Abstract
Small organic molecules have proven to be invaluable tools for investigating biological systems, but there is still much to learn from their use. To discover and to use more effectively new chemical tools to understand biology, strategies are needed that allow us to systematically explore ‘biological-activity space’. Such strategies involve analysing both protein binding of, and phenotypic responses to, small organic molecules. The mapping of biological-activity space using small molecules is akin to mapping the stars — uncharted territory is explored using a system of coordinates that describes where each new feature lies.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Brenner, S. The genetics of Caenorhabditis elegans. Genetics 77, 71–94 (1974).
Hartwell, L. H. Twenty-five years of cell cycle genetics. Genetics 4, 975–80 (1991).
Stockwell, B. R. Chemical genetics: ligand-based discovery of gene function. Nature Rev. Genet. 1, 116–25 (2000).
Stockwell, B. R. Frontiers in chemical genetics. Trends Biotechnol. 18, 449–455 (2000).
Stockwell, B. R. Chemical genetic screening approaches to neurobiology. Neuron 36, 559–562 (2002).
Schreiber, S. L. The small-molecule approach to biology: chemical genetics and diversity-oriented organic synthesis make possible the systematic exploration of biology. Chem. Eng. News 81, 51–61 (2003).
Schreiber, S. L. Chemical genetics resulting from a passion for synthetic organic chemistry. Bioorg. Med. Chem. 6, 1127–1152 (1998).
Kuruvilla, F. G., Shamji, A. F., Sternson, S. M., Hergenrother, P. J. & Schreiber, S. L. Dissecting glucose signalling with diversity-oriented synthesis and small-molecule microarrays. Nature 416, 653–657 (2002).
Hannon, G. J. RNA interference. Nature 418, 244–251 (2002).
Moore, P. & Clayton, J. To affinity and beyond. Nature 426, 725–731 (2003).
Schreiber, S. L. Target-oriented and diversity-oriented organic synthesis in drug discovery. Science 287, 1964–1969 (2000).
Young, S. S. & Ge, N. Design of diversity and focused combinatorial libraries in drug discovery. Curr. Opin. Drug Discov. Dev. 7, 318–324 (2004).
Jimonet, P. & Jager, R. Strategies for designing GPCR-focused libraries and screening sets. Curr. Opin. Drug Discov. Dev. 7, 325–333 (2004).
Reid, R. C. et al. Countering cooperative effects in protease inhibitors using constrained beta-strand-mimicking templates in focused combinatorial libraries. J. Med. Chem. 47, 1641–1651 (2004).
Sodeoka, M. et al. Synthesis of a tetronic acid library focused on inhibitors of tyrosine and dual-specificity protein phosphatases and its evaluation regarding VHR and cdc25B inhibition. J. Med. Chem. 44, 3216–3222 (2001).
Stahura, F. L., Xue, L., Godden, J. W. & Bajorath, J. Molecular scaffold-based design and comparison of combinatorial libraries focused on the ATP-binding site of protein kinases. J. Mol. Graph Model 17, 1–9, 51–2 (1999).
Burke, M. D. & Schreiber, S. L. A planning strategy for diversity-oriented synthesis. Angew. Chem. Int. Edn Engl. 43, 46–58 (2004).
Spring, D. R. Diversity-oriented synthesis; a challenge for synthetic chemists. Org. Biomol. Chem. 1, 3867–3870 (2003).
Kubota, H., Lim, J., Depew, K. M. & Schreiber, S. L. Pathway development and pilot library realization in diversity-oriented synthesis: exploring Ferrier and Pauson-Khand reactions on a glycal template. Chem. Biol. 9, 265–276 (2002).
Couve-Bonnaire, S., Chou, D. T., Gan, Z. & Arya, P. A solid-phase, library synthesis of natural-product-like derivatives from an enantiomerically pure tetrahydroquinoline scaffold. J. Comb. Chem. 6, 73–77 (2004).
Arya, P., Wei, C. Q., Barnes, M. L. & Daroszewska, M. A solid phase library synthesis of hydroxyindoline-derived tricyclic derivatives by Mitsunobu approach. J. Comb. Chem. 6, 65–72 (2004).
Kauvar, L. M., Villar, H. O., Sportsman, J. R., Higgins, D. L. & Schmidt, D. E. J. Protein affinity map of chemical space. J. Chromatog. B 715, 93–102 (1998).
Greenbaum, D. C. et al. Small molecule affinity fingerprinting. A tool for enzyme family subclassification, target identification, and inhibitor design. Chem. Biol. 9, 1085–1094 (2002).
Weinstein, J. N. et al. An information-intensive approach to the molecular pharmacology of cancer. Science 275, 343–349 (1997).
Lakey, J. H. & Raggett, E. M. Measuring protein–protein interactions. Curr. Opin. Struct. Biol. 8, 119–123 (1998).
Gray, N. S. et al. Exploiting chemical libraries, structure, and genomics in the search for kinase inhibitors. Science 281, 533–538 (1998).
