Novel Self-Limiting Prothrombinase Inhibitors

新型自限性凝血酶原酶抑制剂

• 批准号: 8313509
• 负责人: Michael N Blackburn
• 金额: $ 34.72万
• 依托单位: SHIFA BIOMEDICAL CORPORATION
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8313509
• 关键词: Accident and Emergency department; Active Sites; Address; Adverse effects; Affinity; Androgen Receptor; Anticoagulant therapy; Anticoagulants; Antithrombin III; Binding; Biochemical; Biochemistry; Biological; Biological Assay; Blood Clot; Blood coagulation; Cause of Death; Chromogenic Substrates; Cleaved cell; Coagulation Process; Collaborations; Complex; Computer Simulation; Computers; Databases; Development; Disease; Docking; Dose; Drug usage; Enzymatic Biochemistry; Evaluation; Factor Va; Factor Xa; Generations; Goals; Hemorrhage; Human; In Vitro; Lead; Letters; Ligand Binding; Low Density Lipoprotein Receptor; Malignant Neoplasms; Methods; Modeling; Molecular Target; Multienzyme Complexes; Myocardial Infarction; Oral; Patients; Pennsylvania; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Plasma; Positioning Attribute; Process; Proteins; Prothrombin time assay; Reagent; Resolution; Risk; Scanning; Screening procedure; Serine Protease; Site; Small Business Innovation Research Grant; Specificity; Stroke; Structure; Surface Plasmon Resonance; System; Tennessee; Testing; Thrombin; Thromboplastin; Thrombosis; Time; Universities; Western World; Work; abstracting; acute coronary syndrome; authority; base; chemical synthesis; clinically relevant; computer network; cost effective; design; disability; drug market; effective therapy; experience; in vitro Assay; inhibitor/antagonist; meetings; novel; prevent; professor; programs; prothrombinase complex; three dimensional structure; virtual

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.

项目总结/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发生在西方世界的三大疾病中：心脏病发作、中风和癌症。两种主要的药物用于治疗，以防止血液凝块是在顶级药物造成严重的不良反应，特别是出血，导致急诊室治疗的病人。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。我们的分子靶点是凝血酶原酶复合物。为此，我们将整合虚拟（计算机）筛选方法和生物物理/生物化学测定，以确定可能优化的先导化合物，以生产治疗血栓形成的新药。虚拟筛选需要靶蛋白的原子分辨率3D结构的可用性，提供了一种具有成本效益的方法来筛选数百万种化合物，以识别仅需购买和在生物或生化测定中测试的几种化合物。我们对因子Xa的这种3D结构的访问使这项工作成为可能。这项工作的具体目标是： 1.使用虚拟筛选方法来鉴定在FXa-Va界面中结合的化合物。 2.使用生物物理测定法测定特异性目标1中选择的化合物与FXa的结合。 3.使用体外试验系统测定特定目标2中确认的选定化合物的抑制活性。