Structure-Based Drug Design – The Use of Protein Structure in Drug Discovery

Abstract

Several examples of structure-based design are illustrated and discussed in this chapter. The examples have been selected to ensure that different design approaches are covered. These include approaches that can be very useful at a very early stage in the discovery process, such as ab initio design or the fragment approach. In addition, examples are shown in which it becomes clear how one can take advantage of the similarity between the target protein and a related protein with known inhibitors. The most common application of structure-based design is the optimization of weakly binding inhibitors. Examples are included in which high-throughput screening (HTS) hits or naturally occurring ligands such as substrates or transition-state analogs have been cocrystallized with their target protein. Based on a careful analysis of theses structures, it is shown how the ligand-binding potency can be increased in subsequent design and synthesis steps. In addition, examples are described that show that structure-based drug design can support the drug discovery process at a very late stage. Examples include the modification of physical chemical properties based on the protein structures, which in many cases has led to more bioavailable inhibitors. Other examples show that protein structures are very useful for understanding the selectivity within protein families and also target-based resistance. Based on the protein structures, modifications of the inhibitors can be proposed which have led to selective inhibitors and to compounds inhibiting the resistant variant of the target protein.