title: Docking and SAR studies of calystegines: binding orientation and influence on pharmacological chaperone effects for Gaucher's disease.
abstract: We report on the identification of the required configuration and binding orientation of nor-tropane alkaloid calystegines against β-glucocerebrosidase. Calystegine B2 is a potent competitive inhibitor of human lysosomal β-glucocerebrosidase with Ki value of 3.3 μM. A molecular docking study revealed that calystegine B2 had a favorable van der Waals interactions (Phe128, Trp179, and Phe246) and the hydrogen bonding (Glu235, Glu340, Asp127, Trp179, Asn234, Trp381 and Asn396) was similar to that of isofagomine. All calystegine isomers bound into the same active site as calystegine B2 and the essential hydrogen bonds formed to Asp127, Glu235 and Glu340 were maintained. However, their binding orientations were obviously different. Calystegine A3 bound to β-glucocerebrosidase with the same orientations as calystegine B2 (Type 1), while calystegine B3 and B4 had different binding orientations (Type 2). It is noteworthy that Type 1 orientated calystegines B2 and A3 effectively stabilized β-glucocerebrosidase, and consequently increased intracellular β-glucocerebrosidase activities in N370S fibroblasts, while Type 2 orientated calystegines B3 and B4 could not keep the enzyme activity. These results clearly indicate that the binding orientations of calystegines are changed by the configuration of the hydroxyl groups on the nor-tropane ring and the suitable binding orientation is a requirement for achieving a strong affinity to β-glucocerebrosidase.
authors.affiliation: Department of Hospital Pharmacy, University of Toyama, Toyama 930-0194, Japan. Electronic address: kato@med.u-toyama.ac.jp.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kato
authors.affiliation: School of Pharmaceutical Sciences, Kitasato University, Tokyo 108-8641, Japan.
authors.forename: Izumi
authors.initials: I
authors.lastname: Nakagome
authors.affiliation: Department of Hospital Pharmacy, University of Toyama, Toyama 930-0194, Japan.
authors.forename: Shinpei
authors.initials: S
authors.lastname: Nakagawa
authors.affiliation: Department of Hospital Pharmacy, University of Toyama, Toyama 930-0194, Japan.
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Koike
authors.affiliation: Institute of Biological, Environmental and Rural Sciences, Phytoquest Limited, Plas Gogerddan, Aberystwyth, Ceredigion SY23 3EB, United Kingdom.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Nash
authors.affiliation: Department of Hospital Pharmacy, University of Toyama, Toyama 930-0194, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Adachi
authors.affiliation: School of Pharmaceutical Sciences, Kitasato University, Tokyo 108-8641, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Hirono
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D002460:Cell Line; D005776:Gaucher Disease / Q000201:enzymology / Q000473:pathology; D005962:Glucosylceramidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D050112:Imino Pyranoses / Q000737:chemistry / Q000378:metabolism; D007536:Isomerism; D062105:Molecular Docking Simulation; D009662:Nortropanes / Q000737:chemistry / Q000378:metabolism; D012991:Solanaceous Alkaloids / Q000737:chemistry / Q000378:metabolism; D055672:Static Electricity; D013329:Structure-Activity Relationship; D014326:Tropanes / Q000737:chemistry / Q000378:metabolism*
chemical_list: D050112:Imino Pyranoses; D009662:Nortropanes; D012991:Solanaceous Alkaloids; D014326:Tropanes; C055033:calystegin; C110568:calystegine A3; C098432:isofagomine; C095613:calystegine B(2); D005962:Glucosylceramidase
keywords: Binding orientation; Calystegine; Gaucher’s disease; Molecular docking study; Pharmacological chaperone; nor-Tropane alkaloids; β-Glucocerebrosidase