Accelerated AChE Reactivator Design by Mechanistic Neutron Scattering Studies
通过机械中子散射研究加速乙酰胆碱酯酶再激活器设计
基本信息
- 批准号:8892277
- 负责人:
- 金额:$ 67.02万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-07-15 至 2019-06-30
- 项目状态:已结题
- 来源:
- 关键词:AcetylcholineAcetylcholinesteraseActive SitesAddressAntidotesBindingCatalysisCholinesterasesCollaborationsComplexComputer AnalysisComputer SimulationConflict (Psychology)CoupledDataDependenceDevelopmentDimensionsDrug DesignElectronicsEnzymesEquilibriumEquipment and supply inventoriesEventFutureGenerationsHealthHumanHydration statusHydrogenJointsKnowledgeLaboratoriesLigandsLocationMediatingMethodsMolecularMonitorMotionMusNeurotransmittersNeutron DiffractionNeutronsOrganophosphatesOximesOxygenPesticidesPhosphorusPositioning AttributeProcessPropertyProteinsProtonsReactionRefractoryRelative (related person)Research InstituteResearch PersonnelResolutionRoentgen RaysSchemeSideSolutionsSolventsSpectrometryStructureSystemTechniquesTechnologyTemperatureTertiary Protein StructureTestingTimeTriad Acrylic ResinUniversitiesUtahWaterX-Ray Crystallographyagedbasebiophysical analysiscomparativedesignimprovedinsightinstrumentionizationmillisecondnerve agentnext generationnovel strategiesnucleophilic substitutionprotonationscreeningthree dimensional structure
项目摘要
DESCRIPTION (provided by applicant): We propose here a cutting edge biophysical study aimed at identifying structurally imposed limiting factors in oxime reactivation of nerve agent and
pesticide organophosphate (OP) inhibited human acetylcholinesterase (hAChE). We will focus on characterizing hAChE protein domain motions in solution critical for facilitating reactivation a well as on precise proton structure in the hAChE active center involved in the nucleophilic substitution of covalently conjugated phosphorus. The study will use cutting edge techniques to characterize reactivation related molecular motions of hAChE in solution based on X-ray and neutron scatter in equilibrium and resolved in time from ps to min intervals. High resolution joint
X-ray/neutron diffraction on hAChE crystals at room temperature will be used to resolve precise positions of protons and complete water molecules in the hAChE active center. Both scattering and diffraction studies will rely on comparative analysis of native, OP-conjugated, and aged hAChE alone, and in complex with selected structurally diverse oxime reactivators and will be aimed at identifying structural features of oximes optimal for overcoming limitations imposed by structural dynamics and proton distribution in the hAChE active center. The acquired information coupled with advanced computational analysis and simulation will be used to design prototypic accelerated oxime reactivator of OP-hAChE. The structures of prototypic accelerated reactivators will be made available for synthesis and refinement using our existing drug design pipeline developed in collaboration with researchers of The Scripps Research Institute in La Jolla.
描述(由申请人提供):我们在此提出了一项尖端生物物理学研究,旨在确定神经毒剂肟再活化中结构上强加的限制因素,
有机磷农药(OP)抑制人乙酰胆碱酯酶(hAChE)。我们将专注于表征hAChE蛋白质结构域的运动在溶液中的关键促进再活化以及精确的质子结构中的hAChE活性中心参与的亲核取代共价共轭磷。这项研究将使用尖端技术来表征再活化相关的分子运动的hAChE在溶液中的基础上的X射线和中子散射的平衡和解决的时间从ps到分钟的间隔。高分辨率接头
在室温下对hAChE晶体的X射线/中子衍射将用于解析hAChE活性中心中质子和完整水分子的精确位置。散射和衍射的研究将依赖于比较分析的本地,OP共轭,和老化的乙酰胆碱酯酶单独,并在复杂的选择结构上不同的肟再活化剂,并将旨在确定肟的结构特征,最佳的克服限制所施加的结构动力学和质子分布在乙酰胆碱酯酶活性中心。所获得的信息加上先进的计算分析和模拟将用于设计原型加速肟活化剂的OP-hAChE。原型加速再活化剂的结构将可用于合成和改进,使用我们与位于拉霍亚的斯克里普斯研究所的研究人员合作开发的现有药物设计管道。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('Zoran Radic', 18)}}的其他基金
In Vivo Efficacy of Novel Uncharged Bis-Oximes in OP Poisoning Treatment
新型不带电双肟治疗 OP 中毒的体内疗效
- 批准号:
10412696 - 财政年份:2022
- 资助金额:
$ 67.02万 - 项目类别:
Refined uncharged Bis-Oximes for Rapid CNS Reactivation of OP-Inhibited hAChE.
用于快速 CNS 重新激活 OP 抑制的 hAChE 的精制不带电双肟。
- 批准号:
10582723 - 财政年份:2022
- 资助金额:
$ 67.02万 - 项目类别:
Refined uncharged Bis-Oximes for Rapid CNS Reactivation of OP-Inhibited hAChE.
用于快速 CNS 重新激活 OP 抑制的 hAChE 的精制不带电双肟。
- 批准号:
10407766 - 财政年份:2022
- 资助金额:
$ 67.02万 - 项目类别:
In Vivo Efficacy of Novel Uncharged Bis-Oximes in OP Poisoning Treatment
新型不带电双肟治疗 OP 中毒的体内疗效
- 批准号:
10598635 - 财政年份:2022
- 资助金额:
$ 67.02万 - 项目类别:
Overlay independent X-ray data analysis for enhanced oxime OP-ChE reactivation
叠加独立 X 射线数据分析,增强肟 OP-ChE 重新激活
- 批准号:
9356345 - 财政年份:2016
- 资助金额:
$ 67.02万 - 项目类别:
Overlay independent X-ray data analysis for enhanced oxime OP-ChE reactivation
叠加独立 X 射线数据分析,增强肟 OP-ChE 重新激活
- 批准号:
9209336 - 财政年份:2016
- 资助金额:
$ 67.02万 - 项目类别:
Accelerated AChE Reactivator Design by Mechanistic Neutron Scattering Studies
通过机械中子散射研究加速乙酰胆碱酯酶再激活器设计
- 批准号:
8735548 - 财政年份:2014
- 资助金额:
$ 67.02万 - 项目类别:
Accelerated AChE Reactivator Design by Mechanistic Neutron Scattering Studies
通过机械中子散射研究加速乙酰胆碱酯酶再激活器设计
- 批准号:
9632884 - 财政年份:2014
- 资助金额:
$ 67.02万 - 项目类别:
BChE reactivators for nerve agent and pesticide OP detoxification in human tissue
BChE 重激活剂用于人体组织中的神经毒剂和农药 OP 解毒
- 批准号:
8610134 - 财政年份:2013
- 资助金额:
$ 67.02万 - 项目类别:
BChE reactivators for nerve agent and pesticide OP detoxification in human tissue
BChE 重激活剂用于人体组织中的神经毒剂和农药 OP 解毒
- 批准号:
8738731 - 财政年份:2013
- 资助金额:
$ 67.02万 - 项目类别:
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