Improved Methods for Encoding and Decoding Dialkylamine-Encoded Combinatorial Libraries

Fitch, William L.; Baer, Ted A.; Chen, Weiwei; Holden, Frank; Holmes, Christopher P.; Maclean, Derek; Shah, Nikhil; Sullivan, Edward; Tang, and Michael; Waybourn, Phaedra; and, Steven M. Fischer; Miller, Christine; Snyder, Lloyd R.

doi:10.1021/cc990001r

Cited by 34 publications

(18 citation statements)

References 8 publications

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“…Chemical encoding is ideal for OBOC non-sequenceable libraries. Therefore various chemical encoding methods, such as using fluorophenyl ether tags [48,49], peptide tags [50,51] and secondary amine tags [52,53] have been developed. Several reviews on this subject have been published [20, 54 -57].…”

Section: A Peptide-based Encoding Methodsmentioning

confidence: 99%

Development and Applications of Topologically Segregated Bilayer Beads in One-bead One-compound Combinatorial Libraries

Liu¹,

Wang²,

Song³

et al. 2005

QSAR Comb. Sci.

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Using a "split -mix" synthesis approach, "One-Bead One-Compound" (OBOC) combinatorial libraries can be generated such that each bead displays only one chemical entity.Tens of thousands to millions of compound-beads can be screened concurrently using a variety of biochemical and cell-based screening methods. Positive beads are then physically isolated for structure determination. Peptide beads or peptoid beads consisting of a-amino acids and with a free N-terminus can be routinely sequenced by an automatic microsequencer using Edman chemistry. Libraries with N-terminally blocked peptides, peptides with unsequenceable building blocks, or small molecules require encoding. To fully exploit the OBOC combinatorial library methods, we have developed topologically segregated bilayer beads. Such bilayer beads allow us to prepare library compound on the outer layer of each bead and the coding tags in the bead interior. In addition, we can use these bilayer beads to prepare OBOC combinatorial libraries that are down-substituted on the bead surface but fully substituted in the bead interior. This configuration enables one to screen at a much higher stringency and yet have enough peptides or coding tags retained in the bead interior for structure determination.

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Section: A Peptide-based Encoding Methodsmentioning

confidence: 99%

Development and Applications of Topologically Segregated Bilayer Beads in One-bead One-compound Combinatorial Libraries

Liu¹,

Wang²,

Song³

et al. 2005

QSAR Comb. Sci.

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“…17.1 b). These tags may be oligonucleotides (Needels et al, 1993), electrophoretic molecular tags (Ohlmeyer et al, 1993), cleavable dialkylamine tags (Fitch et al, 1999) or trityl mass-tags (Shchepinov et al, 1999). How- Zhou et al (2001) ever, additional chemical steps are needed to synthesize the tags on the beads, and artifacts may arise as a result of interfering chemistries between the compound synthesis and the tag synthesis.…”

Section: Encoding Colloids For Combinatorial Librariesmentioning

confidence: 99%

Colloids for Encoding Chemical Libraries: Applications in Biological Screening

Battersby

Grøndahl

Lawrie

et al. 2003

Colloids and Colloid Assemblies

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Screening with MicroarraysMicroarrays are sophisticated tools for applications such as gene expression monitoring of known and unknown genes, genotyping of eukaryotes, micro-organisms and viruses, mutation detection and analysis, antibody-based assays for protein and small molecule analytes (e.g. glycoprotein hormones, steroid hormones, allergen antibodies). Production of microarray devices has become well defined and automated and they are generally created in two formats. In Format I, an array of 17.2 Current High-throughput Screening Technologies 511 1

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“…For each bead, there is a unique correspondence of tag and test compound. The nature of the tagging system has been described recently by Fitch et al (1999).…”

Section: Chemistrymentioning

confidence: 99%

High throughput synthesis and screening: the partner of genomics for discovery of new chemicals for agriculture

2001

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As new targets for herbicide action are identified from genomics research, large and diverse chemical collections and high-throughput assays will be required to maximize the probability of identifying compounds with activity at these targets. The new technology of combinatorial synthesis and high-throughput, miniaturized, in vitro screening, which has become an integral part of pharmaceutical discovery, is now being applied to discover new herbicides, insecticides, and fungicides. Depending on the synthesis design, the products of a combinatorial synthesis, referred to as a library, may be either unbiased or biased toward an intended target. Unbiased libraries are generally prepared to maximize chemical diversity around a central core structure or scaffold. Often containing 10,000 to 30,000 compounds each, these libraries are encoded and prepared by a combinatorial methodology known as mix-and-split, which produces compounds as mixtures. The preparation of these large libraries requires robust synthetic methodology that will accommodate reactants (building blocks) with diverse structures. Biased libraries tend to be smaller in size, ranging from 100 to 2,500 compounds. They are prepared using synthetic methodology that produces collections of discrete compounds (parallel synthesis) or pools of five to 10 compounds per pool (mix-and-split synthesis). Compounds in biased libraries are rationally designed to contain structural motifs or pharmacophores that are presumed to be beneficial for activity on the intended target. Screening is conducted in microtiter assay plates containing from 96 to 864 wells per plate. For in vitro assays, high-density formats (864 wells per plate) are preferred. The higher density format allows for testing higher concentrations and fewer compounds per well, which leads to a more rapid identification of the active molecules. For in vivo assays, 96-well formats are preferred. Regardless of the microtiter plate format, multiple beads are distributed into plates by robotic pipetting, and single beads are distributed via robot-controlled suction pipets. Test compounds are cleaved from the beads and transferred in solvent to assay plates. Required reagents are added to the plate to initiate the assay. A wide range of in vitro and in vivo herbicide, insecticide, and fungicide assays can be conducted in microtiter plates.

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Improved Methods for Encoding and Decoding Dialkylamine-Encoded Combinatorial Libraries

Cited by 34 publications

References 8 publications

Development and Applications of Topologically Segregated Bilayer Beads in One-bead One-compound Combinatorial Libraries

Development and Applications of Topologically Segregated Bilayer Beads in One-bead One-compound Combinatorial Libraries

Colloids for Encoding Chemical Libraries: Applications in Biological Screening

High throughput synthesis and screening: the partner of genomics for discovery of new chemicals for agriculture

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