title: Modeling the mechanism of the glutathione peroxidase mimic ebselen.
abstract: Ebselen (1), the quintessential mimic of the antioxidant selenoenzyme glutathione peroxidase (GPx), is a potential chemopreventative for various diseases associated with oxidative stress. Density-functional theory (DFT) and solvent-assisted proton exchange (SAPE) are used to model the complex mechanism for scavenging of reactive oxygen species by 1. SAPE is a microsolvation method designed to approximate the role of bulk solvent in chemical processes involving proton transfer. Consistent with experimental studies, SAPE studies predict the reaction of 1 with thiol (RSH) to form a selenenyl sulfide 2 to be preferred under most conditions, with an alternate pathway through a selenoxide 3 possible at high reactive oxygen species (ROS) concentrations ([ROS] ≫ [RSH]). The reduction of 2 to the selenol 4, known to be rate-determining in the protein, has a high SAPE activation barrier due to a strong Se···O interaction which reduces the electrophilicity of the sulfur center of the -SeS- bond of 2. Thiols, such as dithiols and peptide-based thiols, are expected to overcome this barrier through structural features that increase the probability of attack at this sulfur. Thus, in vivo, the GPx-like pathway is the most likely mechanism for 1 under most circumstances, except, perhaps, under extreme oxidative stress where initial oxidation to 3 could compete with formation of 2. Simple thiols, used in various in vitro studies, are predicted by SAPE modeling to proceed through oxidation of 2 to a seleninyl sulfide intermediate. Overall, SAPE modeling provides a realistic interpretation of the redox mechanism of 1 and holds promise for further exploration of complex aqueous-phase reaction mechanisms.
authors: Department of Chemistry and Biochemistry, Old Dominion University, Hampton Boulevard, Norfolk, Virginia 23529, USA.
authors: Sonia
authors: S
authors: Antony
authors: Craig A
authors: CA
authors: Bayse
mesh_terms: D001393:Azoles / Q000737:chemistry*; D040761:Biomimetic Materials / Q000737:chemistry*; D016166:Free Radical Scavengers / Q000737:chemistry; D005979:Glutathione Peroxidase / Q000737:chemistry*; D054833:Isoindoles; D008958:Models, Molecular; D008968:Molecular Conformation; D016566:Organoselenium Compounds / Q000737:chemistry*; D010084:Oxidation-Reduction; D011522:Protons; D011789:Quantum Theory; D017382:Reactive Oxygen Species / Q000737:chemistry; D012997:Solvents / Q000737:chemistry
chemical_list: D001393:Azoles; D016166:Free Radical Scavengers; D054833:Isoindoles; D016566:Organoselenium Compounds; D011522:Protons; D017382:Reactive Oxygen Species; D012997:Solvents; C042986:ebselen; D005979:Glutathione Peroxidase