Protein inhibition by targeted small molecule libraries

The p53-MDM2 interaction serves to regulate cellular responses to DNA damage and the over expression of MDM2 is the cause of 7% of all cancers. We report a method of structure-based computational design that produces chemical libraries centered on a scaffold that projects side chain functionalities with distance and angular relationships equivalent to those seen in p53. One library of 173 compounds was synthesized using solution phase parallel chemistry. The in vitro competitive ability of the compounds to block p53 peptide binding to MDM2 was determined using a fluorescence polarization competition assay. The most active compound bound with Kd = 12muM and its binding was characterized by 1H-15N HSQC NMR.