From protein domains to drug candidates--natural products as guiding principles in compound library design and synthesis.

As the human genome is being thoroughly sequenced, projects are being initiated to determine the structures of all protein folds via X-ray crystallography or nuclear magnetic resonance (NMR) (structural genomics). The structural determination is crucial for an understanding of the function of the proteins, and will certainly help us achieve the ultimate goal: altering protein function by small molecules, which either selectively inhibit or activate a particular protein (Mitchison 1994; Schreiber 1998; Stockwell 2000; Alaimo et al. 2001). Combinatorial chemistry will become the method of choice to undertake this Herculean task. But as the universe of thinkable chemical compounds is almost infinite (Bohacek et al. 1996), one important question arises: Where in the universe of chemical structures are compounds with the desired biological properties to be found?

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