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Abstract
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.
Highlights
In recent decades, several studies described the biotechnological potential of marine organisms metabolites in industry and medicine
Dabigratan is an oral DTI licensed for the prevention of thromboembolism and stroke worldwide [26,27] but it is still not known how long it will be effective, as side effects and resistance have been described for some anticoagulant/antiplatelet molecules after long periods of use [28,29,30]
Marine organisms represent a valuable source of molecules, diterpenes, with high biotechnological potential still to be further explored
Summary
Several studies described the biotechnological potential of marine organisms metabolites in industry and medicine. These metabolites have been reported with different biological activities including antiplatelet, anticoagulant, and antithrombotic activities [1,2]. World Health Organization, these biological profiles are of interest given that cardiovascular diseases, According to the World Health. Organization, theseand biological profiles areworld of interest given that including thrombosis, are the main cause of death incapacity in the and the available cardiovascular diseases, including thrombosis, are the main cause of death and incapacity in the treatments present several adverse effects [3]. The current antithrombotic drugs therapies for cardiovascular diseases are based on different
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