Abstract:
:DNA-encoded synthesis is rekindling interest in combinatorial compound libraries for drug discovery and in technology for automated and quantitative library screening. Here, we disclose a microfluidic circuit that enables functional screens of DNA-encoded compound beads. The device carries out library bead distribution into picoliter-scale assay reagent droplets, photochemical cleavage of compound from the bead, assay incubation, laser-induced fluorescence-based assay detection, and fluorescence-activated droplet sorting to isolate hits. DNA-encoded compound beads (10-μm diameter) displaying a photocleavable positive control inhibitor pepstatin A were mixed (1920 beads, 729 encoding sequences) with negative control beads (58 000 beads, 1728 encoding sequences) and screened for cathepsin D inhibition using a biochemical enzyme activity assay. The circuit sorted 1518 hit droplets for collection following 18 min incubation over a 240 min analysis. Visual inspection of a subset of droplets (1188 droplets) yielded a 24% false discovery rate (1166 pepstatin A beads; 366 negative control beads). Using template barcoding strategies, it was possible to count hit collection beads (1863) using next-generation sequencing data. Bead-specific barcodes enabled replicate counting, and the false discovery rate was reduced to 2.6% by only considering hit-encoding sequences that were observed on >2 beads. This work represents a complete distributable small molecule discovery platform, from microfluidic miniaturized automation to ultrahigh-throughput hit deconvolution by sequencing.
journal_name
ACS Comb Scijournal_title
ACS combinatorial scienceauthors
MacConnell AB,Price AK,Paegel BMdoi
10.1021/acscombsci.6b00192subject
Has Abstractpub_date
2017-03-13 00:00:00pages
181-192issue
3eissn
2156-8952issn
2156-8944journal_volume
19pub_type
杂志文章abstract::This work presents the first use of yeast-displayed protein targets for screening mRNA-display libraries of cyclic and linear peptides. The WW domains of Yes-Associated Protein 1 (WW-YAP) and mitochondrial import receptor subunit TOM22 were adopted as protein targets. Yeast cells displaying WW-YAP or TOM22 were magnet...
journal_title:ACS combinatorial science
pub_type: 杂志文章
doi:10.1021/acscombsci.0c00171
更新日期:2020-12-14 00:00:00
abstract::This paper describes the synthesis of a 300 member library of 3,5-substituted enones. The synthesis starts with 6 different bromoenones that are accessed from the corresponding 1,3 diones. These bromides are then diversified by Suzuki coupling with a variety of aromatic and vinyl boronic acids. Additionally a small se...
journal_title:ACS combinatorial science
pub_type: 信件
doi:10.1021/co200070m
更新日期:2011-07-11 00:00:00
abstract::Polymer-supported N-(2-oxo-ethyl)-derivatized Ser/Thr/Cys-containing dipeptides were synthesized and subjected to acid-mediated tandem N-acylium ion cyclization-nucleophilic addition to yield tetrahydro-2H-oxazolo[3,2-a]pyrazin-5(3H)-ones. The reaction conditions and building-block combinations for stereoselective syn...
journal_title:ACS combinatorial science
pub_type: 杂志文章
doi:10.1021/co3001567
更新日期:2013-03-11 00:00:00
abstract::A library of functionalized 3-(α-styryl)-benzo[b]thiophenes, endowed with a high level of molecular diversity, was efficiently synthesized by applying a synthetic sequence that allowed introduction of various substituents on aromatic A, B, and C-rings. The strategy developed involves the synthesis of 3-bromobenzo[b]th...
journal_title:ACS combinatorial science
pub_type: 杂志文章
doi:10.1021/co500115b
更新日期:2014-12-08 00:00:00
abstract::A combinatorial library having 66 different ternary compositions of Pd-Ir-Ce was prepared via the impregnation method to find the optimum ternary composition with the highest performance toward oxygen reduction reaction (ORR) in acid media. Its performance in ORR activity of the combinatorial array was evaluated throu...
