MODELING THE STRUCTURE & DYNAMICS OF ACH ESTERASE CLUSTERS

结构建模

• 批准号: 8169346
• 负责人: PALMER William TAYLOR
• 金额: $ 1.12万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8169346
• 关键词: Biology; Collaborations; Complex; Computer Retrieval of Information on Scientific Projects Database; Development; Docking; Funding; Goals; Grant; Homologous Protein; Homology Modeling; Human; Institution; Lead; Ligand Binding; Ligand Binding Domain; Mental disorders; Modeling; Molecular Conformation; Motion; Neurologic; Nicotinic Receptors; Pharmaceutical Preparations; Phase; Productivity; Research; Research Personnel; Resources; Sampling; Scheme; Source; Structure; United States National Institutes of Health; Work; computerized tools; drug discovery; esterase; human disease; molecular dynamics; novel therapeutics; receptor; small molecule; tool

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. Despite many great advances in our understanding of the fundamental biology of nicotinic acetylcholine receptors, challenges remain to develop new therapeutics. The work proposed in this collaborative project builds significantly on a strong collaboration (Henchman et al., 2003 a,b; Ivanov et al., 2007; Cheng et al., 2007; Wang et al., 2008), taking it in the direction of drug discovery for the treatment of a variety of human diseases. This is expected to enable a great increase in productivity, building on pioneering computational docking efforts of the Sine group in particular (Gao et al., 2003; Wang et al., 2003). Molecular dynamics simulations and accelerated molecular dynamics simulations will be further developed and applied to probe the internal motions of nicotinic acetylcholine receptors and homologous proteins. The results will be analyzed to deepen our understanding of the normal and pathological activity of these receptors. A key goal of this new phase of collaboration will be the use of the sampled conformations along with emerging NBCR workflow tools as targets for the docking of small molecules to suggest lead compounds for drug discovery. In particular, this collaboration focuses on how the discovery of new drugs for neurological and psychiatric diseases represents another important scientific driver and translational opportunity for the continued development of these computational tools and workflow. This collaboration will extend the development and application of our Relaxed Complex Schemes, implemented in new workflows with an increasing array of tools, for drug discovery to examine how selective binding of ligands might be achieved in the receptor ligand-binding domains. Our work will focus not only on homology models of the ligand-binding domains of human receptors, but also on the AChBPs.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 尽管我们对烟碱乙酰胆碱受体的基本生物学的理解取得了巨大进步，但仍在发展新的治疗剂的挑战。 该协作项目中提出的工作在强大的协作基础上（Henchman等，2003 A，B; Ivanov等，2007; Cheng等，2007; Wang等，2008）朝着药物发现方向探索，以治疗各种人类疾病。 预计这将使生产率大大提高，这是基于正弦组的开创性计算对接工作的基础（Gao等，2003; Wang等，2003）。 分子动力学模拟和加速分子动力学模拟将进一步开发，并应用于探测烟碱乙酰胆碱受体和同源蛋白的内部运动。 将对结果进行分析，以加深我们对这些受体正常和病理活性的理解。 这一新的合作阶段的一个关键目标是使用采样构象以及新兴的NBCR工作流程工具作为对接小分子的目标，以暗示用于药物发现的铅化合物。 特别是，这种合作重点是发现新药的神经和精神病药物如何代表着持续开发这些计算工具和工作流程的另一个重要的科学驱动力和转化机会。这项合作将扩展我们放松的复杂方案的开发和应用，并在新的工作流程中使用越来越多的工具实现，以便研究药物发现如何在受体配体结合域中实现配体的选择性结合。 我们的工作不仅将集中在人体受体的配体结合域的同源模型上，而且还集中在ACHBP上。