Predicting and Understanding the Enzymatic Inhibition of Human Peroxiredoxin 5 by 4-Substituted Pyrocatechols by...

Funnel metadynamics is a kind of computational simulation used to enhance the sampling of protein-ligand binding events in solution. By characterization of the binding interaction events, an estimated absolute binding free energy can be calculated. Nuclear magnetic resonance and funnel metadynamics were used to evaluate the binding of pyrocatechol derivatives (catechol, 4-methylcatechol, and 4-tert-butylcatechol) to human peroxiredoxin 5. Human peroxiredoxins are peroxidases involved in cellular peroxide homeostasis. Recently, overexpressed or suppressed peroxiredoxin levels have been linked to various diseases. Here, the catechol derivatives were found to be inhibitors against human peroxiredoxin 5 through a partial mixed type noncompetitive mechanism. Funnel metadynamics provided a microscopic model for interpreting the inhibition mechanism. Correlations were observed between the inhibition constants and the absolute binding free energy. Overall, this study showcases the fact that funnel metadynamics simulations can be employed as a preliminary approach to gain an in-depth understanding of potential enzyme inhibitors.