Salemme, F. R. Chemical genomics as an emerging paradigm for postgenomic drug discovery. Pharmacogenomics 4, 257–267 (2003).
MacBeath, G., Koehler, A. N. & Schreiber, S. L. Printing small molecules as microarrays and detecting protein–ligand interactions en masse. J. Am. Chem. Soc. 121, 7967–7968 (1999).
Winssinger, N., Ficarro, S., Schultz, P. G. & Harris, J. L. Profiling protein function with small molecule microarrays. Proc. Natl Acad. Sci. USA 99, 11139–11144 (2002).
Falsey, J. R., Renil, M., Park, S., Li, S. & Lam, K. S. Peptide and small molecule microarray for high throughput cell adhesion and functional assays. Bioconjug. Chem. 12, 346–353 (2001).
Vetter, D. Chemical microarrays, fragment diversity, label-free imaging by plasmon resonance—a chemical genomics approach. J. Cell Biochem. 39 (suppl.), 79–84 (2002).
Birkert, O., Tunnemann, R., Jung, G. & Gauglitz, G. Label-free parallel screening of combinatorial triazine libraries using reflectometric interference spectroscopy. Anal. Chem. 74, 834–840 (2002).
Birkert, O. & Gauglitz, G. Development of an assay for label-free high-throughput screening of thrombin inhibitors by use of reflectometric interference spectroscopy. Anal. Bioanal. Chem. 372, 141–147 (2002).
Jona, G. & Snyder, M. Recent developments in analytical and functional protein microarrays. Curr. Opin. Mol. Ther. 5, 271–277 (2003).
MacBeath, G. Protein microarrays and proteomics. Nature Genet. 32 (suppl.), 526–532 (2002).
Zhu, H. et al. Global analysis of protein activities using proteome chips. Science 293, 2101–2105 (2001).
Espejo, A., Cote, J., Bednarek, A., Richard, S. & Bedford, M. T. A protein-domain microarray identifies novel protein-protein interactions. Biochem. J. 367, 697–702 (2002).
Newman, J. R. & Keating, A. E. Comprehensive identification of human bZIP interactions with coiled-coil arrays. Science 300, 2097–2101 (2003).
Ziauddin, J. & Sabatini, D. M. Microarrays of cells expressing defined cDNAs. Nature 411, 107–110 (2001).
Ramachandran, N. et al. Self-assembling protein microarrays. Science 305, 86–90 (2004).
Lefurgy, S. & Cornish, V. Finding Cinderella after the ball: a three-hybrid approach to drug target identification. Chem. Biol. 11, 151–153 (2004).
Liberles, S. D., Diver, S. T., Austin, D. J. & Schreiber, S. L. Inducible gene expression and protein translocation using nontoxic ligands identified by a mammalian three-hybrid screen. Proc. Natl Acad. Sci. USA 94, 7825–7830 (1997).
Lunn, M. R. et al. Indoprofen upregulates the survival motor neuron protein through a cyclooxygenase-independent mechanism. Chem. Biol. 11, 1495–1503 (2004).
Dolma, S., Lessnick, S. L., Hahn, W. C. & Stockwell, B. R. Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells. Cancer Cell 3, 285–296 (2003).
Wang, J. & Dreyfuss, G. A cell system with targeted disruption of the SMN gene: functional conservation of the SMN protein and dependence of Gemin2 on SMN. J. Biol. Chem. 276, 9599–9605 (2001).
Aiken, C. T., Tobin, A. J. & Schweitzer, E. S. A cell-based screen for drugs to treat Huntington's disease. Neurobiol. Dis. 16, 546–555 (2004).
Stegmaier, K. et al. Gene expression-based high-throughput screening(GE-HTS) and application to leukaemia differentiation. Nature Genet. 36, 257–263 (2004).
Kapur, R. Fluorescence imaging and engineered biosensors: functional and activity-based sensing using high content screening. Ann. NY Acad. Sci. 961, 196–197 (2002).
Yarrow, J. C., Perlman, Z. E., Westwood, N. J. & Mitchison, T. J. A high-throughput cell migration assay using scratch wound healing, a comparison of image-based readout methods. BMC Biotechnol. 4, 21 (2004).
Kau, T. R. et al. A chemical genetic screen identifies inhibitors of regulated nuclear export of a Forkhead transcription factor in PTEN-deficient tumor cells. Cancer Cell 4, 463–476 (2003).
Root, D. E., Flaherty, S. P., Kelley, B. P. & Stockwell, B. R. Biological mechanism profiling using an annotated compound library. Chem. Biol. 10, 881–892 (2003).
Seidler, J., McGovern, S. L., Doman, T. N. & Shoichet, B. K. Identification and prediction of promiscuous aggregating inhibitors among known drugs. J. Med. Chem. 46, 4477–4486 (2003).
Tuschl, T. Expanding small RNA interference. Nature Biotechnol. 20, 446–448 (2002).
