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Nature continues to provide a wealth of new leads for potential therapeutic agents or pharmacological probes (1). The role of natural products in traditional medicine is well appreciated and has led to many important drugs that either retain the entire natural product structure or that incorporate (usually straightforward) chemical modifications. Today, biologically useful natural products are most commonly discovered through target-based or phenotypic screening, even in the absence of detailed information about the purpose of the natural product in its original biological setting. The success of these efforts has led some researchers to suggest that scaffolds related to natural product substructures may lead to useful chemical libraries due to the presumed preoptimization of these structures by natural selection (2¨C4). This argument loses force as compounds become less similar to the natural products that inspired them, but the use of even highly truncated natural product structures in screening can bear fruit if care is taken to retain features consistent with macromolecular binding in the process (5¨C9). Moreover, it is reasonable to expect that one¡¯s chances for success in identifying structures having activities unrelated to the (possibly unknown) original impetus for evolutionary structure optimization increase if (i) the natural product has multiple bioactivities and (ii) the structure is sufficiently malleable for analogue construction. |
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