Search for Antithrombotic Compounds to Overcome Adverse Effects of Current Drugs
寻找抗血栓化合物以克服现有药物的副作用
基本信息
- 批准号:7481477
- 负责人:
- 金额:$ 25.63万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-04-15 至 2010-04-14
- 项目状态:已结题
- 来源:
- 关键词:Accident and Emergency departmentActive SitesAdsorptionAdverse effectsAffinityAndrogen ReceptorAnimal ModelAntibodiesAnticoagulantsAntithrombin IIIAreaBindingBiochemicalBiologicalBiological AssayBloodBlood ClotBlood coagulationCatalytic DomainCause of DeathCell surfaceCharacteristicsChromogenic SubstratesClassCoagulantsCoagulation ProcessComputer SimulationComputersDatabasesDiseaseDockingDrug Delivery SystemsDrug usageEnzyme PrecursorsEnzymesEvaluationFactor IXFactor VIIaFactor XIFactor XIaFactor XaFeedbackFluorogenic SubstrateGenerationsGoalsHeparinHomoHumanImageryIntestinesKineticsLeadLettersLigandsMalignant NeoplasmsMeasuresMembrane ProteinsMethodsModificationMolecularMolecular TargetMyocardial InfarctionNorth CarolinaNumbersOralPathway interactionsPatientsPharmaceutical PreparationsPhasePhysiologicalPlasmaPlasma CellsPlasminPlayPrincipal InvestigatorProcessPropertyProtease DomainProteinsProthrombin time assayPublic HealthRegulationResolutionRoleScoreScreening procedureSeriesSerine ProteaseSiteSolutionsSpecificityStandards of Weights and MeasuresStrokeStructureSystemTestingThrombinThromboplastinThrombosisTimeTrypsinUniversitiesWaranWestern WorldWorkZinc Compoundsauthoritybaseclinically relevantconceptcost effectivedesigndimerdisabilitydrug marketexperiencein vitro Assayinhibitor/antagonistmolecular modelingnovelpeptidomimeticspreventprofessorprogramssupercomputerthree dimensional structurevirtualvirtual reality
项目摘要
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.
描述(由申请人提供):不受控制的凝血或血栓形成是美国和发达国家的主要死因。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,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。我们的分子靶点是因子XIa(FXIa),这是一种丝氨酸蛋白酶,在凝血级联放大中发挥关键作用。为此,我们将整合虚拟(计算机)筛选方法和生化测定,以识别可能经过优化以生产治疗血栓形成的新药的先导化合物。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FXIa催化结构域的这种3D结构的访问使这项工作成为可能。本工作的具体目标是:1。使用虚拟筛选方法鉴定结合FXIa活性位点的化合物。2.在体外试验中测定所选化合物抑制FXIa活性的能力。3.使用基于血浆或血液的体外试验系统确认特定目标2中测定的选定化合物的活性。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死亡的主要原因。致命的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,导致急诊室治疗的病人。我们的目标是开发新的药物,克服目前上市药物的局限性。
项目成果
期刊论文数量(0)
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Sherin S Abdel-Meguid其他文献
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{{ truncateString('Sherin S Abdel-Meguid', 18)}}的其他基金
Structure-Based Search for Novel Antihypercholestrolemic Agent
基于结构的新型抗高胆固醇药物的搜索
- 批准号:
7909109 - 财政年份:2008
- 资助金额:
$ 25.63万 - 项目类别:
Structure-Based Search for Novel Antihypercholestrolemic Agents
基于结构的新型抗高胆固醇药物的搜索
- 批准号:
7537300 - 财政年份:2008
- 资助金额:
$ 25.63万 - 项目类别:
Structure-Based Search for Novel Antihypercholestrolemic Agent
基于结构的新型抗高胆固醇药物的搜索
- 批准号:
8066009 - 财政年份:2008
- 资助金额:
$ 25.63万 - 项目类别:
Search for Anti-Androgen Compounds to Overcome Resistance of Current Drugs
寻找抗雄激素化合物以克服现有药物的耐药性
- 批准号:
7154608 - 财政年份:2006
- 资助金额:
$ 25.63万 - 项目类别:
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