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1 March 2001 High throughput synthesis and screening: the partner of genomics for discovery of new chemicals for agriculture
F. Dan Hess, Richard J. Anderson, Jeff D. Reagan
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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.

Nomenclature: Agriculture; discovery; genomics; high-throughput synthesis; new chemicals; screening.

F. Dan Hess, Richard J. Anderson, and Jeff D. Reagan "High throughput synthesis and screening: the partner of genomics for discovery of new chemicals for agriculture," Weed Science 49(2), 249-256, (1 March 2001).[0249:HTSAST]2.0.CO;2
Received: 22 May 2000; Accepted: 13 November 2000; Published: 1 March 2001
Combinatorial chemistry
mix-and-split synthesis
parallel synthesis
split-pool synthesis
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