journal_title:ACS combinatorial science
pub_type: 杂志文章
doi:10.1021/co400008v
更新日期:2013-11-11 00:00:00
abstract::We have implemented an aldol-based "build/couple/pair" (B/C/P) strategy for the synthesis of stereochemically diverse 8-membered lactam and sultam scaffolds via S(N)Ar cycloetherification. Each scaffold contains two handles, an amine and aryl bromide, for solid-phase diversification via N-capping and Pd-mediated cross...
journal_title:ACS combinatorial science
pub_type: 杂志文章
doi:10.1021/co2000218
更新日期:2011-07-11 00:00:00
abstract::A three-component reaction of a 2-aminoazine, a 2-oxoaldehyde, and a cyclic 1,3-dicarbonyl compound providing access toward a novel class of imidazo[1,2-a]azine derivatives was developed and studied. The scope of the process was thoroughly explored under three different reaction conditions resulting in the generation ...
journal_title:ACS combinatorial science
pub_type: 杂志文章
doi:10.1021/co5000695
更新日期:2014-10-13 00:00:00
abstract::An unprecedented three-component C(sp(3))-H functionalization of 2-alkylazaarenes with aryl aldehydes and 4-hydroxycoumarins was realized, providing azaarene-substituted 3-benzyl-4-hydroxycoumarins in good to excellent yields. These new target compounds displayed broad-spectrum antibacterial activities, providing a ne...
journal_title:ACS combinatorial science
pub_type: 杂志文章
doi:10.1021/acscombsci.6b00082
更新日期:2016-09-12 00:00:00
abstract::The development of a scanning reactor for planar catalysts is presented here. With respect to other existing models, this reactor is able to scan catalysts even with low turnover frequencies with a minimum sensed circular area of approximately 6 mm in diameter. The downstream gas analysis is performed with a quaprupol...
journal_title:ACS combinatorial science
pub_type: 杂志文章
doi:10.1021/acscombsci.5b00103
更新日期:2016-01-11 00:00:00
abstract::A novel three-component, two-step, one-pot nucleophilic aromatic substitution (SNAr)-intramolecular cyclization-Suzuki coupling reaction was developed for the synthesis of benzo[h][1,6]naphthyridin-2(1H)-ones (Torins). On the basis of the new efficiently convergent synthetic route, a library of Torin analogs was synth...
journal_title:ACS combinatorial science
pub_type: 杂志文章
doi:10.1021/acscombsci.7b00119
更新日期:2017-12-11 00:00:00
abstract::Disulfide exchange screening is a method for evaluating the binding of small molecule fragments to proteins that have at least one accessible cysteine. While operationally simple, it does require a large library of small fragment molecules bearing disulfide-containing side chains. These specialized fragments are not a...
journal_title:ACS combinatorial science
pub_type: 杂志文章
doi:10.1021/co200038g
更新日期:2011-05-09 00:00:00
abstract::A series of LiMn1-x-yFexVyPO4 (LMFVP) nanomaterials have been synthesized using a pilot-scale continuous hydrothermal synthesis process (CHFS) and evaluated as high voltage cathodes in Li-ion batteries at a production rate of 0.25 kg h-1. The rapid synthesis and screening approach has allowed the specific capacity of ...
journal_title:ACS combinatorial science
pub_type: 杂志文章
doi:10.1021/acscombsci.6b00035
更新日期:2016-11-14 00:00:00
abstract::Thirteen 5-hetarylaminopyrazoles were synthesized in 62-93% yield through the arylation of 1-isopropyl- and 1-phenyl-5-aminopyrazoles with electrophilic hetarylhalides under optimized conditions. Condensation of 5-hetarylaminopyrazoles with carbonyl compounds facilitated by AcOH or Me(3)SiCl furnished 23 pyrazolo[3,4-...
