title: Theoretical study on the inhibition of ribonucleotide reductase by 2'-mercapto-2'-deoxyribonucleoside-5'-diphosphates.
abstract: Ribonucleotide reductase (RNR) is responsible for the reduction of ribonucleotides into the correspondent 2'-deoxyribonucleotides in the only physiological process that yields the monomers of DNA. The enzyme has thus become an attractive target for chemotherapies that fight proliferation-based diseases, specifically cancer and infections by some viruses and parasites. 2'-Mercapto-2'-deoxyribonucleoside-5'-diphosphates (SHdNDP) are mechanism-based inhibitors of RNR and therefore potential chemotherapeutic agents for those indications. Previous experimental studies established the in vitro and in vivo activity of SHdNDP. In the in vitro studies, it was observed that the activity was dependent on the oxidative status of the medium, with the inactivation of RNR only occurring when molecular oxygen was available. To better understand the mechanism involved in RNR inactivation by SHdNDP, we performed theoretical calculations on the possible reactions between the inhibitors and the RNR active site. As a result, we propose the possible mechanistic pathways for the chemical events that occur in the absence and in the presence of O2. They correspond to a refinement and a complement of those proposed in the literature.
authors.affiliation: REQUIMTE, Departamento de Química, Faculdade de Ciências do Porto, Rua do Campo Alegre, 687, 4169-007 Porto, Portugal.
authors.forename: Susana
authors.initials: S
authors.lastname: Pereira
authors.forename: Pedro Alexandrino
authors.initials: PA
authors.lastname: Fernandes
authors.forename: Maria João
authors.initials: MJ
authors.lastname: Ramos
mesh_terms: D003853:Deoxyribonucleosides / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D010755:Organophosphates / Q000737:chemistry / Q000494:pharmacology*; D010100:Oxygen / Q000737:chemistry; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013438:Sulfhydryl Compounds / Q000737:chemistry / Q000494:pharmacology*; D013816:Thermodynamics
chemical_list: D003853:Deoxyribonucleosides; D004791:Enzyme Inhibitors; D010755:Organophosphates; D013438:Sulfhydryl Compounds; D012264:Ribonucleotide Reductases; D010100:Oxygen