Residue-level energy view of TP53-MDM2/MDMX inhibitors favors stabilized peptides
- Unrestricted molecular dynamics and QM/MM calculations were used to break down inhibitor binding to MDM2 and MDMX into per-residue electrostatic and van der Waals contributions.
- The set covered all clinical-stage inhibitors with high-resolution structures; this is a computational study without new experiments.
- Binding proved weak and dispersion-driven, with water solvation important; stabilized peptides showed a more favorable interaction pattern than small organic molecules.
💡 Points
Per-residue decomposition is useful for seeing where a ligand loses to repulsion, but a few MD runs with a fixed force field won't give you affinities, and with no experiments the stapled-peptide advantage is an interpretation, not a result. Peptides simply have more contacts to sum. I'd mine it for hot-spot and clash maps to guide small-molecule design, not as evidence that peptides win.