Marine Diterpenes: Molecular Modeling of Thrombin Inhibitors with Potential Biotechnological Application as an Antithrombotic.
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 algaDictyota menstrualiswere 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.
Programa de Pós-Graduação em Ciências e Biotecnologia (PPBI), Instituto de Biologia, Universidade Federal Fluminense, Niterói 24210-130, RJ, Brazil. rebecaccpereira@gmail.com.
Rebeca Cristina Costa
RC
Pereira
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. andrebiouff@gmail.com.|Programa de Pós-Graduação em Patologia, Hospital Universitário Antonio Pedro, Universidade Federal Fluminense, Niterói 24210-130, RJ, Brazil. andrebiouff@gmail.com.
André Luiz
AL
Lourenço
Programa de Pós-Graduação em Ciências e Biotecnologia (PPBI), Instituto de Biologia, Universidade Federal Fluminense, Niterói 24210-130, RJ, Brazil. luterra.santos@gmail.com.
Luciana
L
Terra
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. abreu_pa@yahoo.com.br.
Paula Alvarez
PA
Abreu
Programa de Pós-Graduação em Ciências e Biotecnologia (PPBI), Instituto de Biologia, Universidade Federal Fluminense, Niterói 24210-130, RJ, Brazil. valerialaneuville@gmail.com.
Valéria
V
Laneuville Teixeira
Programa de Pós-Graduação em Ciências e Biotecnologia (PPBI), Instituto de Biologia, Universidade Federal Fluminense, Niterói 24210-130, RJ, Brazil. hcastrorangel@yahoo.com.br.|Programa de Pós-Graduação em Patologia, Hospital Universitário Antonio Pedro, Universidade Federal Fluminense, Niterói 24210-130, RJ, Brazil. hcastrorangel@yahoo.com.br.
Helena Carla
HC
Castro
D000925:Anticoagulants / Q000737:chemistry* / Q000494:pharmacology*; D059001:Aquatic Organisms / Q000737:chemistry; D001777:Blood Coagulation / Q000187:drug effects; D001938:Brazil; D004224:Diterpenes / Q000737:chemistry* / Q000494:pharmacology*; D005343:Fibrinolytic Agents / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D062105:Molecular Docking Simulation / Q000379:methods; D000459:Phaeophyceae / Q000737:chemistry; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors*; D013927:Thrombosis / Q000188:drug therapy
D000925:Anticoagulants; D004224:Diterpenes; D005343:Fibrinolytic Agents; D013917:Thrombin
Dictyota menstrualis; anticoagulant; antithrombotic; diterpenes; marine products; molecular docking