Advances in the use of synthetic combinatorial chemistry: Mixture-based libraries

The conceptual and technical approaches that led to the explosive growth of combinatorial chemistry began approximately 20 years ago. In the past decade, combinatorial chemistry has continued to expand with new chemistries, technological improvements and, most importantly, a clear demonstration of its utility in the identification of active compounds for research and drug-discovery programs. This article describes the conceptual and practical breakthroughs that have been critical for the development of synthetic combinatorial methods and includes the most recent developments and applications of mixture-based combinatorial libraries.

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Figure 1: Conceptual illustration of a tripeptide PS-SCL (top) and representation of a peptide (middle) and heterocyclic (bottom) PS-SCL.
Figure 2: Elucidation of T-cell specificity and the identification of ligands for the μ-opioid receptor using biometrical analysis.

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Acknowledgements

We thank R. Martin and R. Simon for their contributions to the development of the biometrical analysis first used in T-cell studies; C. Dooley for the opioid receptor research; D. Wilson and S. Blondelle for their involvement in the use of combinatorial libraries in many different biological assays; and J. Ostresh, A. Nefzi and the chemistry group at Torrey Pines Institute for Molecular Studies for the continuing development of synthetic chemistry for the preparation of mixture-based combinatorial libraries. Supported by NCI grant PO1 CA78040, NIDA grant RO1 DA09410 and MSNRI funding.

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Correspondence to Richard A. Houghten.

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Pinilla, C., Appel, J., Borràs, E. et al. Advances in the use of synthetic combinatorial chemistry: Mixture-based libraries. Nat Med 9, 118–122 (2003). https://doi.org/10.1038/nm0103-118

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