MODELING THE STRUCTURE & DYNAMICS OF ACH ESTERASE CLUSTERS

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。 尽管我们对烟碱乙酰胆碱受体的基础生物学的理解取得了许多重大进展，但开发新的治疗方法仍然面临挑战。 在这个合作项目中提出的工作显著地建立在强有力的合作基础上（Henchman等人，2003 a，B; Ivanov等人，2007; Cheng等人，2007; Wang等人，2008年），将其引入药物发现的方向，用于治疗各种人类疾病。 预计这将使生产率大幅提高，特别是建立在Sine组的开创性计算对接努力的基础上（Gao et al.，2003; Wang等人，2003年）。 分子动力学模拟和加速分子动力学模拟将进一步发展和应用于探测烟碱乙酰胆碱受体和同源蛋白质的内部运动。 分析结果将加深我们对这些受体的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将是使用采样的构象沿着新兴的NBCR工作流程工具作为小分子对接的靶点，为药物发现提供先导化合物。 特别是，这项合作的重点是如何发现神经和精神疾病的新药代表了另一个重要的科学驱动力和翻译机会，为这些计算工具和工作流程的持续发展。这项合作将扩展我们的放松复杂方案的开发和应用，该方案在新的工作流程中实施，具有越来越多的工具，用于药物发现，以研究如何在受体配体结合域中实现配体的选择性结合。 我们的工作将不仅集中在人类受体的配体结合域的同源模型，但也对乙酰胆碱BPs。

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.