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Science 17 March 2000:
Vol. 287. no. 5460, pp. 1964 - 1969
DOI: 10.1126/science.287.5460.1964
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Review

Target-Oriented and Diversity-Oriented Organic Synthesis in Drug Discovery

Stuart L. Schreiber

Modern drug discovery often involves screening small molecules for their ability to bind to a preselected protein target. Target-oriented syntheses of these small molecules, individually or as collections (focused libraries), can be planned effectively with retrosynthetic analysis. Drug discovery can also involve screening small molecules for their ability to modulate a biological pathway in cells or organisms, without regard for any particular protein target. This process is likely to benefit in the future from an evolving forward analysis of synthetic pathways, used in diversity-oriented synthesis, that leads to structurally complex and diverse small molecules. One goal of diversity-oriented syntheses is to synthesize efficiently a collection of small molecules capable of perturbing any disease-related biological pathway, leading eventually to the identification of therapeutic protein targets capable of being modulated by small molecules. Several synthetic planning principles for diversity-oriented synthesis and their role in the drug discovery process are presented in this review.

The author is at the Howard Hughes Medical Institute, the Department of Chemistry and Chemical Biology, and the Harvard Institute of Chemistry and Cell Biology, Harvard University, Cambridge, MA 02138, USA. E-mail: sls{at}slsiris.harvard.edu

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