MOD THE STRUCT AND DYN OF ACETYLCHOLINESTERASE CLUST- EFF ON ACETYLCHOLINE HYD

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。 随着禽流感大流行的威胁迫在眉睫，由于流感病毒的高突变率，现有的抗病毒抑制剂的疗效可能有限。虽然制药和生物技术行业在开发新的疫苗和新的干预手段方面投入了大量资金，但需要进行更多的基础研究，以了解禽流感感染生命周期的作用机制，特别是在宿主选择性和病毒复制途径中的关键酶方面。最近H5N1 HA蛋白和NA酶的结晶为药物发现和转化医学研究提供了新的机会。 该项目在NBCR的研究和开发中发挥着综合作用，并为与世界各地的研究人员合作提供了机会。我们将开发全面的解决方案，在药物开发中使用松弛络合物方法和分子动力学，从制备蛋白质结构，到选择MD快照，再到使用分子建模技术模拟突变。MD技术还将被开发用于执行对接实验的重新评分，以改进从使用AutoDock和分级筛选程序的虚拟筛选实验中选择最热门的项目。这些研究需要大量的计算，需要使用超级计算机，如Bluegene，以及分布式资源，如开放科学网格，TeraGrid和社区资源，如世界社区网格。通过封装这些新算法得到的软件将在广泛的疾病和蛋白质配体相互作用的机制研究中发挥更大的作用。

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. As the Avian flu pandemic threat is looming in the horizon, existing antiviral inhibitors are likely to be of limited efficacy due to the high mutation rate of the flu virus. While there is significant investment in the pharmaceutical and biotechnology industry to develop new vaccines and new means of intervention, more fundamental research is required to understand the mechanism of action of Avian flu infectious life cycle, especially in terms of host selectivity and key enzymes in the viral replication pathway. The recent crystallization of the H5N1 HA protein and NA enzyme offer new chances for drug discovery and translational medicine research. This project plays an integrative role in NBCR research and development, as well as opportunities for collaboration with researchers worldwide. Well develop comprehensive solutions to the use of Relaxed Complex method and Molecular Dynamics in drug development, from preparation of protein structures, to selection of MD snapshots, to simulations of mutations using molecular modeling techniques. The MD techniques will also be developed to perform rescoring of docking experiments to refine the selection of top hits from virtual screening experiments using AutoDock and hierarchical screening procedures. The large computational requirements for these studies demand the use of supercomputers such as the BlueGene, as well as distributed resources such as the Open Science Grid, TeraGrid and community resources such as the World Community Grid. The resulting software through the encapsulation of these new algorithms will be of greater use to a wide range of diseases and mechanistic studies of protein ligand interactions.