CONFORMATIONAL ANALYSIS OF MANNOSIDASE INHIBITORS USING QUANTUM-NMR CALCULATION

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。Siriwardena团队设计并合成了一系列新型多羟基硫酸盐，已被证明是研究各种糖苷酶作用模式的极佳生物工具。虽然许多异国化合物的结构已经通过单晶X射线研究确定，但仅基于核磁共振光谱数据的分析对其他化合物的结构解释并不总是简单的。一个这样的例子是一种有效的天然甘露糖苷酶抑制剂苦马豆素的硫盐类似物。我们最初的分析已经确定了六个潜在的结构，其中一个是根据核磁共振数据和其他论点被选为最有可能的。然而，这种盐的结构解释和构象行为是复杂的，只能通过应用伍兹小组开发的组合量子力学-核磁共振方法来确定。在这种方法中，计算了所有理论上可能的结构和构象的量子核磁共振数据和NOE强度，并将这些数据与相应的准确确定的实验核磁共振值进行了比较。

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. The Siriwardena group designed and synthesized a series of novel polyhydroxylated sulfonium salts that have proven to be excellent biological tools with which to study the modes-of-action of various glycosidases. Although the structures of a host of these exotic derivatives have been established by single-crystal X-ray studies, structural elucidation of others based on the analyses of NMR spectral data alone has not always been straightforward. One such example is a sulfonium salt analog of the potent natural mannosidase inhibitor, swainsonine. Our original analysis had identified six potential structures of which one was selected as the most likely on the basis of NMR data and other arguments. However, the structure elucidation and conformational behavior of this salt is complex and could only be defined with confidence by application of a combined quantum mechanical-NMR approach developed by the Woods group. In this approach, quantum NMR data and NOE intensities were calculated for all theoretically possible structures and conformers, and these were compared with the corresponding, accurately determined, experimental NMR values.