SELECTIVE INHIBITION OF GOLGI ALPHA-MANNOSIDASE II

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。我们感兴趣的是酶促反应的机制和碳水化合物-酶复合物的动力学。我们目前正在研究的动力学高尔基体α-甘露糖苷酶II（GMII）与甘露醇和aminocyclopentitetrol采用MD模拟复合。甘露糖修剪酶GMII的抑制阻断癌基因诱导的细胞表面寡糖的变化。预计对涉及GMII的相互作用的进一步理解将促进更有效和选择性的GMII抑制剂的开发。我们还进行了配体对接，以研究这些配体可能的其他结合模式。计算的结合模式将有助于设计组合库，以实现选择性抑制GMII。 除了动力学，我们还使用QM方法模拟了GMII催化的水解反应。这些研究包括确定参与水解的中间体的优选反应坐标和几何形状，例如过渡态。这将有助于设计过渡态类似物，这将作为更有效和选择性的GMII抑制剂。

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. We are interested in the mechanisms of enzymatic reactions and the dynamics of the carbohydrate-enzyme complexes. We are currently studying the dynamics of Golgi alpha-mannosidase II (GMII) complexed with mannostatin and aminocyclopentitetrol by employing MD simulations. Inhibition of the mannose-trimming enzyme GMII blocks the oncogene-induced changes in cell surface oligosaccharides. It is anticipated that further understanding of the interactions involving GMII will enhance development of more potent and selective inhibitors of GMII. We have also performed ligand docking to investigate possible additional binding modes of these ligands. The computed binding modes will help in designing combinatorial libraries to achieve selective inhibition of GMII. In addition to the dynamics, we are also simulating the hydrolysis reaction catalyzed by GMII using QM methods. These studies include determination of the preferred reaction coordinate and geometries of the intermediates involved in the hydrolysis, such as the transition state. This will be useful in designing transition state analogs, which will serve as more potent and selective inhibitors of GMII.