Search for Antithrombotic Compounds to Overcome Adverse Effects of Current Drugs

描述（由申请人提供）：不受控制的血液凝固或血栓形成是美国和发达国家死亡的主要原因。致命或使人衰弱的血凝块发生在西方世界的三种主要疾病中：心脏病发作、中风和癌症。用于预防血栓的两种主要药物是引起严重不良反应的顶级药物，导致患者接受急诊室治疗。我们的目标是开发新的抗血栓药物，克服目前上市药物的局限性。我们的分子靶点是因子XIa (FXIa)，一种丝氨酸蛋白酶，在血液凝固级联扩增中起关键作用。为此，我们将整合虚拟（计算机）筛选方法和生化分析，以确定可能被优化的先导化合物，以生产治疗血栓的新药。虚拟筛选需要目标蛋白的原子分辨率3D结构的可用性，它提供了一种经济有效的方法来筛选数百万种化合物，以确定只需购买并在生物或生化分析中进行测试的几种化合物。我们对FXIa催化域的这种三维结构的访问使这项工作成为可能。这项工作的具体目的是：1。使用虚拟筛选方法鉴定结合在FXIa活性位点的化合物。2. 测定所选化合物在体外抑制FXIa活性的能力。3. 使用血浆或血液为基础的体外测定系统确认特异性Aim 2中选定化合物的活性。公共卫生相关性：在美国和发达国家，不受控制的凝血或血栓形成是导致死亡的主要原因。致命或使人衰弱的血凝块发生在西方世界的三种主要疾病中：心脏病发作、中风和癌症。用于预防血栓的两种主要药物是引起严重不良反应的顶级药物，导致患者接受急诊室治疗。我们的目标是开发新药，克服目前上市药物的局限性。

DESCRIPTION (provided by applicant): Uncontrolled blood clotting or 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 leading to emergency room treatment of patients. Our goal is to develop new anti- thrombotic drugs that overcome the limitations of current marketed drugs. Our molecular target is Factor XIa (FXIa), a serine protease that plays a key role in the amplification of the blood coagulation cascade. To that end, we will integrate virtual (computer) screening methods and 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 million 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 the FXIa catalytic domain makes this work possible. The specific aims of this work are to: 1. Use virtual screening methods to identify compounds that bind in the FXIa active site. 2. Determine the ability of the selected compounds to inhibit FXIa activity in an in vitro assay. 3. Confirm the activity of the selected compounds determined in Specific Aim 2 using plasma or blood-based in vitro assay systems. PUBLIC HEALTH RELEVANCE: Uncontrolled blood clotting or 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 leading to emergency room treatment of patients. Our goal is to develop new drugs that overcome the limitations of current marketed drugs.