MOD THE STRUCT & DYN OF NICOTINIC ACETYLCHOLINE RECEPTORS:

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。 A.目标 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。

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. Objectives 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.