Docking and SAR studies of D- and L-isofagomine isomers as human β-glucocerebrosidase inhibitors.

Abstract

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.

• Authors: Atsushi Kato, Saori Miyauchi, Noriko Kato, Robert J Nash, Yuichi Yoshimura, Izumi Nakagome, Shuichi Hirono, Hiroki Takahata, Isao Adachi
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 19 Issue 11 Pg. 3558-68 (Jun 01 2011) ISSN: 1464-3391 [Electronic] England
• PMID: 21546253 (Publication Type: Journal Article)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• Enzyme Inhibitors
• Imino Pyranoses
• isofagomine
• fagomine
• Glucosylceramidase

Topics

• Animals
• Binding Sites
• Cattle
• Computer Simulation
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Glucosylceramidase (chemistry, metabolism)
• Humans
• Hydrogen Bonding
• Imino Pyranoses (chemical synthesis, chemistry, pharmacology)
• Isomerism
• Rats
• Structure-Activity Relationship