Connecting synthetic chemistry decisions to cell and genome biology using small-molecule phenotypic profiling
- PMID: 19825513
- PMCID: PMC2787914
- DOI: 10.1016/j.cbpa.2009.09.018
Connecting synthetic chemistry decisions to cell and genome biology using small-molecule phenotypic profiling
Abstract
Discovering small-molecule modulators for thousands of gene products requires multiple stages of biological testing, specificity evaluation, and chemical optimization. Many cellular profiling methods, including cellular sensitivity, gene expression, and cellular imaging, have emerged as methods to assess the functional consequences of biological perturbations. Cellular profiling methods applied to small-molecule science provide opportunities to use complex phenotypic information to prioritize and optimize small-molecule structures simultaneously against multiple biological endpoints. As throughput increases and cost decreases for such technologies, we see an emerging paradigm of using more information earlier in probe-discovery and drug-discovery efforts. Moreover, increasing access to public datasets makes possible the construction of 'virtual' profiles of small-molecule performance, even when multiplexed measurements were not performed or when multidimensional profiling was not the original intent. We review some key conceptual advances in small-molecule phenotypic profiling, emphasizing connections to other information, such as protein-binding measurements, genetic perturbations, and cell states. We argue that to maximally leverage these measurements in probe-discovery and drug-discovery requires a fundamental connection to synthetic chemistry, allowing the consequences of synthetic decisions to be described in terms of changes in small-molecule profiles. Mining such data in the context of chemical structure and synthesis strategies can inform decisions about chemistry procurement and library development, leading to optimal small-molecule screening collections.
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References
-
- An WF, Tolliday NJ. Introduction: cell-based assays for high-throughput screening. Methods Mol Biol. 2009;486:1–12. - PubMed
-
- Clemons PA. Complex phenotypic assays in high-throughput screening. Curr Opin Chem Biol. 2004;8:334–338. - PubMed
-
- Schriemer DC, Kemmer D, Roberge M. Design of phenotypic screens for bioactive chemicals and identification of their targets by genetic and proteomic approaches. Comb Chem High Throughput Screen. 2008;11:610–616. - PubMed
-
- Terstappen GC, Schlupen C, Raggiaschi R, Gaviraghi G. Target deconvolution strategies in drug discovery. Nat Rev Drug Discov. 2007;6:891–903. - PubMed
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