Medicinal chemistry research has traditionally focused upon a limited set of biological targets. Many other human disease-related targets have been termed ‘undruggable’ as they have proved largely impervious to modulation by small molecules. However, it is becoming increasingly evident that such targets can indeed be modulated; they are simply being challenged with the wrong types of molecules. Traditionally, screening libraries were composed of large numbers of structurally similar compounds. However, library size is not everything; the structural diversity of the library, which is largely dictated by the range of molecular scaffolds present, is crucial. Diversity-oriented synthesis (DOS) generates small molecule libraries with high levels of scaffold, and thus structural, diversity. Such collections should provide hits against a broad range of targets with high frequency, including ‘undruggable’ targets. Examples in the area of scaffold diversity generation taken from the author’s laboratories are given.
 O’Connor C. J., Beckmann H. S. G., Spring D.R., Chem. Soc. Rev. 2012, 41, 4444.
 Diversity-Oriented Synthesis, O’Connell K. M. G., Galloway W. R. J. D., Ibbeson B. M., Isidro-Llobet A., O’ Connor C. J., Spring D. R. Book chapter in “Solid-Phase Organic Synthesis: Concepts, Strategies, and Applications”, ed. P. H. Toy, Y. Lam, 2012, Wiley, pp 131-150
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