Deconstruction of a nutlin: dissecting the binding determinants of a potent protein-protein interaction inhibitor.

ABSTRACT: Protein-protein interaction (PPI) systems represent a rich potential source of targets for drug discovery, but historically have proven to be difficult, particularly in the lead identification stage. Application of the fragment-based approach may help toward success with this target class. To provide an example toward understanding the potential issues associated with such an application, we have deconstructed one of the best established protein-protein inhibitors, the Nutlin series that inhibits the interaction between MDM2 and p53, into fragments, and surveyed the resulting binding properties using heteronuclear single quantum coherence nuclear magnetic resonance (HSQC NMR), surface plasmon resonance (SPR), and X-ray crystallography. We report the relative contributions toward binding af

SUBMITTER: Fry DC 

PROVIDER: S-EPMC4027557 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature