Novel Tocopherol Analogs Nitric Oxide Donors: Binding to a-Tocopherol Transfer Protein, Docking and Affinity Studies.
López. G.V.1,3; Boiani, M.1; Campillo, N.E.4; Cerecetto, H.1,3; Galli, F.5; González, M.1,3; Paez, J.A4; Piro, O.E.6; Rubbo, H.2,3
1Departamento de Orgánica, Facultad de Química-Facultad de Ciencias; 2Departamento de Bioquímica, Facultad de Medicina; and 3Center for Free Radical and Biomedical Research, Universidad de la República, Montevideo, Uruguay. 4Instituto de Química Médica (CSIC), Madrid, España. 5Departamento de Medicina Interna, Sección de Bioquímica Aplicada y Ciencias Nutricionales, Universidad de Perugia, Perugia, Italia. 6Universidad Nacional de La Plata and Instituto IFLP(CONICET), Departamento de Física, Facultad de Ciencias Exactas, La Plata, Argentina.
Low density lipoprotein (LDL) oxidation may play a critical role in atherogenesis. a-tocopherol (a -T), the major component of vitamin E, is selectively targeted into LDL during its metabolism mostly due to its binding to a -tocopherol-transfer protein (a -TTP). Nitric oxide (.NO) is a free radical species that has strong biological antioxidant actions. In fact, .NO inhibits LDL oxidation by scavenging of lipid propagatory radicals and is capable to diffuse into LDL being a more effective lipid antioxidant than a-T. The aim of our work was to synthesize and biologically characterize hybrid molecules combining the vitamin E structure and .NO releasing moieties, to target ·NO delivery in vivo specifically into the LDL particle, sparing LDL during oxidative and nitrative stress conditions. In order to study the affinity of synthesized compounds to a-TTP, we performed theoretical and experimental binding studies. The 3D model of a -TTP have been established using as template the X-ray coordinates of a-TTP in complexes with a-T. Conformational studies for the considered ligands were carried out taking into account the X-ray coordinates. a-TTP/synthesised compounds complexes were studied by docking, using the titled 3D model. The structural effects of ligand binding were studied and analysed on the basis of hydrogen bond interactions and binding energy calculations. Finally, we analysed the experimental affinities of synthesized compound to a-TTP and their correlation with modelling calculations. In vivo bioavailability and antiatherogenic properties of these novel .NO donors are still in progress. Convenio Instituto de Química Médica (CSIC), España-UdelaR, Uruguay
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