Figure 2 Modify structure of known drugs. Figure 3 Screening: extensive history of natural products and microbial secondary metabolites.

This sourcing of drugs from natural products has changed over the past 5-10 years, with increasing numbers of drugs coming from chemical libraries rather than from natural products. The reason for this is that over the last 30 or 40 years pharmaceutical companies and chemical companies have established significant inventories of small molecules. These inventories were not being exploited as potential sources of drugs because of the absence of broad-based, automated screening methods and biologically relevant assays. This has changed dramatically in the last decade. Today one can come up with an extensive list of potential drug candidates coming from the screening of chemical libraries (Fig. 4), and this has become the basis for significant new technologies in the area of high-through-put screening and combinatorial chemistry. So how did one discover drugs in the past? To recapitulate, in large part, one did it by modifying the structure of known drugs or screening inventories of natural products.