I am currently undertaking my PhD across the Aggarwal, Butts and Mulholland groups looking at the use of conformationally constrained hydrocarbons as inhibitors of protein-protein interactions. Previously in the Aggarwal group they have established that contiguously methyl-substituted hydrocarbons, accessible through iterative lithiation–borylation, are conformationally constrained into either helical or linear conformations depending on the stereochemistry of the methyl groups. NMR data based on NOE-derived interproton distances and scalar coupling constants confirmed the conformation of the molecules in solution.
Both the linear and helical conformations project side chains onto the same face of the molecule with distances between them varying from 5 – 7 Å. These distances closely match those observed between the residues on an α-helix, making these potential α-helix mimetics, capable of inhibiting PPIs that are mediated through an α-helix, such as the p53-Mdm2 PPI. The p53-Mdm2 PPI is dominated by three ‘hot-spot’ residues on p53: Phe19, Trp23 and Leu26 which insert into a hydrophobic cleft on Mdm2. We envisage carrying out an iterative lithiation-borylation sequence using the appropriate substituents at judicious points in the sequence to design a hydrocarbon framework that is capable of mimicking the three ‘hot-spot’ residues on p53. To experimentally confirm their conformation in solution, we will use a combined NMR and computational approach, comparing experimental interproton distances and scalar coupling constants to those calculated at the DFT level of theory. Molecular docking and molecular dynamics will be used to investigate the binding mode of the inhibitors to Mdm2. Finally, we will use well established biological assays to determine their binding affinity and specificity to the Mdm2-p53 interface. We hope that this project will serve as a strong foundation for the use of conformationally constrained hydrocarbons as scaffolds for the design of proteomimetics targeting a number of other important PPIs.