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Bioorg Med Chem. 2012 Mar 15;20(6):1929-39. doi: 10.1016/j.bmc.2011.10.088. Epub 2012 Jan 17.

Determining the mode of action of bioactive compounds.

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M.G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences and the Department of Chemistry, McMaster University, Hamilton, Ontario, Canada L8N 3Z5.


Matching bioactive molecules with molecular targets is key to understanding their modes of action (MOA). Moving beyond the mere discovery of drugs, investigators are now just beginning to integrate both biochemical and chemical-genetic approaches for MOA studies. Beginning with simple screens for changes in cell phenotype upon drug treatment, drug bioactivity has been traditionally explored with affinity chromatography, radiolabeling, and cell-based affinity tagging procedures. However, such approaches can present an oversimplified view of MOA, especially in light of the recent realization of the extent of polypharmacology and the unexpected complexity of drug-target interactions. With the advent of more sophisticated tools for genetic manipulation, a flood of powerful techniques has been used to create characteristic drug MOA 'fingerprints'. In particular, whole genome expression profiling and deletion and overexpression libraries have greatly enhanced our understanding of bioactive compounds in vivo. Here we highlight challenges and advances in studying bioactive compound-target interactions.

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