Docking and SAR studies of D- and L-isofagomine isomers as human β-glucocerebrosidase inhibitors.
Docking and SAR studies of D- and L-isofagomine isomers as human β-glucocerebrosidase inhibitors.
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DOI：
10.1016/j.bmc.2011.04.011
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发表时间：
2011-06
影响因子：
3.5
通讯作者：
A. Kato;Saori Miyauchi;N. Kato;R. Nash;Y. Yoshimura;I. Nakagome;S. Hirono;H. Takahata;I. Adachi
中科院分区：
文献类型：
--
作者：
A. Kato;Saori Miyauchi;N. Kato;R. Nash;Y. Yoshimura;I. Nakagome;S. Hirono;H. Takahata;I. Adachi
我们报告了一系列作为糖苷酶抑制剂的 d-、l-异法戈明和法戈明异构体的构效关系。我们的研究表明，d-异法戈明异头位置的正电荷增强了对 β-糖苷酶的效力，而 C3 OH 基团的差向异构化则大大降低了其抑制效力三个以上数量级。此外，d-3,4-di-epi-isofagomine 消除了对所有酶的抑制活性。l-Isofagomine 也是一种相当有效的人 β-葡萄糖脑苷脂酶抑制剂，IC50 值为 8.7 μM。分子对接研究发现d-3-epi-isofagomine哌啶环在结合位点的位置和方向与ofd-isofagomine相似，而d-3-epi-isofagomine缺失了Asp127与3-OH基团之间以及Trp179与3-OH基团之间的氢键相互作用。此外，IFDscore排名前10的对接模型表明d-3,4-di-epi-isofagomine不能以稳定的相互作用模式与β-葡萄糖脑苷脂酶结合。这些结果为开发戈谢病的新型药理学伴侣提供了对异法戈明异构体的结构要求的深入了解。
We report the structure–activity relationship of a series ofd-, andl-isofagomine and fagomine isomers as glycosidase inhibitors. Our study revealed that a positive charge at the anomeric position ofd-isofagomines enhanced the potency toward β-glycosidases, while the epimerization at the C3 OH group drastically reduced their inhibitory potency by over three orders of magnitude. Furthermore,d-3,4-di-epi-isofagomine abolished their inhibition activities against all enzymes.l-Isofagomine was also a fairly potent inhibitor of human β-glucocerebrosidase, with an IC50value of 8.7 μM. A molecular docking study revealed that the positions and orientations of the piperidine ring ofd-3-epi-isofagomine in the binding site was similar to that ofd-isofagomine, whiled-3-epi-isofagomine missed the hydrogen bond interactions between Asp127 and the 3-OH group and between Trp179 and the 3-OH group. Furthermore, the top 10 docking models ranked by IFDscore suggested thatd-3,4-di-epi-isofagomine can not bind to β-glucocerebrosidase at a stable interaction mode. These results provide an insight into the structural requirements of isofagomine isomers for developing a new type of pharmacological chaperone for Gaucher disease.