The impact of structure-guided drug design on clinical agents

trial scientists have used the 3D atomic structures of proteins, derived mostly from macromolecular crystallographic studies, as design templates for small molecule ligands. In some cases, a targeted protein structure is used directly. In other cases, the template is a ‘homology model,’ based upon an experimental study of a structural homolog of the actual target. Here we look at the impact of structure-guided drug design (SGDD) on drug discovery and development. Utility of structure-guided methods Table 1 lists 40-plus compounds, discovered with the aid of structure-guided methods, that have entered clinical trials. These drugs and drug candidates are directed against two-dozen different molecular targets, in a wide range of therapeutic areas, although over half of the compounds are used for oncology or viral infections. There may even be additional compounds that we have overlooked in our survey of information in the public domain. At the time of writing (August 2003), seven of these compounds have become approved and marketed drugs. Captopril was the first drug whose discovery relied upon the explicit use of Xray structural information as a guide for small molecule design. This occurred over two decades ago. Although the template used for discovery of captopril was a homology model (based on the X-ray structure of bovine carboxypeptidase A), the recognition of the ‘heuristic’ value of such a model was a landmark. A similar conceptual model of acetylcholinesterase