title: Molecular simulations enlighten the binding mode of quercetin to lipoxygenase-3.
abstract: Inhibition of lipoxygenases (LOXs) by flavonoid compounds is now well documented, but the description of the associated mechanism remains controversial due to a lack of information at the molecular level. For instance, X-ray determination of quercetin/LOX-3 system has led to a structure where the enzyme was cocrystallized with a degradation product of the substrate, which rendered the interpretation of the reported interactions between this flavonoid compound and the enzyme difficult. Molecular modeling simulations can in principle allow obtaining precious insights that could fill this lack of structural information. Thus, in this study, we have investigated various binding modes of quercetin to LOX-3 enzyme in order to understand the first step of the inhibition process, that is the association of the two entities. Molecular dynamics simulations and free energy calculations suggest that quercetin binds the metal center via its 3-hydroxychromone function. Moreover, enzyme/substrate interactions within the cavity impose steric hindrances to quercetin that may activate a direct dioxygen addition on the substrate.
authors.affiliation: Laboratoire de Chimie des Molécules Bioactives et des Arômes, UMR-CNRS 6001, Faculté des Sciences, Université de Nice Sophia Antipolis, 06108 Nice Cedex 2, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Fiorucci
authors.forename: Jérôme
authors.initials: J
authors.lastname: Golebiowski
authors.forename: Daniel
authors.initials: D
authors.lastname: Cabrol-Bass
authors.forename: Serge
authors.initials: S
authors.lastname: Antonczak
mesh_terms: D000975:Antioxidants / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D003198:Computer Simulation; D008084:Lipoxygenase / Q000737:chemistry / Q000378:metabolism*; D008956:Models, Chemical; D011794:Quercetin / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000975:Antioxidants; D011794:Quercetin; C095864:lipoxygenase 3; D008084:Lipoxygenase