EXPLORING BINDING MODES OF BENZTROPINE-LIKE INHIBITORS OF DOPAMINE TRANSPORTER

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 申请30，000 SU的开发补助金，用于在显式膜和水中使用多巴胺转运蛋白（DAT）进行苯扎托品（BZT）的分子动力学模拟。该项目的长期目标是推导BZT样抑制剂的结合模式，在DAT结构的背景下理解它们的结构-活性关系（SAR），并设计没有精神刺激作用的抑制剂。高选择性和有效的BZT样DAT抑制剂与可卡因样抑制剂不同，它们表现出较少的欣快作用，因此显示出发展成为抗可卡因治疗剂的前景。BZT样抑制剂与可卡因样抑制剂具有非常不同的SAR。然而，它从来没有被理解为不同的SAR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欣快效应的抑制剂。我们请求在IU e1350（大红色）、NCSA Altix（钴）或TACC PowerEdge 1955（Lonestar）上使用NAMD运行模拟的计算时间。机器的选择是基于NAMD基准（http：//www.ks.uiuc.edu/Research/namd/performance.html）做出的，该基准表明这些机器在使用NAMD 2.6的92 K原子系统上运行得比其他机器快得多，该系统具有多达128个处理器。我们的系统大约有88 K个原子。平衡（3纳秒）和生产（10纳秒）阶段将分别花费大约2000和7000 SU。我们将测试上述机器，以比较哪一个在我们的系统中运行得更快。然后将通过模拟退火对接方案产生的BZT的有希望的结合模式进行平衡，然后通过10 ns的生产运行来研究最有希望的结合模式。

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.