MOD THE STRUCT & DYN OF NICOTINIC ACETYLCHOLINE RECEPTORS:

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 A.目标 尽管我们对尼古丁的基本生物学的理解有了很大的进步 对于乙酰胆碱受体来说，开发新的治疗方法仍然是一个挑战。建议的工作 该协作项目在很大程度上建立在强大的协作之上(Henchman等人， 2003年a，b；伊万诺夫等人，2007年；程等人，2007年；王等人，2008年)，在 治疗多种人类疾病的药物发现方向。这是 预计将在开创性的计算基础上大幅提高工作效率 尤其是Sine集团的对接努力(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 进一步开发和应用于烟碱型乙酰胆碱的内部运动探测 受体和同源蛋白。将对结果进行分析，以加深我们的 了解这些受体的正常和病理活动。这样做的一个关键目标是 合作的新阶段将是使用采样构象以及新兴的 NBCR工作流工具作为小分子对接的目标，以建议铅 用于药物发现的化合物。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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.