Metadynamics Simulations Meet Ligand Design for the Reversible Inhibition of Human Peroxiredoxin 5

High Resolution Image Download MS PowerPoint Slide Using insights from funnel metadynamics, a molecular dynamics protocol that provides a detailed representation of protein–ligand interactions, we investigated how a single heavy-atom modification can enhance the activity of an initial hit against human peroxiredoxin 5. This improvement was validated by NMR experiments and enzyme-inhibition assays. Our results illustrate how molecular dynamics simulations offer a rational framework for designing ligands with improved properties, starting from low affinity but selective hits with minimal structural modifications.