Chapter 11:Structure-based Design Technology CONTOUR and its Application to Drug Discovery

Structure-based design has had a significant impact on the drug discovery process over the past two decades by identifying novel and efficacious molecules for a variety of therapeutic targets. Among the approaches used for structure-based drug design, the de novo design approach has a great potential to generate novel molecules that best complement a protein binding site, but had failed to meet expectations in its initial attempts. More recently this approach has met with success due to algorithmic developments in the methodologies. In this chapter we introduce a state-of-the-art de novo design technology called CONTOUR®, provide details of the algorithmic enhancements we have implemented and show improvements in performance over past methods. CONTOUR was developed to grow novel drug like molecules by assembling fragments in the context of the binding site using a high resolution crystal structure of a protein as a starting point. The technology comprises a sophisticated growth algorithm that works in concert with an effective scoring function. The growth algorithm creates molecules in a context sensitive manner by assembling fragments that are dynamically selected from a fragment library and screened to optimally complement features of a given binding site. The scoring function was developed to capture essential elements of the binding interactions and to rank order grown molecules with a high probability of exhibiting activity against a protein target of interest. The application of CONTOUR to identify inhibitors against human 11β HSD1 enzyme will be discussed here.