Content area
Full text
Received Sep 14, 2017; Revised Nov 30, 2017; Accepted Dec 31, 2017
This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
1. Introduction
Thrombosis persists as a leading cause of death and incapacity worldwide [1]. The formation of thrombosis is a very complex pathological process involving the platelets and blood coagulation components. Thrombin plays a vital role in blood coagulation by promoting platelet aggregation and by converting fibrinogen to form the fibrin clot in the final step of the coagulation cascade [2]. Thrombin is composed of two polypeptide chains of 36 (A chain) and 259 (B chain) residues that are covalently linked through a disulfide bond, and the B chain carries the functional epitopes of the enzyme [3]. As same as all chymotrypsin-like serine proteases, thrombin has a conserved active centre located inside the molecule and contains amino acid residues of HIS57, ASP102, and SER195, which are called the catalytic triad [4]. Except for its active centre, thrombin possesses two exosites (1 and 2), positively charged domains located at opposite poles of the enzyme, among them, exosite 1 is utilized to dock on the substrates such as fibrinogen, and exosite 2 serves as the heparin-binding domain [5].
The current antithrombotic therapies include heparin (unfractionated heparin and low-molecular-weight heparins), fondaparinux, vitamin K antagonists, factor Xa inhibitors, and direct thrombin inhibitors [6]. Direct thrombin inhibitors (DTIs), such as argatroban, dabigatran, lepirudin, desirudin, and bivalirudin, which bind to thrombin and block its enzymatic activity, are widely and effectively used in the treatment of thromboembolic diseases; however, dabigatran is not orally available due to its high polarity [7]. Therefore, dabigatran etexilate as prodrug was developed to facilitate gastrointestinal absorption by adding an ethyl group at the carboxylic acid group and a hexyloxycarbonyl side chain at the amidine group [8]. Compared with heparins, DTIs do not require antithrombin as a cofactor and do not bind to plasma proteins; therefore, they produce a more predictable anticoagulant effect, and variability of patient response is low relative to other drug classes [9]. In reality, they still present limitations such as a narrow therapeutic window, and bleeding and anaphylaxis as side effects [10]....