Design, synthesis, and biological evaluation of iminosugars as pharmacological chaperone for Gaucher disease

我们报道了亚氨基糖对抗b-葡萄糖脑苷酶所需的结构和结合方向的鉴定。分子对接研究表明，强结合亚氨基糖具有良好的范德华相互作用和氢键。Calystegines是一种候选的药物伴侣，它与异胍胺结合在相同的活性位点，并与Asp127、Glu235和Glu340形成必要的氢键。但它们的结合方向有明显差异。值得注意的是，在N370S成纤维细胞中，1型定向的酪氨酸能有效稳定b-葡糖脑苷酶，从而提高细胞内b-葡糖脑苷酶的活性，而2型定向的酪氨酸不能保持酶的活性。这些结果清楚地表明，亚糖的结合取向是由羟基的构型改变的。

We report on the identification of the required configuration and binding orientation of iminosugars against b-glucocerebrosidase. A molecular docking study revealed that strong-binding iminosugars had a favorable van der Waals interactions and the hydrogen bonding. Calystegines, which is one of the candidates for pharmacological chaperone, bound into the same active site as isofagomine and the essential hydrogen bonds formed to Asp127, Glu235 and Glu340 were maintained. However, their binding orientations were obviously different. It is noteworthy that Type 1 orientated calystegines effectively stabilized b-glucocerebrosidase, and consequently increased intracellular b-glucocerebrosidase activities in N370S fibroblasts, while Type 2 orientated calystegines could not keep the enzyme activity. These results clearly indicate that the binding orientations of iminosugars are changed by the configuration of the hydroxyl groups.