Drugs, Naturally

Natural products and their structures are often used as leads in drug discoveries. But should they be? In the Pipeline's Derek Lowe reviews a paper in the Journal of the American Chemical Society by the Broad Institute's Stuart Schreiber and Paul Clemons, that says natural products tend to target high-gene interaction targets for the treatment of disease, ignoring the more specific targets, Lowe says. "That actually seems reasonable — most natural products are produced by organisms as essentially chemical warfare, and the harder they can hit, the better," he adds. The paper concludes that other sources of small molecules need to be found outside of natural products. While that seems like a sound argument, however, Lowe doesn't agree with the implications of it. "Schreiber has long been a proponent of 'diversity-oriented synthesis' (DOS), and would seem to be making a case for it here without ever mentioning it by name," he says. DOS, he continues, is about making large collections of molecules to cover as much "chemical space" as possible. "My worries are that the space it covers doesn't necessarily overlap very well with the space occupied by potential drugs, and that chemical space is too humongously roomy in any event to be attacked very well by brute force," Lowe says.