Novel Self-Limiting Prothrombinase Inhibitors

项目摘要/摘要 血栓形成是美国和发达国家的主要死亡原因。致命或使人衰弱的血栓出现在西方世界的三大疾病中：心脏病发作、中风和癌症。在治疗上用于预防血栓的两种主要药物都位居榜首，这些药物会产生严重的不良反应，特别是出血，导致患者在急诊室接受治疗。我们的目标是开发新的抗血栓药物，以克服当前市场药物的局限性。我们的分子靶标是凝血酶原酶复合体。为此，我们将整合虚拟(计算机)筛选方法和生物物理/生化分析，以确定可能优化的先导化合物，以生产治疗血栓形成的新型药物。虚拟筛选需要获得目标蛋白质的原子分辨率3D结构，它提供了一种成本效益高的方法来筛选数百万种化合物，以识别仅需购买的几种化合物，并在生物或生化分析中进行测试。我们对因子Xa的这种3D结构的了解使这项工作成为可能。这项工作的具体目标是： 1.使用虚拟筛选方法鉴定结合在FXA-Va界面上的化合物。 2.用生物物理方法确定在特定目标1中选择的化合物与FXA的结合。 3.使用体外测定系统测定在特定目的2中确认的所选化合物的抑制活性。

Project Summary/Abstract Thrombosis is a primary cause of death in the US and developed world. Fatal or debilitating blood clots occur in the three major diseases of the western world: heart attacks, stroke and cancer. Two of the major drugs used therapeutically to prevent blood clots are in the top drugs causing serious adverse effects, particularly bleeding, leading to emergency room treatment of patients. Our goal is to develop new antithrombotic drugs that overcome the limitations of current marketed drugs. Our molecular target is the prothrombinase complex. To that end, we will integrate virtual (computer) screening methods and biophysical/biochemical assays to identify lead compounds that can potentially be optimized to produce novel drugs for the treatment of thrombosis. Virtual screening, which requires the availability of atomic resolution 3D structures of the target protein, provides a cost effective way to screen millions of compounds to identify just a few to be purchased and tested in a biological or biochemical assay. Our access to such 3D structures of Factor Xa makes this work possible. The specific aims of this work are to: 1. Use virtual screening methods to identify compounds that bind in the FXa-Va interface. 2. Determine the binding of compounds selected in Specific Aim 1 to FXa using biophysical assays. 3. Determine inhibitory activity of the selected compounds confirmed in Specific Aim 2 using in vitro assay systems.