Elbashir, S. M. et al. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411, 494–498 (2001).
Lassus, P., Rodriguez, J. & Lazebnik, Y. Confirming specificity of RNAi in mammalian cells. Sci. STKE 147, PL13 (2002).
Root, D. E., Kelley, B. P. & Stockwell, B. R. Global analysis of large-scale chemical and biological experiments. Curr. Opin. Drug Discov. Dev. 5, 355–360 (2002).
Burke, T. J., Loniello, K. R., Beebe, J. A. & Ervin, K. M. Development and application of fluorescence polarization assays in drug discovery. Comb. Chem. High Throughput Screen. 6, 183–194 (2003).
Timasheff, S. N., Andreu, J. M. & Na, G. C. Physical and spectroscopic methods for the evaluation of the interactions of antimitotic agents with tubulin. Pharmacol. Ther. 52, 191–210 (1991).
Bulseco, D. A. & Wolf, D. E. Fluorescence correlation spectroscopy: molecular complexing in solution and in living cells. Methods Cell Biol. 72, 465–498 (2003).
Misra, R. Modern drug development from traditional medicinal plants using radioligand receptor-binding assays. Med. Res. Rev. 18, 383–402 (1998).
Hicks, R. P. Recent advances in NMR: expanding its role in rational drug design. Curr. Med. Chem. 8, 627–650 (2001).
Siegel, M. M. Early discovery drug screening using mass spectrometry. Curr. Top. Med. Chem. 2, 13–33 (2002).
Homola, J. Present and future of surface plasmon resonance biosensors. Anal. Bioanal. Chem. 377, 528–539 (2003).
Jelesarov, I. & Bosshard, H. R. Isothermal titration calorimetry and differential scanning calorimetry as complementary tools to investigate the energetics of biomolecular recognition. J. Mol. Recogn. 12, 3–18 (1999).
Burke, M. D., Berger, E. M. & Schreiber, S. L. Generating diverse skeletons of small molecules combinatorially. Science 302, 613–618 (2003).
Oprea, T. I. & Matter, H. Integrating virtual screening in lead discovery. Curr. Opin. Chem. Biol. 8, 349–358 (2004).
Ewing, T. J., Makino, S., Skillman, A. G. & Kuntz, I. D. DOCK 4.0: search strategies for automated molecular docking of flexible molecule databases. J. Comput. Aided Mol. Des. 15, 411–428 (2001).
Osterberg, F., Morris, G. M., Sanner, M. F., Olson, A. J. & Goodsell, D. S. Automated docking to multiple target structures: incorporation of protein mobility and structural water heterogeneity in AutoDock. Proteins 46, 34–40 (2002).
Kramer, B., Rarey, M. & Lengauer, T. Evaluation of the FLEXX incremental construction algorithm for protein-ligand docking. Proteins 37, 228–241 (1999).
Halgren, T. A. et al. Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. J. Med. Chem. 47, 1750–1759 (2004).
Vangrevelinghe, E. et al. Discovery of a potent and selective protein kinase CK2 inhibitor by high-throughput docking. J. Med. Chem. 46, 2656–2662 (2003).
Peng, H. et al. Identification of novel inhibitors of BCR-ABL tyrosine kinase via virtual screening. Bioorg. Med. Chem. Lett. 13, 3693–3699 (2003).
Bajorath, J. Integration of virtual and high-throughput screening. Nature Rev. Drug Discov. 1, 882–894 (2002).
Lipinski, C. A., Lombardo, F., Dominy, B. W. & Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 46, 3–26 (2001).
Hann, M. M. & Oprea, T. I. Pursuing the leadlikeness concept in pharmaceutical research. Curr. Opin. Chem. Biol. 8, 255–263 (2004).
Acknowledgements
B.R.S. is supported in part by a Career Award at the Scientific Interface from the Burroughs Wellcome Fund.
Author information
Authors and Affiliations
Ethics declarations
Competing interests
The author declares no competing financial interests.
Rights and permissions
About this article
Cite this article
Stockwell, B. Exploring biology with small organic molecules. Nature 432, 846–854 (2004). https://doi.org/10.1038/nature03196
Published:
Issue Date:
DOI: https://doi.org/10.1038/nature03196
This article is cited by
-
Development and photo-properties and intracellular behavior of visible-light-responsive molecule localizing to organelles of living cell
Chemical Papers (2023)
-
Focused small molecule library of 5,6,7,8-tetrahydro[1,2,4]triazolo-[4,3-a]pyrazines: a brick for the house of medicinal chemistry
Chemistry of Heterocyclic Compounds (2023)
-
Super-assembled sandwich-like Au@MSN@Ag nanomatrices for high-throughput and efficient detection of small biomolecules
Nano Research (2022)
-
Organoids in image-based phenotypic chemical screens
Experimental & Molecular Medicine (2021)
-
Cellular model system to dissect the isoform-selectivity of Akt inhibitors
Nature Communications (2021)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.