کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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1358844 | 981369 | 2011 | 11 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: 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](/preview/png/1358844.png)
We report the structure–activity relationship of a series of d-, and l-isofagomine and fagomine isomers as glycosidase inhibitors. Our study revealed that a positive charge at the anomeric position of d-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 IC50 value of 8.7 μM. A molecular docking study revealed that the positions and orientations of the piperidine ring of d-3-epi-isofagomine in the binding site was similar to that of d-isofagomine, while d-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 that d-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.
A molecular docking study revealed that d-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 that d-3,4-di-epi-isofagomine can not bind to β-glucocerebrosidase (Gcase) at a stable interaction mode.Figure optionsDownload as PowerPoint slide
Journal: Bioorganic & Medicinal Chemistry - Volume 19, Issue 11, 1 June 2011, Pages 3558–3568