MODELING THE STRUCTURE & DYNAMICS OF ACH ESTERASE CLUSTERS

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。 尽管我们对烟碱型乙酰胆碱受体的基础生物学有了很大的了解，但开发新的治疗方法仍然存在挑战。这一合作项目中提出的工作在很大程度上建立在强有力的合作基础上(Henchman等人，2003a，b；Ivanov等人，2007年；Cheng等人，2007年；Wang等人，2008年)，使其朝着治疗各种人类疾病的药物发现的方向发展。预计这将大大提高生产率，特别是建立在Sine集团开创性的计算对接努力的基础上(Gao等人，2003年；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索烟碱型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的正常和病理活动的理解。这一新阶段合作的一个关键目标将是使用采样构象和新兴的NBCR工作流程工具作为小分子对接的目标，以建议用于药物发现的先导化合物。特别是，这项合作的重点是神经和精神疾病新药的发现如何成为继续开发这些计算工具和工作流程的另一个重要的科学推动力和翻译机会。这一合作将扩展我们的宽松复杂方案的开发和应用，这些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配体结合域的同源模型上，而且还将集中在AChBPs上。

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.