Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 4, Issue 7, Pages 95-100Publisher
AMER CHEMICAL SOC
DOI: 10.1021/ml400062c
Keywords
Nutlin; protein-protein interaction inhibitor; p53; MDM2; binding affinity
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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 affinity for each key substituents of the Nutlin molecule and show that this series could hypothetically have been discovered via fragment approach. We find that the smallest fragment of Nutlin that retains binding accesses two subpockets of MDM2 and has a molecular weight at the high end of the range that normally defines fragments.
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