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Review
. 2006 Jul;11(13-14):661-8.
doi: 10.1016/j.drudis.2006.05.002.

Chemical microarray: a new tool for drug screening and discovery

Haiching Ma  1 , Kurumi Y Horiuchi
Affiliations
Review

Chemical microarray: a new tool for drug screening and discovery

Haiching Ma et al. Drug Discov Today. 2006 Jul.

Abstract

HTS with microtiter plates has been the major tool used in the pharmaceutical industry to explore chemical diversity space and to identify active compounds and pharmacophores for specific biological targets. However, HTS faces a daunting challenge regarding the fast-growing numbers of drug targets arising from genomic and proteomic research, and large chemical libraries generated from high-throughput synthesis. There is an urgent need to find new ways to profile the activity of large numbers of chemicals against hundreds of biological targets in a fast, low-cost fashion. Chemical microarray can rise to this challenge because it has the capability of identifying and evaluating small molecules as potential therapeutic reagents. During the past few years, chemical microarray technology, with different surface chemistries and activation strategies, has generated many successes in the evaluation of chemical-protein interactions, enzyme activity inhibition, target identification, signal pathway elucidation and cell-based functional analysis. The success of chemical microarray technology will provide unprecedented possibilities and capabilities for parallel functional analysis of tremendous amounts of chemical compounds.

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Figures

Figure 1
Figure 1
Small-molecule microarray. Chemical compounds synthesized with the same linking functional group are arrayed and covalently immobilized on the surface of microarray chips using a standard microarrayer. Biological targets in cell lysates or in purified forms are added to the chips, this is followed by several washing steps to eliminate non-specific and weak binding. The compounds that bind to the target with high affinity are then identified by immunoassays (the chemical structures shown in all figures are for illustration purposes only).
Figure 2
Figure 2
Fragment chemical microarray. Thousands of chemical fragments are synthesized and immobilized on microarrays, then coated with a thin layer of gold. After treating the chips with target proteins, a surface plasmon resonance (SPR)-based Plasmon Imager® is used to record the mass change when soluble proteins bind immobilized chemicals. Wavelength shifts in SPR corresponding to the amount of protein binding to the chemical surface, creating protein–ligand affinity fingerprints. After SAR analysis, the first generation of drug-like compounds and analogs are synthesized and tested, and lead candidates will then be further optimized.
Figure 3
Figure 3
Dry chemical microarray. Chemical compounds are arrayed and dried on polystyrene sheets that have the same footprint as a 384-well plate. An agarose gel embedded with enzyme and substrate is applied to the surface of the array. After a short incubation, a second gel containing radioactive ATP is applied to initiate the biological reaction. The final reactions are detected using a standard phosphorimager.
Figure 4
Figure 4
Solution-phase chemical microarray. Existing chemical compounds in assay buffer containing dimethyl sulfoxide (DMSO) and 10% glycerol are arrayed on the surface of the microarray. The compounds are always in solution without any chemical linking to the microarray. For homogeneous reactions, the biological target and substrate are added into each reaction dot by aerosol deposition technology, and, in the case of kinases, the reactions are initiated by spraying on ATP. The reaction products are detected by a laser scanner or imager. For heterogeneous ELISA-based reactions, such as kinase assays using whole proteins as substrates, the substrate is immobilized on the microarray surface first, before compounds are microarrayed. The kinase is then sprayed on to the array and the reactions initiated by spraying on ATP. The reactions are then detected by conventional ELISA protocols.
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