Protein-protein interactions (PPIs) have attracted considerable attention as targets for disruptive inhibitors. Such molecules can be used to probe cellular processes, or act as therapeutic drugs. Targeting these interfaces with small drug-like molecules has been challenging to the large interaction surfaces involved, driving interest toward a new class of larger molecules designed to mimic peptides and proteins--peptidomimetics.
Cyclic peptides have showed great promise as potential peptidomimetic drugs (1, 2). A recent experimental NMR study of four cyclic beta-hairpins designed to mimic the p53 TAD alpha helix and competitively inhibit its binding partner, MDM2, suggests that ligand flexibility is an important determinant of affinity (3).
This work has inspired us to use molecular dynamics simulation to understand the binding these designed ligands with MDM2. We hope the thermodynamic and kinetic information obtained from our simulations will help us understand the molecular mechanism of binding in atomic detail, and give insight into how to leverage the role of ligand flexibility in future drug discovery efforts.
1. Hewitt, W. M., Leung, S. S. F., Pye, C. R., Ponkey, A. R., Bednarek, M., Jacobson, M. P., & Lokey, R. S. (2015). Cell-Permeable Cyclic Peptides from Synthetic Libraries Inspired by Natural Products. Journal of the American Chemical Society, 137(2), 715–721. http://doi.org/10.1021/ja508766b
2. Heinis, C. (2014). Drug discovery: Tools and rules for macrocycles. Nature Chemical Biology, 10(9), 696–698. http://doi.org/10.1038/nchembio.1605
3. Danelius, E., Pettersson, M., Bred, M., Min, J., Waddell, M. B., Guy, R. K., et al. (2016). Flexibility is important for inhibition of the MDM2/p53 protein-protein interaction by cyclic β-hairpins. Organic & Biomolecular Chemistry. http://doi.org/10.1039/c6ob01510g
List of Contributors
This project is managed by Prof. Vincent Voelz at Temple University.
Dr. Voelz's research focuses on using new simulation methods to unravel the mysteries of how proteins self-assemble into their functional folds, and to design folding and binding properties of proteins and peptide mimetics from first principles. The Voelz Lab participates in the Folding@home project, hosting two servers at Temple University. Dr. Voelz was formerly a postdoctoral scholar in the Vijay Pande lab at Stanford University.
Enter the project number: