Combinatorial and Computational Approaches in Structure-based Drug Design

The increasing number of protein 3D structures and the success of structure-based approaches has led to the development of several experimental and theoretical techniques for the rational design of protein ligands. Combinatorial chemistry significantly speeds up the synthesis of potential new drug candidates. Diversity considerations, as well as the use of 3D structural information of the biological targets, reduce the size of huge libraries to a reasonable number of rationally-designed ligands. New NMR techniques (SAR by NMR) allow the construction of high-affinity ligands from small molecules with much lower affinities. Computer-aided drug design uses building, linking, and/or rigid docking procedures to search for ligands for a certain binding site. Scoring functions provide a rank order of the designed ligands according to their estimated binding affinities. Further developments in computer-aided drug design are automated approaches for the flexible alignment of molecules, the flexible docking of ligands to their binding sites, and the stepwise assembly of synthetically easily accessible ligands from combinatorial libraries of fragments.