title: On the interactions of leflunomide and teriflunomide within receptor cavity--NMR studies and energy calculations.
abstract: Leflunomide is a disease-modifying antirheumatic drug with antiinflammatory and immunosuppressive activity used for the treatment of psoriatic and rheumatoid arthritis. It undergoes rapid metabolization to teriflunomide, a metabolite that is responsible for the biological activity of leflunomide. Continuing our investigations on the interactions of biologically important azahetarenes with the environment, we focused on leflunomide and its active metabolite, teriflunomide, considering the interactions teriflunomide-amino acid within the target protein (dihydroorotate dehydrogenase) using density functional theory, as well as ONIOM techniques. The results of theoretical studies have shown that the interactions of teriflunomide with tyrosine and arginine involve principally the amide fragment of teriflunomide. The presence of the internal hydrogen bond between (Z)-teriflunomide carbonyl oxygen and enolic hydroxyl decreases the interaction strength between teriflunomide and tyrosine or arginine. Even the E isomer of teriflunomide would usually provide a stronger interaction teriflunomide-amino acid than the Z isomer with the internal hydrogen bond.
authors: Department of Organic Chemistry, Faculty of Pharmacy, Poznan University of Medical Sciences, Grunwaldzka 6 street, 60-780, Poznań, Poland, jacekkuj@ump.edu.pl.
authors: Jacek
authors: J
authors: Kujawski
authors: Marek K
authors: MK
authors: Bernard
authors: Elżbieta
authors: E
authors: Jodłowska
authors: Kornelia
authors: K
authors: Czaja
authors: Beata
authors: B
authors: Drabińska
mesh_terms: D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D001665:Binding Sites; D003437:Crotonates / Q000737:chemistry* / Q000378:metabolism; D000090722:Dihydroorotate Dehydrogenase; D004734:Energy Metabolism / Q000187:drug effects; D006801:Humans; D006860:Hydrogen Bonding; D006885:Hydroxybutyrates; D007555:Isoxazoles / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D000077339:Leflunomide; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009570:Nitriles; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors / Q000737:chemistry; D014052:Toluidines / Q000737:chemistry* / Q000378:metabolism
chemical_list: D018501:Antirheumatic Agents; D003437:Crotonates; D000090722:Dihydroorotate Dehydrogenase; D006885:Hydroxybutyrates; D007555:Isoxazoles; D009570:Nitriles; D014052:Toluidines; C527525:teriflunomide; D044925:Oxidoreductases Acting on CH-CH Group Donors; D000077339:Leflunomide