Starting Small

Building drug molecules from small fragments is an alternative to massive libraries.

In drug discovery, millions of molecules may be screened, typically, before a drug candidate is found. But several companies now hope to improve this one-in-a-million yield by looking, instead, for more plentiful "fragments" of a drug molecule and fashioning them into the real thing. Testifying to the success of this approach, a small flurry of publications have announced the discovery of molecules (nanomolar inhibitors) as good as or better than those found by needle-in-a-haystack methods.^1,2,3

Traditionally, finding drug candidates has required a huge collection of potential drug molecules, a target biomolecule (almost always a protein) implicated in disease, and a way to tell which molecules affect the drug target. The problem with this method is that the potential number of unique molecules with druglike characteristics is mind-boggling–more than the number of stars in the universe. Even a collection of, say, a million different molecules represents much less than one-trillionth of the potential, and million-molecule collections are expensive. A more efficient method is to assemble a drug candidate from smaller, and thus cheaper, fragments. Because the number of potential fragments is smaller, scientists can sample a larger fraction of the possible diversity.

Unfortunately, finding drug fragments is downright difficult; usually, the smaller the ligand (a molecule that binds to a larger molecule), the weaker its interaction with the target molecule, and the more difficult it is to detect. Furthermore, assembling these fragments into potential drugs is not easy. Nonetheless, these technologies promise not only to accelerate drug discovery, but also to find molecules that are inaccessible through other means.

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1  Braisted, A. C. (2003) Discovery of a potent small molecule IL-2inhibitor through fragment assembly. Journal of the American Chemical Society 125:3714-5.

2  Erlanson, D. et al. (2003) In situ assembly of enzyme inhibitors using extended tethering. Nature Biotechnology 21:308-14.

3  Szczepankiewicz, B.G. et al. (2003). Discovery of a potent, selective protein tyrosine phosphatase 1B inhibitor using a linked-fragment strategy. Journal of the American Chemical Society 125:4087-96.