Abstract
The development of new anticoagulants is an important goal for the improvement of thrombosis treatment. Recent studies have suggested the importance of thrombin inhibitors in the modulation of thromboembolic disorders. The aim of this study was to discover a new small-molecule thrombin inhibitor. In this study, the compound JJ1, which has a novel scaffold, was selected by structure-based docking simulation to determine its potential inhibitory activity against thrombin. JJ1 was shown to inhibit the catalytic activity of human α-thrombin with a Ki of 0.019 μM by direct binding to the active site and with at least 10,000-fold selectivity relative to that reported for the inhibition of other biologically important serine proteases. JJ1 prolonged clotting times (activated partial thromboplastin time and prothrombin time) and inhibited the activity and production of thrombin. Furthermore, it inhibited thrombin-catalyzed fibrin polymerization and platelet aggregation. Similar to its in vitro antithrombotic activities, JJ1 showed enhanced antithrombotic effects in an in vivo pulmonary embolism and arterial thrombosis model. It also exhibited anticoagulant effects in mice. Collectively, these results demonstrated that JJ1 was a potent, direct, and selective thrombin inhibitor that may be useful in the management of various thrombotic disorders.
Highlights
Thrombin is an important multifunctional serine protease that is central to the bioregulation of hemostasis and thrombosis[1]
Because the earlier enrichment of true positives is more important for high throughput structure-based virtual screening (SBVS), we used the value of logarithmically scaled area under the curve (LogAUC) as a metric, selecting 2CF9-H18 as the best structure
The values of LogAUC and enrichment factor at 1% (EF1) were approximately two-fold higher than the averages (26.1 for LogAUC and 17.1 for EF1) (Figs 1 and S1)
Summary
Thrombin is an important multifunctional serine protease that is central to the bioregulation of hemostasis and thrombosis[1]. Heparin and other vitamin K antagonists such as coumarin derivatives are essential components of anti-thrombotic treatment, both drugs have well-known side effects such as a narrow therapeutic window and a highly variable dose-response relationship These limitations drive the continual and intense effort to develop new anticoagulants, which predominantly target specific coagulation factors[7]. Direct thrombin inhibitors (DTIs) represent potentially useful drugs for the treatment of both venous and arterial thrombosis[8,9,10,11]. They are small, synthetic, and specific inhibitors of thrombin that are independent of antithrombin action[12]. The present report describes the kinetic properties and antithrombotic efficacy of this novel thrombin inhibitor via evaluation of in vitro and in vivo clotting times, fibrin polymerization, platelet aggregation, fibrinopeptide A (FPA) formation, thrombus formation, and thrombin activity and production
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