title: 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.affiliation: Department of Hospital Pharmacy, University of Toyama, Toyama 930-0194, Japan. kato@med.u-toyama.ac.jp
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kato
authors.forename: Saori
authors.initials: S
authors.lastname: Miyauchi
authors.forename: Noriko
authors.initials: N
authors.lastname: Kato
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Nash
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Yoshimura
authors.forename: Izumi
authors.initials: I
authors.lastname: Nakagome
authors.forename: Shuichi
authors.initials: S
authors.lastname: Hirono
authors.forename: Hiroki
authors.initials: H
authors.lastname: Takahata
authors.forename: Isao
authors.initials: I
authors.lastname: Adachi
mesh_terms: D000818:Animals; D001665:Binding Sites; D002417:Cattle; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D005962:Glucosylceramidase / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D050112:Imino Pyranoses / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D007536:Isomerism; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D050112:Imino Pyranoses; C098432:isofagomine; C105643:fagomine; D005962:Glucosylceramidase