RESUMO
Thrombosis related diseases are among the main causes of death and incapacity in the world. Despite the existence of antithrombotic agents available for therapy, they still present adverse effects like hemorrhagic risks which justify the search for new options. Recently, pachydictyol A, isopachydictyol A, and dichotomanol, three diterpenes isolated from Brazilian marine brown alga Dictyota menstrualis were identified as potent antithrombotic molecules through inhibition of thrombin, a key enzyme of coagulation cascade and a platelet agonist. Due to the biotechnological potential of these marine metabolites, in this work we evaluated their binding mode to thrombin in silico and identified structural features related to the activity in order to characterize their molecular mechanism. According to our theoretical studies including structure-activity relationship and molecular docking analysis, the highest dipole moment, polar surface area, and lowest electronic density of dichotomanol are probably involved in its higher inhibition percentage towards thrombin catalytic activity compared to pachydictyol A and isopachydictyol A. Interestingly, the molecular docking studies also revealed a good shape complementarity of pachydictyol A and isopachydictyol A and interactions with important residues and regions (e.g., H57, S195, W215, G216, and loop-60), which probably justify their thrombin inhibitor effects demonstrated in vitro. Finally, this study explored the structural features and binding mode of these three diterpenes in thrombin which reinforced their potential to be further explored and may help in the design of new antithrombotic agents.
Assuntos
Anticoagulantes/química , Anticoagulantes/farmacologia , Diterpenos/química , Diterpenos/farmacologia , Fibrinolíticos/química , Fibrinolíticos/farmacologia , Trombina/antagonistas & inibidores , Organismos Aquáticos/química , Coagulação Sanguínea/efeitos dos fármacos , Brasil , Modelos Moleculares , Simulação de Acoplamento Molecular/métodos , Phaeophyceae/química , Relação Estrutura-Atividade , Trombose/tratamento farmacológicoRESUMO
Dictyota menstrualis (Hoyt) Schnetter, Hörning & Weber-Peukert (Dictyotales, Phaeophyceae) was studied for the production of oil-based bioproducts and co-products. Experiments were performed to evaluate the effect of carbon dioxide (CO2) concentration, under nitrogen (NO3 (-)) limiting and saturation conditions, on growth rate (GR), photosynthesis, as well as nitrate reductase (NR), carbonic anhydrase (CA), and Rubisco activities. In addition, the biochemical composition of D. menstrualis under these conditions was estimated. GR, protein content, and N content in D. menstrualis were higher in treatments containing NO3 (-), irrespective of CO2 addition. However, when CO2 was added to medium saturated with NO3 (-), values of maximum photosynthesis, Rubisco, and NR activity, as well as total soluble carbohydrates and lipids, were increased. CA activity did not vary under the different treatments. The fatty acid profile of D. menstrualis was characterized by a high content of polyunsaturated fatty acids, especially the omega-3 fatty acids, making it a possible candidate for nutraceutical use. In addition, this species presented high GR, photosynthetic rate, and fatty acid content, highlighting its economic importance and the possibility of different biotechnological applications.