The role of protein 3D-structures in the drug discovery process.

The majority of drugs available today were discovered either by chance observations or by screening synthetic or natural products libraries. In many cases, a trialand-error based approach of chemical modification of lead compounds led to an improvement with respect to potency and reduced toxicity. Since this approach is labor and time-intense, researchers in the pharmaceutical industry are constantly developing methods to increase the efficiency of the drug finding process. Simply put, two directions have evolved from these efforts. The “random” approach involves the development of high-throughput screening assays and the testing of a large number of compounds. Combinatorial chemistry is used to satisfy the need for huge substance libraries. The “rational,” structure-based approach relies on an iterative procedure of structure determination of the target protein, prediction of hypothetical ligands by molecular modeling, specific chemical synthesis and biological testing of compounds (the structure-based drug design cycle). It is becoming evident, that the future of drug discovery does not lie in one of these approaches solely, but rather an intelligent combination. In this chapter, we will concentrate on the protein structure-based drug discovery approach and discuss possible overlaps with complementary technologies.