The Evolution of Quantitative Drug Design

The body of information used by drug designers to decide the future direction of their programs has changed enormously over the last 30 years, both in scope and degree of precision. In addition, the data analysis and visualization tools used to explore this information have been transformed, as computing power and the sophistication of desk-top applications have grown. For example, in 1981, the molecular details of the interaction between a drug-lead and its target would be unknown, and drug receptors were depicted via simple, hand-drawn schemes comprised of lines and angles. In contrast, the drug designer of 2011 is likely to have access to dozens of serial X-ray structures of relevant protein–ligand complexes, visible in high resolution 3D graphics, and be studying ‘spotfire’ plots of slices through multi-parametric structure–property space, displayed on their personal lap-top computer. This chapter will attempt to explore how and when these advances in drug design sophistication emerged, assess where the current leading edge of drug-design stands, and try to project how these evolutionary changes might continue into the future.