Structural Biology and Drug Design

The discovery of new drugs is a time and labor-intensive process. On average, the discovery of a new drug requires the preparation and evaluation of approximately 10,000 compounds over 12 years at a cost of more than $350 million. Once in the market place, many drugs fail to recover their development costs (as many as 30%, according to data from the 1980s, and many others are ultimately withdrawn from the market. These facts coupled with limits on patent lifetime, escalating global competition, and increasingly stringent government regulations for drug approval have demanded more efficient and accelerated approaches to drug discovery. Conventional "brute force" methods of lead discovery via high-throughput screening (HTS) of proprietary synthetic, combinatorial, or natural product libraries, while effective in many cases, are expensive and have limitations; they require access to large compound libraries (sometimes over 1,000,000 compounds), often yield hits with high molecular weight, poor ligand efficiency, limited or no potential for optimization, and provide no information to guide ligand optimization. Structural information on protein-ligand complexes can eliminate much of the complexity involved in the discovery and optimization of prospective drug leads. Structure-Based Drug Design (SBDD) and Fragment-Based Drug Design (FBDD) have become key tools for the development of novel drugs. The process involves elucidating the three-dimensional structure of the potential drug molecule/fragment bound to the target protein that has been identified as playing a key role in the disease state. Using this three dimensional information facilitates the process of making improvements to the potential drug molecule by highlighting existing and possible new interactions within the binding site. This knowledge is used to inform increases in potency and selectivity of the molecules as well as to help improve other drug like properties. The speed and numbers of samples that can be studied, combined with the improved resolution of the structures that can be obtained using synchrotron radiation, have had a significant impact on the utilization of crystallography in the drug discovery process. Indeed, structure-guided drug design efforts have led to the discovery of high profile drugs in multiple therapeutic areas, including the peptidomimetic HIV protease inhibitors for the treatment of HIV, the neuraminidase inhibitor Tamiflu(TM) for the treatment of influenza, the carbonic anhydrase inhibitor dorzolamide for the treatment of glaucoma, and the thrombin inhibitor ximelagatran, an oral anticoagulant. Access to structural information on the target of interest can streamline all aspects of drug discovery, from target selection to lead discovery and optimization. The role of SBDD/FBDD with respect to two different classes of widely investigated pharmaceutical targets: ?-amyloid and acetylcholinesterase is discussed.