title: Predicting and Understanding the Enzymatic Inhibition of Human Peroxiredoxin 5 by 4-Substituted Pyrocatechols by Combining Funnel Metadynamics, Solution NMR, and Steady-State Kinetics.
abstract: 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.
authors.affiliation: Université de Lyon, Institut des Sciences Analytiques, UMR 5280, CNRS, Université Lyon 1, ENS Lyon-5, rue de la Doua, F-69100 Villeurbanne, France.
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Chow
authors.affiliation: Université de Lyon, Institut des Sciences Analytiques, UMR 5280, CNRS, Université Lyon 1, ENS Lyon-5, rue de la Doua, F-69100 Villeurbanne, France.
authors.forename: Laura
authors.initials: L
authors.lastname: Troussicot
authors.affiliation: Université de Lyon, Institut des Sciences Analytiques, UMR 5280, CNRS, Université Lyon 1, ENS Lyon-5, rue de la Doua, F-69100 Villeurbanne, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Martin
authors.affiliation: Université de Lyon, Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, UMR 5246, Université Claude Bernard Lyon 1, CNRS, INSA, CPE-Lyon, 43 Bd du 11 novembre 1918, F-69622 Villeurbanne, France.
authors.forename: Bastien
authors.initials: B
authors.lastname: Doumèche
authors.affiliation: Université de Lyon, Institut des Sciences Analytiques, UMR 5280, CNRS, Université Lyon 1, ENS Lyon-5, rue de la Doua, F-69100 Villeurbanne, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Guillière
authors.affiliation: Université de Lyon, Institut des Sciences Analytiques, UMR 5280, CNRS, Université Lyon 1, ENS Lyon-5, rue de la Doua, F-69100 Villeurbanne, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Lancelin
mesh_terms: D001669:Biochemical Phenomena; D002396:Catechols / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D054464:Peroxiredoxins / Q000037:antagonists & inhibitors*; D012996:Solutions
chemical_list: D002396:Catechols; D004791:Enzyme Inhibitors; D012996:Solutions; C515974:PRDX5 protein, human; D054464:Peroxiredoxins