimental data and possible interstitial sites. For each M-H system, the calculated enthalpies of formation were represented as functions of H composition. The zero point energy correction was considered for the most stable hydrides via additional harmonic phonon calculations. The sequence of stable hydrides (ground-state) given by the convex hull was found in satisfactory agreement with the experimental data. Besides, new high pressure dihydrides and trihydrides were predicted, providing orientations for new materials synthesis. The overall results provide a global overview of hydride relative stabilities and relevant input data for thermodynamic modeling methods.

    更新日期:2017-07-11
  • The Poisson Statistics of Combinatorial Library Sampling Predict False Discovery Rates of Screening
    ACS Comb. Sci. (IF 3.168) Pub Date : 2017-07-06
    Andrew B MacConnell, Brian M Paegel

    Microfluidic droplet-based screening of DNA-encoded one-bead-one-compound combinatorial libraries is a miniaturized, potentially widely distributable approach to small molecule discovery. In these screens, a microfluidic circuit distributes library beads into droplets of activity assay reagent, photochemically cleaves the compound from the bead, then incubates and sorts the droplets based on assay result for subsequent DNA sequencing-based hit compound structure elucidation. Pilot experimental studies revealed that Poisson statistics describe nearly all aspects of such screens, prompting the development of simulations to understand system behavior. Monte Carlo screening simulation data showed that increasing mean library sampling (ε), mean droplet occupancy, or library hit rate all increase the false discovery rate (FDR). Compounds identified as hits on k > 1 beads (the replicate k class) were much more likely to be authentic hits than singletons (k = 1), in agreement with previous findings. Here, we explain this observation by deriving an equation for authenticity, which reduces to the product of a library sampling bias term (exponential in k) and a sampling saturation term (exponential in ε) setting a threshold that the k-dependent bias must overcome. The equation thus quantitatively describes why each hit structure’s FDR is based on its k class, and further predicts the feasibility of intentionally populating droplets with multiple library beads, assaying the micro-mixtures for function, and identifying the active members by statistical deconvolution.

    更新日期:2017-07-11
  • Identification of Biologically Active Pyrimido[5,4-b] indoles that Prolong NF-κB Activation Without Intrinsic Activity
    ACS Comb. Sci. (IF 3.168) Pub Date : 2017-06-28
    Michael Chan, Alast Ahmadi, Shiyin Yao, Fumi Sato-Kaneko, Karen Messer, Minya Pu, Brandon Nguyen, Tomoko Hayashi, Maripat Corr, Dennis Carson, Howard B. Cottam, Nikunj Shukla

    Most vaccine adjuvants directly stimulate and activate antigen presenting cells, but do not sustain immunostimulation of these cells. A high throughput screening (HTS) strategy was designed to identify compounds that would sustain NF-κB activation by a stimulus from toll-like receptor (TLR)4 ligand, lipopolysaccharide (LPS). Several pilot studies optimized the parameters and conditions for a cell based NF-κB reporter assay in human monocytic THP-1 cells. The final assay evaluated prolongation of LPS induced NF-κB activation at 12h (hours). The dynamic range of the assay was confirmed in a pilot screen of 14,631 compounds, and subsequently in a main extensive screen with 166,304 compounds. Hit compounds were identified using an enrichment strategy based on unsupervised chemoinformatic clustering, and also by a naïve ‘Top X’ approach. 2,011 compounds were then rescreened for levels of co-activation with LPS at 5h and 12h, which provided kinetic profiles. Of the 407 confirmed hits, compounds that showed correlation of the kinetic profiles with the structural similarities led to identification of four chemotypes: pyrimido[5,4-b]indoles; 4H-chromene-3-carbonitriles; benzo[d][1,3]dioxol-2-ylureas; and tetrahydrothieno[2,3-c]pyridines, which were segregated by 5h and 12h kinetic characteristics. Unlike the TLR4 agonistic pyrimidoindoles identified in previous studies, the revealed pyrimidoindoles in the present work did not intrinsically stimulate TLR4 nor induce NF-κB, but rather prolonged NF-κB signaling induced by LPS. A 42-member combinatorial library was synthesized which led to identification of potent N3-alkyl substituted pyrimidoindoles that were not only active in vitro but also enhanced antibody responses in vivo when used as a co-adjuvant. The novel HTS strategy led to identification of compounds that are intrinsically quiescent but functionally prolong stimulation by a TLR4 ligand and thereby potentiate vaccine efficacy.

    更新日期:2017-07-11
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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