EXPLORING BINDING MODES OF BENZTROPINE-LIKE INHIBITORS OF DOPAMINE TRANSPORTER

探索苯托品类多巴胺转运蛋白抑制剂的结合模式

• 批准号: 7956258
• 负责人: JUFANG SHAN
• 金额: $ 0.09万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7956258
• 关键词: Benchmarking; Benztropine; Binding; Biomedical Research; Cobalt; Cocaine; Computer Retrieval of Information on Scientific Projects Database; Development; Docking; Exhibits; Funding; Goals; Grant; High Performance Computing; Institution; Membrane; Production; Protocols documentation; Research; Research Personnel; Resources; Running; Simulate; Source; Staging; Structure; Structure-Activity Relationship; System; Testing; Therapeutic Agents; Time; United States National Institutes of Health; Water; analog; base; design; dopamine transporter; inhibitor/antagonist; insight; molecular dynamics; nanosecond; simulation

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A development grant of 30,000 SU is requested to run molecular dynamics simulation of benztropine (BZT) with the dopamine transporter (DAT) in explicit membrane and water. The long term goal of the project is to derive the binding modes of BZT-like inhibitors, understand their structure-activity relationship (SAR) in the context of the DAT structure and design inhibitors without psycho-stimulating effects. Highly selective and potent BZT-like DAT inhibitors differ from cocaine-like inhibitors that they exhibit less euphoric effects and thus show promises in developing into anti-cocaine therapeutic agents. BZT-like inhibitors have very different SAR than cocaine-like inhibitors. However, it has never been understood the structural basis for their different SAR. We will investigate the binding modes of BZT analogues to gain structural insights into the SAR of BZT which will help us to design inhibitors without euphoric effects. We request computational time on IU e1350 (Big Red), NCSA Altix (Cobalt) or TACC PowerEdge 1955 (Lonestar) to run simulations by using NAMD. The choice of machine is made based on NAMD Benchmarks (http://www.ks.uiuc.edu/Research/namd/performance.html) which shows that these machines run much faster than other machines on a system of 92K atoms with up to 128 processors by using NAMD 2.6. Our system has about 88K atoms. The equilibration (3 nanoseconds) and production (10 nanoseconds) stages will approximately take 2000 and 7000 SU, respectively. We will test the above machines to compare which runs faster for our system. Then promising binding modes of BZT produced by a simulated-annealing docking protocol will be equilibrated and then the most promising binding modes will be studied by the 10ns production run.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 申请了30,000苏的开发经费，用于在显性膜和水中用多巴胺转运体(DAT)对苯托品(BZT)进行分子动力学模拟。该项目的长期目标是推导出BZT类抑制剂的结合模式，在DAT结构的背景下了解它们的构效关系(SAR)，并设计没有心理刺激效应的抑制剂。高选择性和强效的BZT样DAT抑制剂与可卡因类抑制剂不同，它们表现出较少的兴奋作用，因此有望发展成为抗可卡因的治疗药物。BZT类抑制剂与可卡因类抑制剂具有非常不同的SAR。然而，人们从来没有理解过他们不同的特区的结构基础。我们将研究BZT类似物的结合模式，以获得对BZT的SAR的结构见解，这将有助于我们设计没有兴奋效应的抑制剂。我们在Iu e1350(Big Red)、NCSA Altix(Cobalt)或TACC PowerEdge 1955(Lonestar)上请求计算时间，以便使用NAMD运行模拟。机器的选择是基于NAMD基准(http://www.ks.uiuc.edu/Research/namd/performance.html)做出的，它表明这些机器在使用NAMD2.6的92K原子系统上运行得比其他机器快得多，该系统最多有128个处理器。我们的系统大约有88K个原子。平衡(3纳秒)和生产(10纳秒)阶段将分别大约需要2000和7000SU。我们将测试上述机器，以比较哪个机器运行得更快。然后，将平衡由模拟退火法对接协议产生的BZT最有希望的结合模式，然后将通过10 ns的生产运行来研究最有希望的结合模式。