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
BACKGROUND: Hepatitis A virus (HAV) and hepatitis E virus (HEV) are both transmitted by the faecal-oral route, and represent common causes of acute hepatitis in developing countries. The endemicity of HAV infection has shifted from high to moderate in Brazil. Human cases of HEV infection seem to be rare, although the virus has been detected in swine livestock and effluents of slaughterhouses. This study was to determine the epidemiology of hepatitis A and E in one of the largest agricultural settlements in the Amazon Basin of Brazil. METHODS: Serum samples collected from 397 individuals aged between 5 and 90 years during a population-based cross-sectional survey were tested for anti-HAV and anti-HEV antibodies. Associated risk factors and spatial clustering of HAV and HEV seropositivity were also analyzed. RESULTS: The overall rate of HAV seropositivity was 82.9% (95% confidence interval (CI), 79.2-86.6%). Multilevel logistic regression analysis identified increasing age (in years; odds ratio (OR), 1.097; 95% CI, 1.050-1.147; P < 0.001) and crowding (OR, 1.603; 95% CI, 1.054-2.440; P = 0.028) as significant risk factors for HAV seropositivity. Anti-HEV IgG was detected in 50/388 settlers (12.9%, 95% CI, 9.5-16.2%). Anti-HEV IgM was detected in 7/43 (16.3%) anti-IgG positive samples, and 4 of them had a confirmed result by immunoblot. Increasing age was the only significant determinant of HEV seropositivity (OR, 1.033; 95% CI, 1.016-1.050; P < 0.001). No significant spatial clustering of HAV and HEV seropositivity was detected in the area. CONCLUSIONS: Both HAV and HEV are endemic, with differing rates of infection in children and adults in this rural setting of the Brazilian Amazon. Anti-HEV prevalence was considerably higher than those previously reported in Brazil. The detection of HEV- specific IgM antibodies in four asymptomatic individuals is highly suggestive of the circulation of HEV in this rural population.