journal_title:ACS combinatorial science
pub_type: 杂志文章
doi:10.1021/co300063x
更新日期:2012-08-13 00:00:00
abstract::A combination of flow and batch chemistries has been successfully applied to the assembly of a series of trisubstituted drug-like pyrrolidines. This study demonstrates the efficient preparation of a focused library of these pharmaceutically important structures using microreactor technologies, as well as classical par...
journal_title:ACS combinatorial science
pub_type: 杂志文章
doi:10.1021/co2000357
更新日期:2011-07-11 00:00:00
abstract::A new one-pot, three component reaction involving the use of Julia reagent, aldehyde, and sodium azide was developed for the efficient synthesis of N-unsubstituted 1,2,3-triazoles. This reaction could be carried out under mild reaction conditions without any precaution, and broad scope of substrates, both respect to J...
journal_title:ACS combinatorial science
pub_type: 杂志文章
doi:10.1021/co5001597
更新日期:2015-03-09 00:00:00
abstract::A Fe-Co-Nb thin film materials library was deposited by combinatorial magnetron sputtering and investigated by high-throughput methods to identify new noncubic ferromagnetic phases, indicating that combinatorial experimentation is an efficient method to discover new ferromagnetic phases adequate for permanent magnet a...
journal_title:ACS combinatorial science
pub_type: 杂志文章
doi:10.1021/acscombsci.5b00116
更新日期:2015-11-09 00:00:00
abstract::A one-bead one-compound (OBOC) library of peptide-based imaging agents was developed where a 19F-containing moiety was added onto the N-terminus of octamer peptides through copper-free click chemistry prior to screening of the library. This created a library of complete imaging agents that was screened against CXCR4, ...
journal_title:ACS combinatorial science
pub_type: 杂志文章
doi:10.1021/acscombsci.9b00146
更新日期:2020-03-09 00:00:00
abstract::Magnetization using cheap and minimally toxic materials, such as iron oxide nanoparticles can enable easy separation of cells from culture medium and is relevant to several industrial applications. Here, we show that cell surface expression of a mutant protein that binds iron oxide can enable efficient magnetization o...
journal_title:ACS combinatorial science
pub_type: 杂志文章
doi:10.1021/acscombsci.8b00084
更新日期:2018-10-08 00:00:00
abstract::Optical bandgap mapping of Nb-Ti mixed oxides anodically grown on a thin film parent metallic combinatorial library was performed via variable angle spectroscopic ellipsometry (VASE). A wide Nb-Ti compositional spread ranging from Nb-90 at.% Ti to Nb-15 at.% Ti deposited by cosputtering was used for this purpose. The ...
journal_title:ACS combinatorial science
pub_type: 杂志文章
doi:10.1021/acscombsci.6b00162
更新日期:2017-02-13 00:00:00
abstract::A novel parallel medicinal chemistry (PMC)-enabled synthesis of 1H-pyrazolo[3,4-d]pyrimidines employing condensation of easily accessible N-pyrazolylamides and nitriles has been developed. The presented studies describe singleton and library enablements that allowed rapid generation of molecular diversity to examine C...
journal_title:ACS combinatorial science
pub_type: 杂志文章
doi:10.1021/acscombsci.7b00116
更新日期:2017-11-13 00:00:00
abstract::Unfunctionalized alkylbiphenyls were fabricated by a parallel and combinatorial synthesis using pentaerythritol as a tetrapodal soluble support for a sulfonate-based traceless multifunctional linker system. Nickel N-heterocyclic carbene-catalyzed reactions of pentaerythritol tetrakis(biphenylsulfonate)s with primary a...
journal_title:ACS combinatorial science
pub_type: 杂志文章
doi:10.1021/co400136k
更新日期:2014-05-12 00:00:00
abstract::Functionalized chromenes have been synthesized via highly selective metal-free domino reactions from ketones and phenols. 2H-Chromenes, 4H-chromenes, spiran and benzocyclopentane can be respectively prepared starting from the corresponding cyclic ketones, aryl methyl ketones, acetone, and 3-pentanone. ...
