Fragment Based Discovery – Opportunities for computational chemistry and cheminformatics
It is now twenty years since the first publication on fragment based drug discovery and the methods have matured in the past ten years to provide a powerful addition to the armory of methods used in ligand discovery1. The central tenet is that a small library of low MW compounds can effectively sample chemical space to identify compounds that bind to a range of protein targets; these small fragments can then be grown into potent ligands (usually by structure-guided design)2. Some of these compounds have been developed into effective inhibitors to probe the mechanism of action of certain protein targets. Others have been optimized to provide many clinical candidates3 and there are now two fragment-derived compounds on the market.
In this presentation, I will briefly summarize the methods and then focus on the various areas where computational and cheminformatics methods can have impact. These include the design of libraries (including novel libraries of so-called 3D fragments4), computational screening of fragments5,6, using fragments to identify novel mechanisms of enzyme action7 and the difficult challenge of growing and merging fragments to give potent ligands.