CONFORMATIONAL ANALYSIS OF MANNOSIDASE INHIBITORS USING QUANTUM-NMR CALCULATION

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。Siriwardena团队设计并合成了一系列新型多羟基磺酸盐，这些盐已被证明是研究各种糖苷酶作用模式的优秀生物工具。尽管通过单晶x射线研究已经确定了这些奇异衍生物的结构，但仅基于核磁共振光谱数据分析的其他衍生物的结构阐明并不总是直截了当的。一个这样的例子是一种磺酸盐类似物的天然甘露糖苷酶抑制剂，苦马豆素。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参数选择的最可能的结构。然而，这种盐的结构解析和构象行为是复杂的，只能通过Woods小组开发的量子力学-核磁共振联合方法来确定。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，并将其与相应的精确测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.