Metadynamics Simulations Meet Ligand Design for the Reversible Inhibition of Human Peroxiredoxin 5
Published in ACS Omega, 2026
Laura Troussicot, Florian E. C. Blanc, Yoann Pascal, Sebastien Vidal, Jean-Marc Lancelin, Florence Guillière
ACS Omega, 2026
In this drug design project, we combine funnel metadynamics, NMR and biochemical assays to improve an inhbitor of Human peroxiredoxin 5, a target enzyme for innovative treatments against strokes.
Abstract
Abstract 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.