Structure-Based Ligand Design

Structure-based ligand design has matured over the last decade. This process has been driven by an exploding wealth of biostructural information and by a detailed understanding of the mechanism of action of a wide range of biochemical systems. While 10 years ago only few structures relevant for human pathology were known, today most newly initiated pharmaceutical research projects have at least some relation to known three-dimensional (3D) structures. Examples of research areas where solid biostructural information is available are: Serine proteases (e.g., elastase (Powers et al. 1990)), coagulation factors (Banner 1993), metalloproteinases (e.g., collagenase (Borkakoti et al. 1994), astacin (Bode et al. 1992)), aspartyl proteases [e.g., renin (Dealwis et al. 1994), HIV protease (Lam et al. 1994)], serine esterases [several lipases (Winkler et al. 1990; Cygler et al. 1993)], acetylcholine esterase (Sussman et al. 1991; Gubernator et al. 1993), dihydrofolate reductase (Oefner et al. 1988), tymidylate synthetase (Shoichet et al. 1993), major histocompatibility complex (Silver et al. 1992), cyclosporin-cyclophilin (Ke et al. 1994; Spitzfaden et al. 1994), hemagglutinin (Von Itzstein et al. 1993), and protein—DNA interaction [transcription factors (Harrison 1991), nucleases (Winkler 1993)].