Analysis and screening of combinatorial libraries using mass spectrometry

Shin, Young Geun; Breemen, Richard B. van

doi:10.1002/bdd.278

Cited by 60 publications

(49 citation statements)

References 71 publications

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“…Target-ligand interactions (so-called 'hits') are unambiguously identified in the absence of confounding variables. For example, fluorescent-based methods for detecting the LIGAND-INDUCED CONFORMATIONAL STABILIZATION of proteins 14 or MASS-SPECTROMETRY-based detection systems 15,16 have been described as a means to examine the effect of bound ligands. By contrast, cell-based and organismal assays -in which selected compounds are delivered directly to cells or organisms in vitro -identify hits within a relevant cellular context, but, because of the interaction with multiple targets, hits require additional mechanistic characterization.…”

Section: Lead Optimizationmentioning

confidence: 99%

Chemogenomics: an emerging strategy for rapid target and drug discovery

2004

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Section: Lead Optimizationmentioning

confidence: 99%

Chemogenomics: an emerging strategy for rapid target and drug discovery

2004

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“…T he speed and sensitivity of modem mass spectrometers make them attractive tools for high throughput screening (HTS) assays, and several mass spectrometry-based HTS assays have been developed in recent years [1][2][3]. We recently reported on a mass spectrometry-based assay for protein-ligand binding detection that utilizes an abbreviated version of stability of unpurified j;!roteins by rates of H/D exchange (SUPREX), which is an H/D exchange-and mass spectrometry-based technique capable of detecting and quantifying protein-ligand binding interactions [4][5][6][7][8][9].…”

mentioning

confidence: 99%

Throughput and efficiency of a mass spectrometry-based screening assay for protein—Ligand binding detection

Hopper

Roulhac

Campa

et al. 2008

J. Am. Soc. Mass Spectrom.

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An H/D exchange-and MALDI mass spectrometry-based screening assay was applied to search for novel ligands that bind to cyclophilin A, a potential therapeutic and diagnostic target in lung cancer. The assay is based on stability of unpurified j;!roteins from rates of H/D exchange (SUPREX), which exploits the H/D exchange properties of amide protons to measure the increase in a protein's thermodynamic stability upon ligand binding in solution.The current study evaluates the throughput and efficiency with which 880 potential ligands from the Prestwick Chemical Library (Illkirch, France) could be screened for binding to cyclophilin A. Screening was performed at a rate of 3 min/ligand using a conventional MALDI mass spectrometer. False positive and false negative rates, based on a set of control data, were as low as 0% and 9%, respectively. Based on the 880-member library screening, a false positive rate of 0% was observed when a two-tier selection strategy was implemented. Although novel ligands for cyclophilin A were not discovered, cyclosporin A, a known ligand to CypA and a blind control in the library, was identified as a hit. We also describe a new strategy to eliminate some of the complications related to back exchange that can arise in screening applications of SUPREX. (J

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“…Mass spectrometry (MS), especially tandem mass spectrometry (MS/MS), has been one of the important physicochemical methods for the identification of trace natural products due to its rapidity, sensitivity, and low levels of sample consumption, [10][11][12][13] and some benzofuran derivatives have been rapidly analyzed using electrospray ionization (ESI)-MS. 14,15 Seeds of the Styracaceae family are known to contain various benzofuran derivatives. [16][17][18][19][20] In our laboratory, a series of benzofuran derivatives ( Fig.…”

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confidence: 99%

Analysis of benzofuran derivatives using electrospray ionization ion trap and electrospray ionization quadrupole time‐of‐flight mass spectrometry

Han²,

Chen

et al. 2010

Rapid Comm Mass Spectrometry

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Analysis of benzofuran derivatives using electrospray ionization ion trap and electrospray ionization quadrupole time-of-flight mass spectrometry Benzofurans and their analogues constitute a major group of naturally occurring compounds 1 and exhibit anti-tumor activity, 2 anti-complement activity, 3 cytotoxic activity, 4 activity against human leukaemic cells, 5 and antifungal and antibacterial activity. 6,7 Their broad range of biological activities has attracted the attention of synthetic organic chemists, 8,9 and such potential applications point to the need for reliable, fast and low-cost analysis of this class of compounds.Mass spectrometry (MS), especially tandem mass spectrometry (MS/MS), has been one of the important physicochemical methods for the identification of trace natural products due to its rapidity, sensitivity, and low levels of sample consumption, 10-13 and some benzofuran derivatives have been rapidly analyzed using electrospray ionization (ESI)-MS. 14,15 Seeds of the Styracaceae family are known to contain various benzofuran derivatives. [16][17][18][19][20] In our laboratory, a series of benzofuran derivatives ( Fig. 1) was isolated from Styrax perkinsiae and Styrax macranthus 4,18 and, to our knowledge, these compounds have not been studied by ESI-MS/MS. To obtain information on the structural elucidation of this class of compounds, such as their degradation products, metabolites and biosynthesis intermediates, the detailed fragmentation patterns of benzofuran derivatives were studied using ESI-MS n in positive ion mode. For several representative benzofuran derivatives, the elemental compositions of most of the product ions were confirmed by low-energy ESI-MS/MS using a quadrupole time-of-flight (QTOF) instrument.HPLC-grade methanol was purchased from Fisher Scientific (Pittsburgh, PA, USA). The MS n experiments were performed on a Esquire 6000 ion trap (IT) mass spectrometer (Bruker, Bremen, Germany). The capillary voltage was set at 4 kV and the source temperature was maintained at 3008C. High-purity nitrogen gas was used as the nebulizer gas at a pressure of 20 psi. Tandem mass spectra were obtained by collision-induced dissociation (CID) of selected precursor ions with helium as the collision gas, by applying collision voltages between 0.3 and 0.5 V. High-resolution experiments were performed on a Bruker micrOTOF Q (quadrupole time-of-flight) mass spectrometer in positive ion mode. The Agilent (Agilent Technologies, Santa Clara, CA, USA) ESI-MS tuning mixture (ES Tuning Mix, PN G2421A), with reference masses at m/z 322.0481, 622.0290 and 922.0098, was used to calibrate the instrument in positive ion mode. Helium was used as the collision gas and highpurity nitrogen as the nebulizer and drying gas at a pressure of 30 psi. The samples were introduced into the mass spectrometer at a flow rate of 115 mL/h. The ESI source conditions were as follows: capillary voltage, À4500 V; end plate voltage, À4000 V; capillary exit voltage, 120 V; and drying gas temperature, 1508C. The collision energ...

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Analysis and screening of combinatorial libraries using mass spectrometry

Cited by 60 publications

References 71 publications

Chemogenomics: an emerging strategy for rapid target and drug discovery

Chemogenomics: an emerging strategy for rapid target and drug discovery

Throughput and efficiency of a mass spectrometry-based screening assay for protein—Ligand binding detection

Analysis of benzofuran derivatives using electrospray ionization ion trap and electrospray ionization quadrupole time‐of‐flight mass spectrometry

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