Chapter 5: Contribution of Structure-Based Drug Design to the Discovery of Marketed drugs

Structure-based drug design has played a role in the discovery of many drugs from many different disease areas, and it is now arguably an essential contributor to addressing the need to improve research and development productivity faced by the pharmaceutical industry. The purpose of this review is to highlight the impact of protein structures solved by X-ray and NMR techniques, as well as other techniques such as isothermal titration calorimetry, on structure-based discovery. The importance of these methods in drug discovery will be underscored by examples of drugs approved up until the end of 2009, which were discovered utilising structural information. These examples will highlight that structure-based drug design has moved on from just using structural knowledge to optimise potency to using it also with selectivity, pharmacokinetic and pharmaceutical properties in mind. Following on from this, a medicinal chemist's perspective aims to highlight the benefits and advantages of structure-based drug design but also to provide an opinion on the pitfalls and hype surrounding this technology. In particular, this section will draw on examples to highlight its impact and limitations on assessing druggability, as well as factors to consider when using structure-based drug design in lead generation and the optimisation of leads for potency, selectivity and pharmacokinetic properties. Finally, some forward looking thoughts will be proposed with regard to the future of structure-based drug design and where emphasis could be placed to increase the impact of this approach on drug discovery productivity.