Abstract
Thromboxane A2 (TXA2 ) is a hormone derived from arachidonic acid (AA) through cyclooxygenases (COX) and thromboxane synthase (TXS), and it is a platelet aggregator by activating thromboxane A2 receptor (TP) to induce platelet aggregation and cell proliferation. Based on the action of platelet activation, TXA2 is associated with thrombosis, acute myocardial infarction and many diverse inflammatory diseases. There are some different approaches to achieve antiplatelet therapy through this prostanoid pathway. One strategy is to inhibit COX so that TXA2 could not be produce from AA, such as the most well-known antiplatelet drug, aspirin. Despite aspirin could resist myocardial infarction and stroke, it may lead to gastrointestinal disorder and allergy. TXS inhibition is one kind of inhibitors for suppressing TXS to generate TXA2, but it does not work efficiently because other endoperoxides and isoprostanes can also active TP just like TXA 2. Accordingly, the method to directly inhibit TP seems to be attractive. However, TP antagonists include ifetroban, sulotroban, GR32191 and other antithrombotic agents still stay in phase II or III of clinical development due to the safety concerns and efficacy. The previous studies were not proposed available co-complex structure between TP and Thromboxane A2 (TXA2) or any of its inhibitors, it is necessary to establish a screening model for rational drug design in silico. Our research is focus on building the TP phaemacophore hypothesis for discovering other potential TP inhibitors. This study report, we developed pharmacophore hypothesis for discovery new TP inhibitors. The best hypothesis has one hydrogen-bond acceptor (A) and three hydrophobic aromatic groups (HYAR), its correlation coefficient of training set and testing set were 0.933 and 0.923, respectively. According to statistical validation and chemical features analysis, our best pharmacophore hypothesis has excellent ability to help medicinal chemists in their efforts to identify or design new TP inhibitors.