Changing Paradigms Industrialization Of Discovery

New chemical entities with a novel mode of action are urgently needed in the pharmaceutical industry for further improvement of the individual company product portfolio and to meet the expectations from the financial community. The number of drugs to be marketed by the major pharmaceutical companies needs to be tripled over the next years for companies to stay competitive and justify their current valuation (10).

The fundamental strategies in industrial drug discovery have changed over the past decades. Until the 1980s, basic research, low-throughput screening, and serendipity were the basis for successful drug discovery. During the 1980s "rational" design was developed as a new strategy. Based on protein structures, usually obtained by X-ray crystallography, chemical modulators were sought "in silico." Unfortunately, despite large investments by the pharmaceutical industry, this strategy did not fulfill its promises and new technologies were developed in the early 1990s. These strategies still dominate the drug discovery process in most companies (10).

The principal paradigm of drug discovery today is shown in Fig. 1. A key step in the discovery process is the identification of a biochemical target that is causally involved in a certain disease or a phenotype that one wishes to modify by drug application. Pharmaceutical companies focus on diseases for which a potential drug may lead to at least U.S. $100 million in yearly revenues. Diseases for which the market is smaller are usually not targeted, although recent legislation on such "orphan drugs" may change the situation and allow especially smaller companies to develop drugs for such often severe diseases. Natural compounds or derived structures may be particularly interesting for such orphan diseases.

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