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Mar. Drugs 2017, 15(3), 79; doi:10.3390/md15030079

Marine Diterpenes: Molecular Modeling of Thrombin Inhibitors with Potential Biotechnological Application as an Antithrombotic

1
Programa de Pós-Graduação em Ciências e Biotecnologia (PPBI), Instituto de Biologia, Universidade Federal Fluminense, Niterói 24210-130, RJ, Brazil
2
Laboratório de Trombose e Câncer, Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21944-970, RJ, Brazil
3
Programa de Pós-Graduação em Patologia, Hospital Universitário Antonio Pedro, Universidade Federal Fluminense, Niterói 24210-130, RJ, Brazil
4
Laboratório de Modelagem Molecular e Pesquisa em Ciências Farmacêuticas—LAMCIFAR, NUPEM, Universidade Federal do Rio de Janeiro, Campus Macaé, Rio de Janeiro27965-045, RJ, Brazil
*
Authors to whom correspondence should be addressed.
Academic Editor: Paul Long
Received: 14 December 2016 / Revised: 10 March 2017 / Accepted: 14 March 2017 / Published: 20 March 2017
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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. View Full-Text
Keywords: marine products; molecular docking; diterpenes; Dictyota menstrualis; anticoagulant; antithrombotic marine products; molecular docking; diterpenes; Dictyota menstrualis; anticoagulant; antithrombotic
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MDPI and ACS Style

Pereira, R.C.C.; Lourenço, A.L.; Terra, L.; Abreu, P.A.; Laneuville Teixeira, V.; Castro, H.C. Marine Diterpenes: Molecular Modeling of Thrombin Inhibitors with Potential Biotechnological Application as an Antithrombotic. Mar. Drugs 2017, 15, 79.

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