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Target identification and mechanism of action in chemical biology and drug discovery

Abstract

Target-identification and mechanism-of-action studies have important roles in small-molecule probe and drug discovery. Biological and technological advances have resulted in the increasing use of cell-based assays to discover new biologically active small molecules. Such studies allow small-molecule action to be tested in a more disease-relevant setting at the outset, but they require follow-up studies to determine the precise protein target or targets responsible for the observed phenotype. Target identification can be approached by direct biochemical methods, genetic interactions or computational inference. In many cases, however, combinations of approaches may be required to fully characterize on-target and off-target effects and to understand mechanisms of small-molecule action.

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Figure 1: Mechanism-of-action and target identification in chemical genetics.
Figure 2: Illustration of stable isotope labeling and quantitative MS.
Figure 3: Illustrations of yeast genomic methods for target-identification and mechanism-of-action studies.
Figure 4: Illustrations of RNAi-based methods for target-identification and mechanism-of-action studies.
Figure 5: Illustration of computational inference methods for target-identification and mechanism-of-action studies.
Figure 6: Illustration of a conceptual workflow for integrated target-identification and mechanism-of-action studies.

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Acknowledgements

This work was supported by US National Institutes of Health Genomics Based Drug Discovery–Target ID Project grant RL1HG004671, which is administratively linked to the US National Institutes of Health grants RL1CA133834, RL1GM084437 and UL1RR024924.

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Correspondence to Paul A Clemons.

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Schenone, M., Dančík, V., Wagner, B. et al. Target identification and mechanism of action in chemical biology and drug discovery. Nat Chem Biol 9, 232–240 (2013). https://doi.org/10.1038/nchembio.1199

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