Metadynamics Simulations for Rational Ligand Design in the Reversible Inhibition of Human Peroxiredoxin 5
Troussicot, L.; Blanc, F. E. C.; Pascal, Y.; Vidal, S.; Lancelin, J.-M.; Guilliere, F.
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Based on Funnel-Metadynamics, a molecular dynamics protocol that provides an accurate representation of protein-ligand interaction, the activity of an initial hit of Human peroxiredoxin 5 was improved by several orders of magnitude by the introduction of a single heavy-atom modification. This improvement was followed by molecular dynamics simulation and NMR experiments with striking agreement. We demonstrate that molecular dynamics is a rational basis for the design of straightforward improved ligands starting from low-affinity but selective hits with a minimum adaptation. This result can only be reached by analyzing the statistical quantitative description of the protein-ligand interactions available through molecular dynamics simulations.
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