Strategies and recent technologies in drug discovery.

In the last years, the paradigms of drug research changed significantly. New technologies were developed, in several different fields. Combinatorial chemistry and high-throughput screening increase our chances to find new lead structures, with less effort than by dedicated syntheses. Gene technology, in addition to providing therapeutically useful proteins, significantly contributes to rational drug design. The primary structure of a protein can be derived from the DNA sequence of the corresponding gene. Its relevance for a certain disease is investigated in transgenic animals. Expression of the protein in bacteria or in cell culture produces material for screening systems and for 3D structure determination by protein crystallography. NMR techniques, or electron cryo-microscopy. Structure-based and computer-aided design methods are applied to optimize lead structures with the least effort. A serious problem in the application of such techniques is their limitation to ligand-protein interactions. For the design of a therapeutically useful drug, also absorption, distribution, metabolism and elimination have to be considered. QSAR methods help in this respect. Scope and limitations of the new technologies are discussed in the context of conventional approaches in drug discovery.