Fragment-based drug discovery approaches (FDD) make extensive use of structural target information and drug design. Thus they comprise the opposite of chance-based high throughput screening exercises (HTS). A fragment is discovered by screening low molecular weight libraries of molecules in assays yielding structural binding information (NMR, X-ray). Based on the generated hits chemical optimization programs can be started. Fragment-based drug discovery approaches are highly successful and complementary to HTS campaigns.

We herein describe a novel fragment-based approach that is based on the interplay of structural target information, docking and very efficient multicomponent reaction chemistry (MCR). Potential advantages are the following:

� public available structural target data (pdb) can be used - thus there is no need for expensive and/or advanced techniques & instrumentations;

� a very large chemical space based on hundreds of relevant scaffolds is screened � thus the chances of discovery of expandable hits is greatly enhanced;

� due to the efficient chemistry used (MCR), there is a high ratio of success to effort;

� the discovery of multiple target interacting compound classes allows for their parallel optimization, thus greatly enhancing the chance to develop compounds with excellent PKPD properties.

As a validation of our new drug discovery approach we present the parallel discovery of several potent scaffold classes of selective and dual active p53/mdm2/mdm4 antagonists with potential applications in cancer.