Chemical genetics natural products

Nature is a highly innovative chemist, and we know only a small fraction of the universe of natural products. Currently, about half of the most widely prescribed drugs in the United States are either small-molecule natural products, such as penicillin, or synthetic molecules that are based on natural products but have better properties. The other half are products of the creative imagination of medicinal chemists. Nature s genetic and chemical diversity is a treasure that should not be squandered. One reason to maintain ecosystems such as rain forests intact is that less than 10% of plant species have been systematically investigated for their chemical products. Also, many microbes, insects, and other species have not been explored for useful products. 

The examples given above demonstrate that natural products play an important role in various areas of fine chemicals. By genetic modification, yields of desired compounds might be further enhanced. Moreover, improved separation techniques will contribute to optimal crop use. 

It is critical to this chemical genetic approach to have a library of compounds that have a high probability of being relatively selective otherwise, the ability to interpret the results becomes at least as complex as deciphering highly poly-genetic phenotypes. To address this, diversity-oriented synthesis has been proposed to provide arrays of complex small molecules that are easily synthesized. The natural-product basis for many of the molecules and their complexity are believed to contribute to their cellular potency and selectivity (6). This chemical genetic approach has been applied to identify novel inhibitors of alpha-tubulin and histone deactylation (7). 

Although the natural products of aromatic PKSs can be much more challenging to predict, their enzymes are much smaller and are often considered to be more tractable to routine heterologous expression, genetic modification and protein structure determination. Indeed, because large modular systems are so much more difficult to work with in vitro, much of what we now know about modular systems has been inferred from direct analogy to biochemical studies of aromatic systems. Aromatic PKSs can now be classified into several specialised families based upon both chemical product type and domain structure. Notably, NRPS analogues of the aromatic PKSs have not been observed. 

The Value of Chemical Genetics in Drug Discovery Table 3.1 Natural products used to identify targets. 

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