title: Human thromboxane synthase: comparative modeling and docking evaluation with the competitive inhibitors Dazoxiben and Ozagrel.
abstract: Thromboxane synthase (TXAS) is a P450 epoxygenase that synthesizes thromboxane A2 (TXA2), a potent mediator of platelet aggregation, vasoconstriction and bronchoconstriction. This enzyme plays an important role in several human diseases, including myocardial infarction, stroke, septic shock, asthma and cancer. Despite of the increasing interest on developing TXAS inhibitors, the structure and activity of TXAS are still not totally elucidated. In this study, we used a comparative molecular modeling approach to construct a reliable model of TXAS and analyze its interactions with Dazoxiben and Ozagrel, two competitive inhibitors. Our results were compatible with experimental published data, showing feasible cation-π interaction between the iron atom of the heme group of TXAS and the basic nitrogen atom of the imidazolyl group of those inhibitors. In the absence of the experimental structure of thromboxane synthase, this freely available model may be useful for designing new antiplatelet drugs for diseases related with TXA2.
authors.affiliation: School of Pharmacy, Federal University of Rio de Janeiro , Niterói, Rio de Janeiro , Brazil .
authors.forename: Plínio Cunha
authors.initials: PC
authors.lastname: Sathler
authors.forename: Marcos
authors.initials: M
authors.lastname: Santana
authors.forename: André Luiz
authors.initials: AL
authors.lastname: Lourenço
authors.forename: Carlos Rangel
authors.initials: CR
authors.lastname: Rodrigues
authors.forename: Paula
authors.initials: P
authors.lastname: Abreu
authors.forename: Lúcio Mendes
authors.initials: LM
authors.lastname: Cabral
authors.forename: Helena Carla
authors.initials: HC
authors.lastname: Castro
mesh_terms: D001667:Binding, Competitive / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D008689:Methacrylates / Q000737:chemistry / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D013329:Structure-Activity Relationship; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; D008024:Ligands; D008689:Methacrylates; C029166:dazoxiben; D013930:Thromboxane-A Synthase; C034364:ozagrel
keywords: Antiplatelet; comparative molecular modeling; docking; thromboxane A2; thromboxane synthase