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

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. TOC Graphic