Vitamin and antioxidant properties of tocopherols: characteristic of the molecular mechanisms of action

Abstract

The molecular docking method was used to study the structural characteristics determining the competitive transport in the blood, and also the subsequent binding with enzymes of tocopherols and their metabolites to yield a specific biological activity. The target proteins were α-tocopherol-transport protein (α-TTP), tocopherol-associated protein 1 (TAP1), cyclooxygenase-2 (COX-2), protein phosphatase 2A (PP2A) and 3-hydroxy3-methylglutaryl-Coenzyme A (HMG-CoA) reductase. RRR-tocopherol (α-, β-, γand δ-forms), RRR-13’-carboxychromanol (α-, β-, γ- and δ-forms) and carboxyethyl hydroxychromanol (α-, β-, γ- and δ-forms) were used as ligands in this research. The conducted studies confirmed that among all homologues the α-tocopherol had the greatest affinity for the transport proteins α-TTP and TAP1 (ΔG=-11.40 and ΔG=-10.28 kcal/mol, respectively). It was shown that in all cases carboxyethyl hydroxychromanol metabolites had the greatest free binding energy (ΔG>-8 kcal/mol), that was why it has been concluded that they were not effective ligands for the proteins under study. In contrast, the metabolites of 13’-carboxychromanol, when bound to both α-TTP and TAP1 proteins, preferentially formed more stable complexes than their precursors. It was shown for the first time that γ-13’-carboxychromanol with TAP1 has less free binding energy (ΔG=-10.64 kcal/mol) in comparison to the α-tocopherol complex (ΔG=-10.28 kcal/mol). It has also been shown that 13’-carboxychromanole metabolites were more efficiently bound to COX-2 enzymes (ΔG=-9.56 kcal/mol for α-13’-carboxychromanol complex) and HMG-CoA reductase (ΔG=-9.46 kcal/mol for the complex with δ-13’-carboxychromanol). In relation to the PP2A protein, 13’-carboxychromanol metabolites had similar affinities as their precursors. The results of the work indicate the possibility of 13’-carboxychromanols to competitively bind to α-tocopherol transporters and act as effective ligands of COX-2 and HMG-CoA, that can be used to correct nutritional status in conditions accompanied by deficiency of tocopherols.

Keywords:tocopherols, metabolism of tocopherols, carboxyethyl hydroxychromanol, carboxychromanol, antioxidant and vitamin activity, molecular docking