journal_title:ACS combinatorial science
pub_type: 杂志文章
doi:10.1021/co3000506
更新日期:2012-08-13 00:00:00
abstract::When isolating binders from yeast displayed combinatorial libraries, a soluble, recombinantly expressed form of the target protein is typically utilized. As an alternative, we describe the use of target proteins displayed as surface fusions on magnetized yeast cells. In our strategy, the target protein is coexpressed ...
journal_title:ACS combinatorial science
pub_type: 杂志文章
doi:10.1021/acscombsci.9b00147
更新日期:2019-12-09 00:00:00
abstract::The Au-Al alloy system was investigated via a combinatorial thin film sputtering method for its potential as a plasmonic material. Au xAl1- x combinatorial libraries were cosputtered from Au and Al elemental targets and the composition, phase, and dielectric function of a ∼350 nm film was determined using energy dispe...
journal_title:ACS combinatorial science
pub_type: 杂志文章
doi:10.1021/acscombsci.8b00091
更新日期:2018-11-12 00:00:00
abstract::Cr-Al-N thin film materials libraries were synthesized by combinatorial reactive high power impulse magnetron sputtering (HiPIMS). Different HiPIMS repetition frequencies and peak power densities were applied altering the ion to growth flux ratio. Moreover, time-resolved ion energy distribution functions were measured...
journal_title:ACS combinatorial science
pub_type: 杂志文章
doi:10.1021/acscombsci.9b00123
更新日期:2019-12-09 00:00:00
abstract::Yeast surface display empowers selection of protein binding ligands, typically using recombinant soluble antigens. However, ectodomain fragments of transmembrane targets may fail to recapitulate their true, membrane-bound form. Direct selections against adhered mammalian cells empower enrichment of genuine binders yet...
journal_title:ACS combinatorial science
pub_type: 杂志文章
doi:10.1021/acscombsci.0c00036
更新日期:2020-05-11 00:00:00
abstract::Solid-phase synthetic strategies toward the generation of libraries of biologically relevant molecules were developed using olefin cross-metathesis as a key step. It is remarkably the formal alkane metathesis based on a one-pot, microwave-assisted, ruthenium-catalyzed cross-metathesis and reduction to obtain Csp3-Csp3...
journal_title:ACS combinatorial science
pub_type: 杂志文章
doi:10.1021/co500176b
更新日期:2015-02-09 00:00:00
abstract::An efficient discovery strategy by combining diversity-oriented synthesis and converging cellular screening is described. By a three-round screening process, we identified novel tricyclic pyrido[2,3-b][1,4]benzothiazepines showing potent inhibitory activity against paclitaxel-resistant cell line H460TaxR (EC50 < 1.0 μ...
journal_title:ACS combinatorial science
pub_type: 杂志文章
doi:10.1021/acscombsci.6b00010
更新日期:2016-05-09 00:00:00
abstract::Dispiro-pyrrolidino/pyrrolizidino fused oxindoles/acenaphthoquinones have been derived from andrographolide via azomethine ylide cycloaddition to the conjugated double-bond under microwave (MW) irradiation. The reactions are chemo-, stereo-, and regioselective in nature. Change in amino acid from sarcosine/N-benzyl gl...
journal_title:ACS combinatorial science
pub_type: 杂志文章
doi:10.1021/co3001154
更新日期:2013-01-14 00:00:00
abstract::A fast and facile synthesis of a series of 4-nitrophenyl 2-azidoethylcarbamate derivatives as activated urea building blocks was developed. The N-Fmoc-protected 2-aminoethyl mesylates derived from various commercially available N-Fmoc-protected α-amino acids, including those having functionalized side chains with acid...
journal_title:ACS combinatorial science
pub_type: 杂志文章
doi:10.1021/acscombsci.6b00160
更新日期:2017-03-13 00:00:00